Diabetes, Arterial Calcification and Statin Drugs

Coronary_Calcium_Score_CAT_ScanDiabetes, Arterial Calcification and Statin Drugs

George is a 54 year old diabetic on statin drug for coronary artery disease. Five years ago, George had an episode of chest pain, which prompted a cardiac cath, during which a stent was placed in the LAD (left anterior descending). Even though George’s total cholesterol has always been normal (200), George’s cardiologist placed him on simvastatin, a statin drug to lower his cholesterol.  However, George has been reading about statins and he wants to stop taking the drug. Above image showing calcified coronary arteries on CAT scan courtesy of Hecht 2015.

Apparently, George discovered that statin drugs are ineffective for primary prevention of heart disease in healthy people, nor do they reduce mortality from heart disease in selected populations such as women, the elderly, renal dialysis, and COPD patients. Statins do not reduce mortality in primary prevention studies (in healthy populations), and seem to have the best effects in secondary prevention, ie in patients with known heart disease.  George wants to know if he really needs the statin drug, and “is it OK to stop taking it?”  See Statin Drugs Revisited

Statins are Effective in Diabetic Populations

That brings us to the question of “what is the efficacy of statin drugs in the Diabetic population?” Lucky for us, this question has been studied and answered by a number of randomized trials.  Statin use in Diabetics (even with normal cholesterol levels) reduces cardiovascular events and cardiovascular mortality by 20-30 per cent compared to placebo treated diabetics. (68-70)  In addition, Statin therapy reduces amputation rate in diabetics by 25%.(28)  Notice the statin recommendation in Diabetics is made even with normal cholesterol levels.

Statin Benefit in Diabetics Are Not Due to Cholesterol Lowering 

Statin drug benefits in Diabetics are not due to cholesterol lowering. Rather statin benefits in Diabetics are due to their “pleiotrophic effects”, which include:

1) anti-inflammatory effects (40-42)(49-51)

2) antibacterial effects. (52-58)  (43-48)

Proof comes from studies in Diabetics using non-statin lowering drugs such a fibrates and CETP inhibitors which reduce serum cholesterol levels, yet provide no cardiovascular benefit.   This lack of benefit is due to the fact that Non-Statin cholesterol lowering drugs lack the pleotrophic effects of statins (anti-inflammatory and anti-bacterial effects). (61-64)

Diabetics Have Greater Mortality than Non-Diabetics with Same Calcium Score

Coronary artery calcium with and without diabetes Raggi P J Amer Col Card 2004 F2.large

Above image shows Calcium Score Charts for Non-Diabetics) Left and Diabetics(Right). Diabetics (right) have more rapidly declining survival for same CAC as non-diabetics (Left) .  Courtesy of Raggi et al. (22) Prognostic value of coronary artery calcium screening in subjects with and without diabetes. Journal of the American College of Cardiology 2004;43(9):1663-1669.

Statin Drugs Increase Coronary Artery Calcification

In 2017, Dr Anand studied calcium score progression in Statin treated diabetics.  In spite of lower cholesterol in the statin treated diabetics, they experienced greater calcium score progression compared to untreated diabetics: (65)  Dr Anand states:

“statin therapy failed to inhibit the progression of CAC (Calcium Score). On the contrary, statin-treated patients had a greater degree of progression”.(65)

In 2012, Dr. Aramesh Saremi studied 197 diabetic veterans with baseline and follow up calcium score 4.6 years later.(11)   Dr Saremi reported statin use was associated with more accelerated calcification:

“In this cohort of T2DM patients with advanced atherosclerosis, we found that more frequent statin use was associated with accelerated progression of CAC”.(11)

Others have reported similar findings, that statin drug treatment increases coronary artery calcification(1-3)(12)(106)

CAC Progression in Diabetics Predicts Future CHD Event Risk

In 2012 Dr Nathan Dr Wong studied the diabetic sub-population of the MESA study.  He found that glycated hemoglobin (Hgb A1c) greater than 7.0  predicts progression of calcium score, and that progression of calcium score is highly predictive of future cardiac event (heart attack etc.) (16)

Calcium Score Progression is Independent Predictor of All-Cause Mortality in Diabetics

in 2013, Dr Sarkis Kiramijyan reported that “CAC (Calcium Score) progression is an independent predictor of all-cause mortality in patients with DM.” (see chart at left)  (20)

Dr Sarkis Kiramijyan studied 296 asymptomatic Diabetics compared to 300 controls with baseline and 2 year follow-up Calcium Score scans.

Left chart:  Non-Progressors (top two lines)  have best event free survival (99.1% Non-DM, 95.5% DM).

Progressors (lower two lines) , those with >15% annual progression, had worse prognosis.(91.1% non-DM, 79.6% DM)  Annual progression of calcium score is greater in diabetics (30%) compared to control non-diabetics (10%).(20)  Dr Sarkis Kiramijyan states:

“CAC progression was greater and event-free survival lower in patients with DM compared to controls in proportion to the extent of CAC progression. These results suggest that CAC progression is an independent predictor of all-cause mortality in patients with DM.”(20)

Mesa Study Graded Relationship Between CAC Progression and  Cardiac Event

In 2013 , Dr Matthew Budoff reported on the MESA study which followed 6,778 patients for 7.6 years for all CHD events. (15)  Dr Budoff reports:

“The most striking findings in the current study were the graded relationships of CAC progression with CHD event risk, strongly suggesting that the functions are linear, with greater progression associated with greater risk. We demonstrated that progression of CAC is associated with total and hard CHD risk; these relationships were attenuated but still significant after adjusting for risk factors and baseline calcium.”

CAC Progression on Statin is Therapeutic Failure Dr Harvey Hecht

Similar to many others, Dr Harvey Hecht reports that statin treatment increases Calcium Score progression in the MESA study.(18) Others have confirmed statins increase progression of coronary artery calcification.(12)(106)

Some authors such as Nissen and Rufi suggest statin induced vascular calcification is “benign plaque healing”.(1,2)  Dr Hecht disagrees and point to studies like the above MESA showing calcium score progression predicts increased mortality.  Dr Harvey Hecht says that Calcium score progression while on statin drug treatment implies a therapeutic failure:

Of particular interest was the greater CAC progression in those taking statins (in the MESA study), which has been interpreted as benign conversion of pre-existing noncalcified to calcified plaque by the drug. However, the greater progression in patients with events while on statin therapy negates this theory, supports the predominant formation of new plaque that then becomes calcified, and implies a therapeutic failure of statins to sufficiently halt the atherosclerotic process.(18)

Statins Reduce Calcium Score Progression in Diabetics Dr Raggi 2005

In 2005, Dr Paolo Raggi studied Calcium Score Progression in 1153 nondiabetics compared to 157 diabetics.   The study excluded patients with known Cardiovascular Disease, or renal failure because of rapid progression of calcium score in these groups, and lack of benefit of statins for diabetics on hemodialysis. Somewhat at odds with the above studies, Dr Raggi found a statin drug benefit in this population of Diabetics for which statins reduced calcium score progression down to 17% from the 33% annual progression seen in non-statin treated diabetics. (21)

“Calcium progression was 33% greater in diabetic patients than nondiabetic subjects  if no statin therapy was provided and 17.7% greater when statins were used ….Among the 49 subjects who experienced a myocardial infarction, the calcium score increased on average 20% more in diabetic than nondiabetic patients ….findings support the notion that diabetes mellitus causes accelerated atherosclerosis, even in the presence of statin therapy, and provide evidence that coronary calcium monitoring is an effective method to assess treatment efficacy…..among patients receiving statins, the progression of CVS (Calcium Score) was greater in patients who experienced an MI than among all others who received statins (27% versus 10 %).” (21)

Diabetics with Zero Calcium Score

Diabetics with no coronary artery calcium (zero calcium score) are at similar low risk for cardiovascular disease compared to non-diabetics with zero score.(105)(22) These patients at low risk do not require statin treatment.   Dr Paolo Raggi states:(22)

However, patients suffering from diabetes with no coronary artery calcium demonstrated a survival similar to that of individuals without diabetes and no detectable calcium (98.8% and 99.4%, respectively, p = 0.5).(22)

Diabetics who suffer heart attacks typically have the highest calcium score progression in the 30-50% range.  Those Diabetics who remain event free typically have slower progression, less than15% annually.

No Benefit for Statins in Diabetics undergoing HemoDialysis

In spite of high mortality from cardiovascular disease in dialysis patients, statins provide no clinical benefit in this patient population. Dr An S. De Vriese, in the June 2017 Journal of Nephrology asks.“Should statins be banned from dialysis?”(24)  Statins increase vascular calcification by inhibiting synthesis of vitamin K2.(24)

4D Study 2005 Wanner NEJM Diabetics on Hemodialysis

In 2018, Dr Fariha Naeem reviewed the 4D study of statin treatment in Diabetics on HemodialysisShe found no benefit.(68):

“The 4D study is worthy of mention, however, as it included only patients with T2DM (Type 2 Diabetics) on maintenance haemodialysis. Most of the patients in the 4D study had some form of vascular disease at baseline. No benefit on major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke) was found comparing atorvastatin 20 mg to placebo over the 4 years of the study.”(68)

Dr Christoph Wanner studied the routine use of Atorvastatin (Lipitor 20 mg day) vs. placebo  in patients with type 2 diabetes mellitus undergoing hemodialysis in a prospective randomized trial over 4 years. His results were published in the 2005 New England Journal. (60)  Dr Wanner concludes that in diabetics on hemodialysis:

“routine treatment with a statin to reduce the primary composite end point of death from cardiac causes, myocardial infarction,and stroke is not warranted.”(60)

You might ask the obvious question: “Why are statin drugs effective (for reducing mortality), in diabetics with normal renal runction, but not in diabetics on hemodialysis (renal failure)?”  The answer, in my opinion, goes back to the pleiotrophic effects of statins which are sufficient in early diabetics to influence clinical course beneficially.  However, in advanced disease diabetics on hemodialysis, pleotrophic effects are insufficient to provide any clinical benefit.

Atherosclerotic Plaque is infected Biofilm

Numerous studies show that atherosclerotic plaque is infected biofilm, seeded from gut or periodontal flora. If so, then this would certainly explain why pleotrophic effects of statins are beneficial in cardiovascular disease.

In 2012, Dr Wolcott studied atherosclerotic plaque from 10 patients using 16S rDNA techniques.(31)  Dr Wolcott states:

“Several samples demonstrated large amounts of bacterial DNA. … For all the samples combined, the predominant microbial species identifi ed have often been associated with the oral cavity. Several samples show bacterial DNA far exceeding what would be expected by contamination, suggesting the bacteria may be propagating in the plaque. …Biofilm is known to produce a hyperinflammatory response….a candidate for being the “engine” for the persistent inflammation necessary for the pathogenesis of atherosclerosis.”(31)

In 2016, Dr Snow studied arterial plaque recovered from amputated legs of diabetic patients using fluorescence microscopy and fluorescence in-situ hybridisation (FISH), finding bacterial biofilm within the plaques.(29)  In 2016, Dr. Gorm Hanson used 16sRibosome techniques to study aspirated coronary thrombi from 22 patients with myocardial infarction for presence of bacterial DNA.(30)  He found:

“DNA from Pseudomonas aeruginosa represented the only species that was significantly associated with either thrombi or blood and was >30 times more abundant in thrombi than in arterial blood …Whole and intact bacteria present as biofilm microcolonies were detected in selected thrombi using universal and P. aeruginosa-specific PNA-FISH probes.”(30)

In 2017, Dr Annika Jonsson confirmed the presence of bacterial DNA in atherosclerotic plaques by 16S rRNA technique.(36)

Genically Modified Mouse Model of Oral Pathogens Invading Atherosclerotic Plaque

Dr Chukkapalli studied genetically modified mice to determine whether periodontal bacteria that infect the periodontium (gums) can also infect vascular tissues.  (32,33)  In a mouse model, Dr Chukkapalli showed that colonization of periodontal pathogens sequentially induces both periodontal disease and atherosclerosis.(32,33)  Dr Chukkapalli  states:

“Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta.”(32)

My previous articles discussed this:

Atherosclerotic Plaque as Infected Biofilm

LPS Endotoxemia Theory of Heart Disease

Elevated Blood Sugar Causes Leaky Gut and Endotoxemia in Diabetes

The major abnormality in Diabetes is elevated blood sugar,  “a driver of Intestinal Barrier Dysfunction”. (37)  In 2018, Dr Christoph Thaiss studied a mouse model of obesity and diabetes, finding that hyperglycemia was the driver for “leaky gut” via reprogramming of intestinal epithelial cells, and alteration of “tight junction” integrity.(37)  Dr Christoph Thaiss says:

“In this study, we have identified glucose as an orchestrator of intestinal barrier function....these experiments establish hyperglycemia as a direct and specific cause for intestinal barrier dysfunction and susceptibility to enteric infection…. our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes“(37)

The HgbA1C, long term marker for elevated blood sugar, is a cardiovascular risk factor.(38)  In 2011 Dr Frank Pistrosch concludes:

“We conclude that hyperglycemia is still a key cardiovascular risk factor for patients with type 2 diabetes, and treatment of hyperglycemia to near-normal levels might reduce cardio-vascular events and mortality of these patients.”(38)

In 2016, Dr Carnevale studied 35 patients with (impaired fasting glucose) IFG compared to controls. Patients with elevated fasting blood sugar had significantly higher levels of sP-selectin, LPS, zonulin and oxLDL compared to control subjects.(39)

“Our study provides evidence that patients with IFG have increased platelet activation, and suggests LPS as a potential trigger for in vivo platelet activation in this patient population.”(39)

In 2015 Dr Aravindhan studied  197 Type 1 diabetics, measuring serum LPS (lipopolysaccharide) , its translocation markers and cytokines.  Diabetics had significantly higher serum LPS, and higher inflammatory cytokines IL-6 and TNF-alpha.(40)  Dr Aravindhan concludes his findings suggest:

“sustained endotoxin activity in T1-DM subjects even before the onset of microvascular complications.”(40)

Diabetes and Metabolic Endotoxemia

The major metabolic abnormality in diabetes, elevated blood sugar, orchestrates increased gut permeability and translocation of LPS and gram negative organisms into the bloodstream, also known as metabolic endotoxemia.

LPS More Elevated in Advanced Diabetic Complications

In 2017, Dr Gomes reviewed the literature on Metabolic endotoxemia and diabetes mellitus. (102)  Dr Gomes observed that serum LPS was more elevated in diabetics patients with advanced complications:

“that diabetic subjects presented higher fasting and postprandial LPS concentrations compared to lean non-diabetic subjects and/or obese subjects….
LPS was more elevated in diabetic patients with advanced complications, such as macroalbuminuria [17] ,and those treated with insulin….diabetics seem to have increased intestinal permeability [28]  and higher LPS absorption after a high-fat meal [20,25]….diabetic subjects seem to have lower clearance of LPS and consequently, increased LPS concentrations.”(102)

Why Statins are Effective in Mild to Moderate Diabetes, but not Advanced Diabetes ?

The observation has been made that statins reduce mortality in asymptomatic early stage diabetics by 20-30%, yet have no benefit in advanced endstage diabetics on hemodialysis.  Perhaps the increased levels of LPS reach a tipping point as diabetic complications advance, eventually overwhelming the pleoiotrphic effects and rendering the statin drug ineffective in end stage diabetics on hemodialysis.

The above studies show Diabetics with elevated blood sugar have  “Leaky Gut” , and higher Zonulin Levels and circulating LPS (endotoxin) when compared to non-diabetics.  Elevated blood sugar causes increased Zonulin levels and increased gut permeability, ie “Leaky Gut”.  Additional risk factors: obesity, hypertension and cigarette smoking.

Atherosclerotic Plaque is Infected Biofilm

Pleotrophic Effects of StatinsImpaired LPS Signalling

In 2004, Dr Tushar Patel showed that simvastatin suppressed LPS signalling in human monocytes to improve the host response to Gram-negative endotoxemia.(41)

Statins are Anti-inflammatory for  Metabolic Syndrome

In 2006, Dr Devaraj  studied the anti-inflammatory effects of statin drugs in metabolic syndrome in a randomized, double-blind, placebo-controlled study .  40 mg Simvastatin or placebo was administerd for 8 weeks.(42) Dr Devaraj  found:

“Simvastatin treatment decreased CRP levels, with significant reduction in LPS -activated monocyte release of IL-6 and TNF.  Nuclear factor-kappaB was decreased, showing a direct antiinflammatory effect.”(42)

In Vitro Anti-Inflammatory Effects of Statins – Blocks NFKB Activation

In 2005, Dr Hölschermann studied the effect of statin drugs on human endothelial cells in-vitro.(43)  He found that statin drug prevented Nuclear Factor Kappa Beta activation by TNF-alpha :

Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC.(43)

Pleiotrophic Effects of Statins – Antimicrobial Effects

In 2016, Dr Emma Hennessy asks the question,

“Is there potential for repurposing statins as novel antimicrobials? (53)  

Interest in antimicrobial properties of statin drugs was stimulated by studies showing improved survival in statin treated patients who had sepsis and pneumonia.  The anti-inflammatory effects of statins are due to blocking expression of transcription factors such as NFκB (Nuclear Factor Kappa Beta). (53)

Hennessy Emma Is there potential for repurposing statins as novel antimicrobials Antimicrobial agents and chemotherapy F2Above Image Courtesy of Emma Hennesy (53): FIG 2 Statins modulate bacterial growth and virulence. (A) In vitro effects of statins on bacterial species. Statins reduce in vitro bacterial growth, motility, and attachment. (B) Key antivirulence mechanisms of statins. At physiological concentrations, statin treatment can reduce bacterial invasion and translocation in addition to inhibiting lipid raft production. The inhibition of Rho GTPase activity and cholesterol production by statins contributes to reduced bacterial virulence, decreased toxicity, and impaired intracellular survival. (C) At physiological concentrations, statin treatment can reduce bacterial load and dissemination and increase bacterial clearance in mouse models of infection

Statin Drugs Anti-Bacterial Effects

In 2013, Dr Emma Hennessy reported that “Statins inhibit in vitro virulence of Pseudomonas aeruginosa” by reducing modulating swarming motility and Pseudomonas-induced pro-inflammatory cytokines in the host (54)    In 2014, Dr Emani did an in-vitro study reporting simvastatin  had antibacterial activity against against periodontal pathogens. Dr Emani  suggested,

simvastatin can be prescribed as a dual action drug in patients with both hyperlipidemia and periodontal disease.” (48)

Others have confirmed these findings, atorvastatin and simvastatin being the most effective. (47-49)(56-57)

Statins Protect Mice from Septic Shock

In 2008, Dr Chaudhry studied the beneficial effect of statins (Cerivastatin) in a mouse model of septic shock.(55)  Statin treatment conferred a 20-60% reduction in mortality after bacterial challenge. Dr Chaudhry  concludes:

“Cerivastatin protects mice against LPS- and live bacteria-induced death, an effect associated with cerivastatin-attenuated pro-inflammatory cytokine production and enhanced bacterial clearance. Hence, application of statins in the clinical setting may prove beneficial in prevention of LPS or bacterial infection-related sepsis.”(55)

Pleotrophic Effects of Statins – Benefits for Infected Biofilm

If atherosclerotic plaque is infected biofilm, then the anti-inflammatory and anti-bacterial properties of statins provide the real benefits, independent of the cholesterol lowering  effects.  As mentioned above, lowering serum cholesterol with non-statin drugs have no cardiovascular benefit because they lack pleotrophic effects of statins.

Leaky Gut as Infection Source for Atherosclerotic Plaque

In 2016, Dr Li used 16s rRNA techniques to study blood and plaque samples from 16 patients, finding  enteric (intestinal) bacteria in both the blood sample and atherosclerotic plaques, supporting the hypothesis that enteric (intestinal) bacteria in plaques may originate from the intestine via “Leaky Gut”.(59)  Dr Li Also studied Circulating Zonulin levels in 126 CAD patients compared to 80 non-CAD patients. (CAD= Coronary Artery Disease) Circulating Zonulin was almost double in CAD patients compared to non-CAD patients (7.3 vs 4.0).  This led Dr Li to conclude:

“Given the fact that zonulin is significantly elevated in atherosclerosis and increase intestinal IP, it’s possible that targeting zonulin using monoclonal antibody or inhibitors maybe a provocatively new way to move forward in CAD prevention and treatment.”(59)

Vascular Calcification Indicates Response to Infection and Inflammation in Artery Wall

Arterial Calcification on CAT and Microscopic Doherty 2003Coronary Artery calcification has emerged as the single most important technological advance in management of cardiovascular disease. Vascular calcification is a response to infection and inflammation in the wall of the vessel. Left Image Fig 1 from
Doherty, Terence M., et al. “Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads.” PNAS (2003) A: CAT Scan LAD Coronary Artery Calcification.B and C: B;ack Arrows point to Green Stain Arterial Calcification within Plaque.(104)

Dr. Moeen Abedin (2004) states that vascular calcification is a marker for atherosclerosis, the result of chronic inflammation. Vascular calcification is “a clinical marker for atherosclerosis and may represent a special example of the general phenomenon of soft tissue calcification surrounding chronic inflammatory foci.” (103)

Soft-tissue calcification in response to infection is well known and is commonly seen with modern imaging techniques in human bacterial, fungal, and parasitic infections. I would propose that the chronic inflammation in the wall of the artery is a response to polymicrobial infection with biofilm formation. Progressive calcification indicates worsening inflammation and infection.  No progression of calcification on serial calcium scores indicates stable or “quiescent” atherosclerotic disease.

How to Prevent Heart Attacks in Diabetics on Statins ?

Although statin drug use in Diabetics provide a measurable benefit, a significant number of Diabetic patients will show rapid calcium score progression and proceed to a cardiac “event” such as heart attack, revascularization  or death from heart disease.  The question here is

“How Do We Prevent Heart Attacks and “Events” in Diabetics on Statins”? 

The answer is related to our understanding of the underlying mechanism of atherosclerosis.  Cholesterol is not the cause of cardiovascular disease.  Rather than cholesterol level, we are most concerned about metabolic syndrome, elevated blood sugar, leaky gut, low level endotoxemia and infected biofilm.

The key to reversing Diabetes is Diet and Lifestyle modification to reduce blood sugar and HgbA1c.  The Lyons Heart Study showed the Mediteranean Diet over 5 years after first heart attack,  reduced mortality by 70%, an impressive result.(91)  Others have advocated  Atkins type low carbohydrate diet combined with high intensity exercise for reduction in cardiovascular disease. (92-84) Also recommended: elimination of wheat and grains, monitoring blood sugar with home glucometer, exercise program, and intermittent fasting for weight loss, and reduction in blood sugar.

Interventions which prevent leaky gut, and low level endotoxemia are beneficial. We have a “Leaky gut Protocol” for this. Interventions which inhibit vascular calcification are beneficial, such as Magnesium and Vitamin K2 supplements.  Serial calcium score is useful to monitor treatment.  In George’s case, however, presence of a metal stent makes calcium score impossible in the stented artery due to metal streak artifact.  However the other 2 vessels can be evaluated and this can be helpful in monitoring treatment.

Magnesium and Vitamin K2 Inhibit Arterial Calcification

Two such non-drug interventions which inhibit arterial calcification are Magnesium and Vitamin K2, inexpensive and safe supplements found at the health food store.(4-10)

Other Useful Interventions:

Tocotrienol Vitamin E

Vitamin C

Aged Garlic Prevents Progression of Calcium Score

Berberine Antidote for Leaky Gut

Conclusion:  Statin drugs reduce mortality in Diabetes, not from cholesterol reduction effect .  Their benefit arise from pleotrophic effects, the antibacterial and anti-inflammatory effects of statin drugs.  Mainstream cardiology admits this by offering statins to Diabetics regardless of their cholesterol level.  While serum Cholesterol levels fail to predict future cardiac events, the serial Calcium score is highly predictive of future cardiac events.  Those diabetics with rapid calcium score progression are failing treatment and remain at high risk for cardiac event.  Since the underlying pathophysiology in the diabetic is high blood sugar with “Leaky gut’, and Low level endotoxemia which seeds atherosclerotic plaque as infected biofilm, correct therapy addresses this rather than the serum cholesterol level.

Heart Book by Jeffrey dach MDLeft image: Read more: “Heart Book” on Amazon

Articles with Related Interest:

Thiamine Deficiency and Diabetes

Testosterone Found Beneficial for Diabetes

Metformin, the Good Diabetic Drug

Improve Insulin Resistant Diabetes

Jeffrey Dach MD
7450 Griffin Road Suite 180
Davie, Fl 33314
954-792-4663

References

1) Plaque Paradox: Statins Increase Calcium in Atheromas Even as They Shrink Them….Not all coronary calcium is the same, analysis shows.  Cleveland Clinic

As part of the pooled analysis, serial IVUS measures of coronary calcification were obtained over 18 to 24 months in 3,495 patients with CAD who received either no statins (n = 224), low-intensity statin therapy (n = 1,726) or high-intensity statin therapy (n = 1,545).

All groups had statistically significant increases in plaque calcium indices from baseline; the increases ranged from 0.020 in the no-statin group to 0.038 in the low-intensity statin group to 0.044 in the high-intensity statin group.

“What struck me were the differences in changes in plaque calcification between the no-statin and low-intensity statin groups,” says Dr. Puri. “Both groups achieved relatively similar LDL-C levels and demonstrated the same degree of plaque progression over time, yet the increase in calcium index in the low-intensity statin group was nearly double that in the no-statin group. This observation in itself is somewhat telling regarding the possible pro-calcific properties of statins.”

Dr. Nissen says a coronary calcium measurement may be performed once to define a patient’s risk of cardiovascular events, but not when a patient initiates therapy “because the change in calcium isn’t necessarily an accurate predictor of whether or not the patient is benefiting from the therapy.”

The authors of the editorial call for further investigations to get at the question of whether coronary artery calcification is indeed protective and a sign that further progression of high-risk, low-density plaque is being impeded.

Patients with coronary artery disease (CAD) who are treated with statins experience an increase in coronary calcification, an effect that is independent of plaque progression or regression.
Paradoxically, high-intensity statin therapy is associated with the largest increases in coronary calcification despite promoting atheroma regression.

“Patients prescribed the highest doses of statins, despite achieving low levels of cholesterol and demonstrating marked plaque regression, had changes in plaque calcification that were nearly double the changes in patients who received no statins, and greater than changes in those who received low-intensity statin therapy, both of which were associated with plaque progression,” says the study’s principal investigator, Rishi Puri, MBBS, PhD.

pdf

2) Puri, Rishi, et al. “Impact of statins on serial coronary calcification during atheroma progression and regression.” Journal of the American College of Cardiology 65.13 (2015): 1273-1282.

Statins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can modulate coronary atheroma calcification in vivo.
OBJECTIVES: This study compared changes in coronary atheroma volume and calcium indices (CaI) in patients receiving high-intensity statin therapy (HIST), low-intensity statin therapy (LIST), and no-statin therapy.
METHODS: In a post-hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume (PAV) and CaI were measured across matched coronary segments in patients with coronary artery disease.
RESULTS: Following propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline (-0.6 ± 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 ± 0.1% and +1.0 ± 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median [interquartile range] HIST, +0.044 [0.0-0.12]; LIST, +0.038 [0.0-0.11]; no-statin, +0.020 [0.0-0.10]; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no-statin group.
CONCLUSIONS:Independent of their plaque-regressive effects, statins promote coronary atheroma calcification. These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression.

it remains unclear how the findings of the present analysis relate to the measured effects of statins on CT scanning. Lastly,  none of these serial IVUS trials were powered for detecting differences in clinical events, and therefore no specific association to clinical event rates can be drawn from the present analysis.

Our analysis also failed to demonstrate associations between changes in CaI with on-treatment lipoprotein or CRP levels during statin treatment, suggesting that the procalcific effects of statins are possibly mediated by pleiotropic mechanisms unrelated to lipoprotein metabolism

Aside from lipid regression within plaques following long-term potent statin therapies (35) ,statin-mediated atheroma calcification may improve plaque stability.

Lastly,none of these serial IVUS trials were powered for detecting differences in clinical events, and therefore no specific association to clinical event rates can be drawn from the present analysis.

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Accordingly, there is currently a great controversy on whether progression of CAC is a sign of progression or stabilization of coronary artery disease (CAD).

3) pdf available
Rodriguez-Granillo, Gaston A., Patricia Carrascosa, and Nico Bruining. “Progression of coronary artery calcification at the crossroads: sign of progression or stabilization of coronary atherosclerosis?.” Cardiovascular diagnosis and therapy 6.3 (2016): 250.

Coronary artery calcification (CAC) has been strongly established as an independent predictor of adverse events, with a significant incremental prognostic value over traditional risk stratification algorithms. CAC progression has been associated with a higher rate of events. In parallel, several randomized studies and meta-analysis have shown the effectiveness of statins to slow progression and even promote plaque regression. However, evidence regarding the effect of routine medical therapy on CAC has yielded conflicting results, with initial studies showing significant CAC regression, and contemporaneous data showing rather the opposite. Accordingly, there is currently a great controversy on whether progression of CAC is a sign of progression or stabilization of coronary artery disease (CAD). The finding of inexorable CAC progression despite the implementation of intensive contemporaneous medical therapy suggests that further understanding of this phenomenon should be undertaken before the implementation of CAC as a surrogate endpoint for longitudinal studies, or for prospective follow-up of patients under routine medical treatment.

Progression of CAD is undoubtedly related to adverse clinical outcomes. Based on the robust evidence confirming the role of CAC as an independent predictor of death and myocardial infarction, and the fact that CAC is closely associated to the extent of CAD; it might be assumed that CAC progression would also portent a worse prognosis

the significance of CAC alterations with regard to the underlying shift in plaque volume remains unknown. CAC progression might be attributed to plaque progression into a more unstable phenotype with accumulation of microcalcifications, and this would be justified by the aforementioned evidence supporting the deleterious role of CAC progression. However, CAC progression in the context of lifestyle modification and lipid lowering therapies might also be related to a shift towards a more stable phenotype. This paradox is portrayed in Figure 1. In other words: (I) does CAC progression mean plaque progression or plaque stabilization?

long term results of the Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) demonstrated that high-dose statin therapy promoted a significant regression in percent atheroma volume, despite both the necrotic core volume and the frequency of fibroatheromas remained stable. Of note, a significant increase in dense calcium volume was reported in this study (57).

Evidence regarding the effect of routine medical therapy on CAC has yielded conflicting results, with initial studies showing significant CAC regression, and contemporaneous data showing rather the opposite (8-10,73).

Indeed, a study published in the New England of Medicine in 1998 reported a significant reduction in coronary artery calcium volume assessed using electron-beam CT, proposing a new surrogate endpoint for future prospective clinical studies exploring the effect of drug therapies on CAD (8). The study of Callister et al. promoted the idea that CAC regression could be used as an appealing imaging endpoint of both primary and secondary prevention strategies (74-76).

all the randomized controlled clinical trials performed have consistently reported a persistent CAC progression despite intensive lipid-lowering treatment (Table 1) (10,77-80). In fact, a recent meta-analysis that included 8 pooled clinical trials evaluating the effect of high intensity, low intensity or no statin on the percent atheroma volume as assessed by IVUS, showed that aggressive statin therapy induced a significant reduction in percent atheroma volume. Of note, high intensity treatment with statins also promoted a significant increase in calcium index compared to the other two groups (11). Indeed, a recent meta-analysis showed continuing progression of coronary calcification despite treatment with statins (12).

Therefore, in brief: (I) CAC progression is an independent predictor of events; (II) statins promote plaque regression; and (III) statins promote CAC progression.

These paradoxical results are puzzling and warrant the conduction of further studies

Until then, the usefulness of CAC once the patient is under statin treatment should be limited. Indeed, a number of medical therapies and even supplementations often used for the management of patients with hypertension or related complications such as atrial fibrillation have shown a significant association to CAC and/or plaque stabilization (55,87,88).

Until then, the usefulness of CAC once the patient is under statin treatment should be limited.

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Magnesium Inhibits Vascular Calcification

4)  Hruby A, O’Donnell CJ, Jacques PF, et al. Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study. JACC Cardiovasc Imaging 2014;7:59-69.
In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium’s protective associations in stroke and fatal coronary heart disease.

Animal study

5) Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 Jan;28(1):20-3. [The effect of the magnesium supplementation on vascular calcification in rats].
[Article in Chinese] Pen JX1, Li L, Wang X, Zhang YH, Li XF, Wu SY.
To observe the role of magnesium sulfate in vascular calcification, to explore the role and the mechanism of magnesium sulfate in vascular calcification.
METHODS:The vascular calcification model was established by administration of vitamin D3 plus nicotine (VDN) in SD rats. To estimate the extent of calcification by Von Kossa staining, calcium content and alkaline phosphatase activity, osteopontin (OPN) mRNA were determined by using semi-quantitative reverse-transcription polymerase chain reaction.The malondialdehyde (MDA) and nitric oxide (NO) content and activities of superoxide dismutase(SOD) were measured by biochemistry.
RESULTS:A strong positive staining of black/brown areas among the elastic fibers of the medial layer in calcified aorta by Von Kossa staining, calcium content and ALP activity in calcified arteries increased by 3.9-and 3.4-fold as compared with the controls. The expression of OPN mRNA was up-regulated by 40% (P < 0.01). The lipid peroxidation products MDA in vascular were increased 2.0-fold (P < 0.01). The NO content and SOD activity were greatly decreased by 64% and 72% (P < 0.01), respectively, compared with controls. However, calcium content and ALP activity in VDN plus magnesium sulfate group were lower than those in VDN group. Low and high dosage magnesium sulfate obviously relieved degree of calcification in the cardiovascular tissues in a dosage-dependent manner (P < 0.01).
CONCLUSION:Magnesium sulfate plays a role in the pathogenesis of vascular calcification by reducing vascular calcification and decreasing vascular injury.

6) Nagase, N., et al. “Myocardial disorders caused by magnesium deficiency in diabetic KK mice.” Magnesium 8.5-6 (1989): 307-315.

7) Adv Chronic Kidney Dis. 2018 May;25(3):281-290. Magnesium as a Calcification Inhibitor. Hénaut L1, Massy ZA2.
Vascular calcification (VC) is associated with elevated cardiovascular mortality rates in patients with CKD. Recent clinical studies of patients with advanced CKD have observed an association between low serum magnesium (Mg) levels on one hand and elevated VC and cardiovascular mortality on the other. These findings have stimulated interest in understanding Mg’s impact on CKD in general and the associated VC in particular. In vitro and preclinical in vivo data indicate that Mg has the potential to protect vascular smooth muscle cells against calcification via several different molecular mechanisms. Accordingly, data from pilot interventional studies in the clinic suggest that oral Mg supplementation reduces VC in patients with CKD. The present review provides an overview of our current understanding of the impact of Mg on the development of VC in patients with CKD.

8) Sakaguchi, Yusuke, et al. “Association between density of coronary artery calcification and serum magnesium levels among patients with chronic kidney disease.” PLoS One 11.9 (2016): e0163673.
The Agatston score, commonly used to quantify coronary artery calcification (CAC), is determined by the plaque area and density. Despite an excellent predictability of the Agatston score for cardiovascular events, the density of CAC has never been studied in patients with pre-dialysis chronic kidney disease (CKD). This study aimed to analyze the CAC density and its association with serum mineral levels in CKD.
Methods

We enrolled patients with pre-dialysis CKD who had diabetes mellitus, prior cardiovascular disease history, elevated low-density lipoprotein cholesterol levels, or smoking history. The average CAC density was calculated by dividing the Agatston score by the total area of CAC.
Results

The mean estimated glomerular filtration rate (eGFR) of 109 enrolled patients was 35.7 mL/min/1.73 m2. The correlation of the Agatston score with density was much weaker than that with the total area (R2 = 0.19, P < 0.001; and R2 = 0.99, P < 0.001, respectively). Multivariate analyses showed that serum magnesium level was inversely associated with the density, but not with the total area, after adjustment for demographics and clinical factors related to malnutrition-inflammation-atherosclerosis syndrome and mineral and bone disorders including fibroblast growth factor 23 (P = 0.006). This inverse association was pronounced among patients with higher serum phosphate levels (P for interaction = 0.02).
Conclusion

CAC density was inversely associated with serum magnesium levels, particularly in patients with higher serum phosphate levels.

9)  Massy, Ziad A., and Tilman B. Drüeke. “Magnesium and cardiovascular complications of chronic kidney disease.” Nature Reviews Nephrology 11.7 (2015): 432.

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Abundant experimental evidence suggests a physiological role of magnesium in cardiovascular function, and clinical evidence suggests a role of the cation in cardiovascular disease in the general population. The role of magnesium in CKD-mineral and bone disorder, and in particular its impact on cardiovascular morbidity and mortality in patients with CKD, is however not well understood. Experimental studies have shown that magnesium inhibits vascular calcification, both by direct effects on the vessel wall and by indirect, systemic effects. Moreover, an increasing number of epidemiologic studies in patients with CKD have shown associations of serum magnesium levels with intermediate and hard outcomes, including vascular calcification, cardiovascular events and mortality. Intervention trials in these patients conducted to date have had small sample sizes and have been limited to the study of surrogate parameters, such as arterial stiffness, vascular calcification and atherosclerosis. Randomized controlled trials are clearly needed to determine the effects of magnesium supplementation on hard outcomes in patients with CKD.

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Vitamin K

10) Weijs B, Blaauw Y, Rennenberg RJ, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J 2011;32:2555-62.

Vitamin K antagonists (VKA) are currently the most frequently used drug to prevent ischaemic stroke in atrial fibrillation (AF) patients. However, VKA use has been associated with increased vascular calcification. The aim of this study was to investigate the contribution of VKA use to coronary artery calcification in low-risk AF patients.
METHODS AND RESULTS: A prospective coronary calcium scan was performed in 157 AF patients without significant cardiovascular disease (108 males; mean age 57 ± 9 years). A total of 71 (45%) patients were chronic VKA users. The duration of VKA treatment varied between 6 and 143 months (mean 46 months). No significant differences in clinical characteristics were found between patients on VKA treatment and non-anticoagulated patients. However, median coronary artery calcium scores differed significantly between patients without and patients with VKA treatment [0, inter-quartile range (IQR) 0-40, vs. 29, IQR 0-184; P = 0.001]. Mean coronary calcium scores increased with the duration of VKA use (no VKA: 53 ± 115, 6-60 months on VKA: 90 ± 167, and >60 months on VKA: 236 ± 278; P < 0.001). Multivariable logistic regression analysis revealed that age and VKA treatment were significantly related to increased coronary calcium score.
CONCLUSION: Patients using VKA show increased levels of coronary calcification. Age and VKA treatment were independently related to increased coronary calcium score.

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Statins increase vascular calcification in Diabetics

11) Saremi, Aramesh, et al. “Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT).” Diabetes care 35.11 (2012): 2390-2392.

In this cohort of T2DM patients with advanced atherosclerosis, we found that more frequent statin use was associated with accelerated progression of CAC.

 

12) Henein, Michael, et al. “High dose and long-term statin therapy accelerate coronary artery calcification.” International journal of cardiology 184 (2015): 581-586.

In randomized clinical trials statins and placebo treated patients showed the same degree of coronary artery calcium (CAC) progression. We reanalyzed data from two clinical trials to further investigate the time and dose dependent effects of statins on CAC. Additionally, we investigated whether CAC progression was associated with incident cardiovascular events.
METHODS AND RESULTS:Data were pooled from two clinical trials: St. Francis Heart Study (SFHS) (419 and 432 patients treated with placebo and 20 mg atorvastatin daily, respectively) and EBEAT Study (164 and 179 patients respectively treated with 10 mg and 80 mg atorvastatin daily). CAC scores were assessed at baseline, 2 years and 4-6 years in SFHS; in EBEAT they were measured at baseline and 12 months. After a short-term follow-up (12 to 24 months) placebo and low dose atorvastatin showed a similar CAC increase, although 80 mg/daily atorvastatin increased CAC an additional 12-14% over placebo (p<0.001). In the long-term, atorvastatin caused a greater progression of CAC compared to placebo (additional 1.1%, p=0.04). In SFHS 42 cardiovascular events occurred after the second CT scan. The baseline and progression of CAC were greater in patients with events. However, only baseline CAC and family history of premature cardiovascular disease but not CAC progression were independent predictors of events.
CONCLUSIONS: Despite a greater CAC increase with high dose and long-term statin therapy, events did not occur more frequently in statin treated patients. This suggests that CAC growth under treatment with statins represents plaque repair rather than continuing plaque expansion.

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2016   6,000 patients without CVD  – Double Zero

52% CAC=zero  – Mostly Zero Calcium Score,  Low Burden of Disease

13) Radford, Nina B., et al. “Progression of CAC score and risk of incident CVD.” JACC: Cardiovascular Imaging 9.12 (2016): 1420-1429.
The authors sought to determine the relative contributions of baseline coronary artery calcification (CAC), follow-up CAC, and CAC progression on incident cardiovascular disease (CVD).
BACKGROUND:Repeat CAC scanning has been proposed as a method to track progression of total atherosclerotic burden. However, whether CAC progression is a useful predictor of future CVD events remains unclear.
METHODS:This was a prospective observational study of 5,933 participants free of CVD who underwent 2 examinations, including CAC scores, and subsequent CVD event assessment. CAC progression was calculated using the square root method. The primary outcome was total CVD events (CVD death, nonfatal myocardial infarction, nonfatal atherosclerotic stroke, coronary artery bypass surgery, percutaneous coronary intervention). Secondary outcomes included hard CVD events, total coronary heart disease (CHD) events, and hard CHD events.
RESULTS:   CAC was detected at baseline in 2,870 individuals (48%). The average time between scans was 3.5 ± 2.0 years. After their second scan, 161 individuals experienced a total CVD event during a mean follow-up of 7.3 years.

CAC progression was significantly associated with total CVD events (hazard ratio: 1.14, 95% confidence interval: 1.01 to 1.30 per interquartile range; p = 0.042) in the model including baseline CAC, but the contribution of CAC progression was small relative to baseline CAC (chi-square 4.16 vs. 65.92).

Furthermore, CAC progression was not associated with total CVD events in the model including follow-up CAC instead of baseline CAC (hazard ratio: 1.05, 95% confidence interval: 0.92 to 1.21; p = 0.475). A model that included follow-up CAC alone performed as well as the model that included baseline CAC and CAC progression.
CONCLUSIONS: Although CAC progression was independently, but modestly, associated with CVD outcomes, this relationship was no longer significant when including follow-up CAC in the model. These findings imply that if serial CAC scanning is performed, the latest scan should be used for risk assessment, and in this context, CAC progression provides no additional prognostic information.

2018

3281 participants (45–74 years of age), free from cardiovascular disease

14) Lehmann, Nils, et al. “Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the HNR Study (Heinz Nixdorf Recall).” Circulation 137.7 (2018): 665.
Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events.
Methods:  In 3281 participants (45–74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT.   The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed.
Results:  We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events.

Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1–Q3, 23–360] versus 8 [0–83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events.

However, CAC progression did not improve models including CAC5y and 5-year risk factors.

An excellent prognosis was found for 921 participants with double-zero CACb(baseline)=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively.

double-zero CACb and CAC5y, as well, had the best prognosis. Only 10 (1.1%) had a hard coronary and 18 (2.0%) of 921 subjects had a hard cardiovascular event within an 8-year follow-up after the CAC5y CT scan.

When CACb progressed from 1 to 399 to CAC5y≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400.

Participants with CACb≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively).
Conclusions:

CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.

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NICE CHARTS !!  2013 MESA Budoff

15) J Am Coll Cardiol. 2013 Mar 26;61(12):1231-9.  Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis).  Budoff MJ1, Young R, Lopez VA, Kronmal RA, Nasir K, Blumenthal RS, Detrano RC, Bild DE, Guerci AD, Liu K, Shea S, Szklo M, Post W, Lima J, Bertoni A, Wong ND.

The study examined whether progression of coronary artery calcium (CAC) is a predictor of future coronary heart disease (CHD) events.
BACKGROUND: CAC predicts CHD events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression.
METHODS:We studied 6,778 persons (52.8% female) aged 45 to 84 years from the MESA (Multi-Ethnic Study of Atherosclerosis) study. A total of 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n = 1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max = 9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HRs) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors.
RESULTS: A total of 343 and 206 hard CHD events occurred.

The annual change in CAC averaged 24.9 ± 65.3 Agatston units.

Among persons without CAC at baseline (n = 3,396), a 5-unit annual change in CAC was associated with an adjusted HR (95% Confidence Interval) of 1.4 (1.0 to 1.9) for total and 1.5 (1.1 to 2.1) for hard CHD.

Among those with CAC >0 at baseline, HRs (per 100 unit annual change) were 1.2 (1.1 to 1.4) and 1.3 (1.1 to 1.5), respectively.

Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HRs of 3.8 (1.5 to 9.6) for total and 6.3 (1.9 to 21.5) for hard CHD compared to those without progression.

CONCLUSIONS:Progression of CAC is associated with an increased risk for future hard and total CHD events.

“The most striking findings in the current study were the graded relationships of CAC progression with CHD event risk, strongly suggesting that the functions are linear, with greater progression associated with greater risk. We demonstrated that progression of CAC is associated with total and hard CHD risk; these relationships were attenuated but still significant after adjusting for risk factors and baseline calcium.”

Of great interest has been whether risk-reducing therapies such as statins may retard progression of atherosclerosis assessed by serial CAC scanning.

Among 615 hyperlipidemic postmenopausal women randomized to intensive versus moderate lipid-lowering with a statin, with baseline and 12-month follow-up CAC assessed by CT, no difference in calcium volume score change was seen between the treatment groups.

St Francis Study (Dr Arad):  Also, in a clinical trial conducted to evaluate the impact of aggressive lipid-lowering and antioxidant therapy on the progression of CAC in 4,613 asymptomatic persons with baseline and follow-up CT scans at 2 years, while showing no effects of the intervention on progression of CAC, those who sustained a coronary event had a median increase in CAC score of 247 compared to only 4 in those who did not sustain a coronary event at any time during the study. However, the strongest predictor of subsequent CHD events was two-year change in calcium score.

Finally, in a randomized study of statins and CAC progression, the mean progression of CAC volume scores, corrected for the baseline CAC volume score, was 27% in the 80-mg atorvastatin group, similar to the 25% in the 10-mg atorvastatin group. CAC progression showed no relationship with on-treatment LDL cholesterol levels.

Our results are consistent with earlier retrospective and prospective studies showing that persons who experienced CHD events had also greater progression of CAC, as well as a large recent prospective study demonstrating a strong relation of CAC progression with total mortality. We have previously demonstrated in a prospective evaluation of 4,609 patients that, after adjusting for baseline score, age, sex, and time between scans, CAC progression (mean progression was 247 in this group) was associated with a 3.34 fold risk of all-cause mortality (HR 3.34; 95% CI: 2.65 to 4.21; p < 0.0001).

This result is quite similar to results in the present study, where we demonstrated 3.0–6.3 fold increased risk in hard events for those with available data. In a retrospective follow-up study of 817 persons, CAC progression was the strongest predictor of myocardial infarction.

Another study measured CAC change in 495 asymptomatic subjects who underwent sequential CT scanning In this study, the relative risk for acute MI for patients exhibiting ≥15% CAC progression was 17.2 (95% CI: 4.1 to 71.2) when compared to that of patients without CAC progression (p<0.0001).

Also, increased progression of CAC has been recently shown in persons with metabolic syndrome and diabetes, with greater CAC progression also shown to be related to greater CHD event rates.

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Diabetes CAC PRogression MESA

16) Wong, Nathan D., et al. “Metabolic syndrome, diabetes, and incidence and progression of coronary calcium: the Multiethnic Study of Atherosclerosis study.JACC: Cardiovascular Imaging 5.4 (2012): 358-366.

In the Multiethnic Study of Atherosclerosis, persons with MetS or DM have a greater incidence and progression of CAC compared to those without MetS; those with MetS (without DM) have an intermediate incidence and progression. Also, impaired fasting glucose18, insulin resistance23 and DM24–25 have been shown in smaller or selected cohorts to relate to progression of CAC, and in those with DM, a glycated hemoglobin ≥7% predicted progression of CAC.26 Progression of CAC has also been shown to predict total mortality over baseline risk factors and CAC.13 We also found in our study increased progression of CAC in persons with MetS and DM to predict future CHD events.

Persons with both MetS and DM have the greatest incidence and degree of progression of CAC; those with MetS without DM have an incidence and degree of progression of CAC intermediate between those with DM and without these conditions. Moreover, in those with MetS or DM, progression predicts future CHD event risk.

CAT Angio

17) Hadamitzky, Martin, et al. “Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease.” European heart journal 34.42 (2013): 3277-3285.

Harvey Hecht CAC

18) Hecht, Harvey S. “Coronary artery calcium scanning: past, present, and future.” JACC: Cardiovascular Imaging 8.5 (2015): 579-596.  Coronary artery calcium scanning past present future Hecht Harvey JACC Cardiovascular Imaging 2015

Figure 5. Progression of CAC and Risk of First MI in 495 Asymptomatic Patients Receiving Cholesterol-Lowering Therapy

(Left) CAC progression of <15% per year is associated with a benign prognosis irrespective of the baseline CAC, implying stabilization of the atherosclerotic process. (Right) CAC progression of >15% per year is associated with a poor prognosis directly related to the baseline CAC, implying new plaque formation and inadequacy of treatment. CAC = coronary artery calcium; MI = myocardial infarction.

6,778 MESA subjects followed for 7.6 years for all CHD events: Of particular interest was the greater CAC progression in those taking statins, which has been interpreted as benign con-version of pre-existing noncalcified to calcified plaque by the drug. However, the greater progression in patients with events while on statin therapy negates this theory, supports the predominant formation of new plaque that then becomes calcified, and implies a therapeutic failure of statins to sufficiently halt the atherosclerotic process.

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2018 BOOK

latest and greatest…all of Raggi’s charts here

19) Hecht, Harvey S., and Matthew J. Budoff. “Coronary Artery Calcium in Primary Prevention.” Atlas of Cardiovascular Computed Tomography. Springer, London, 2018. 49-67.

” lack of change of CAC after one year indicated successful treatment of the disease process”

CAC less than 400 does not warrant Perfusion imaging in asymptomatic patients. CAC over 400 justifies functional evaluation to determine amount of ishemic myocardium.

A large body of literature supports the role of CAC score as pivotal tool in the prevention of coronary artery disease. Its unparalleled power to predict events has resulted in its incorporation into the most important guidelines

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CAC Progression in DM

Kiramijyan Sarkis AJC 2013 Event free survival with and without DM and CAC progression Fig9These results suggest that CAC progression is an independent predictor of all-cause mortality in patients with DM.

20) Kiramijyan, Sarkis, et al. “Impact of coronary artery calcium progression and statin therapy on clinical outcome in subjects with and without diabetes mellitus.” The American journal of cardiology 111.3 (2013): 356-361.

Coronary artery calcium (CAC) is a marker of atherosclerosis, and CAC progression is independently associated with all-cause mortality in the general population but not convincingly in subjects with diabetes mellitus (DM). The aim of this study was to ascertain the differences in the rates of CAC progression, the effect of statin therapy, and all-cause mortality in subjects with and without DM. The study group consisted of 296 asymptomatic subjects with type 2 DM and 300 controls (mean age 59 ± 6 years, 29% women) who underwent baseline and follow-up CAC scans within a 2-year interval. Absolute annual CAC score change, percentage annual CAC progression(ΔCAC%), event-free survival, and the effect of statin therapy on survival were all assessed. The mean follow-up duration was 56 ± 11 months.

Absolute annual CAC score change was 81 ± 10 in subjects with DM and 34 ± 5 in controls (p = 0.0001).

Percentage annual CAC progression was 29 ± 9% in subjects with DM and 10 ± 7% in controls (p = 0.0001).

The hazard ratios of death in 3 groups of subjects with DM compared to controls without DM were
1.88 (95% confidence interval [CI] 1.51 to 2.36, p = 0.0001) for ΔCAC of 10% to 20%,
2.29 (95% CI 1.56 to 3.38, p = 0.0001) for ΔCAC of 21% to 30%, and
6.95 (95% CI 2.23 to 11.53, p = 0.0001) for ΔCAC >30%, all compared to ΔCAC <10%.

Benefit Demonstrated for Statin Drug                                                               

The adjusted hazard ratios of all-cause mortality in subjects receiving (statins) compared to those not receiving statin therapy were
0.29
(95% CI 0.13 to 0.56, p = 0.001) in those without DM and without CAC progression,
0.51 (95% CI 0.21 to 0.73, p = 0.001) in those with DM and without CAC progression, and
0.71 (95% CI 0.25 to 0.91, p = 0.003) in those without DM and with CAC progression,

with all 3 groups compared to
1.0 (reference) in those with DM, with CAC progression and without statin therapy.

In conclusion, CAC progression was greater and event-free survival lower in patients with DM compared to controls in proportion to the extent of CAC progression. These results suggest that CAC progression is an independent predictor of all-cause mortality in patients with DM.

Raggi Budoff 2005 Observational Study Diabetes Calcium Score

21) Raggi, Paolo, et al. “Progression of coronary artery calcium and occurrence of myocardial infarction in patients with and without diabetes mellitus.” Hypertension 46.1 (2005): 238-243.Progression of coronary calcium and occurrence myocardial infarction in diabetes mellitus Raggi Paolo Hypertension 2005

Progression of coronary artery calcium, a marker of atherosclerosis, can be slowed with statins, and continued progression of calcium is associated with an increased risk of myocardial infarction. However, it is not known whether statins are effective in slowing calcium progression in diabetes mellitus. In a retrospective study, we examined 1153 nondiabetic and 157 diabetic subjects who underwent sequential electron beam tomography scans at a minimum 1-year interval to assess progression of coronary calcium. A yearly score increase >15% was considered evidence of true progression. The use of statins and occurrence of myocardial infarction were recorded. There was no difference in baseline calcium score between diabetic and nondiabetic patients. Diabetic patients with no coronary calcium on the baseline scans developed it more often than nondiabetic subjects (42% versus 25%; P=0.046) during follow-up.

Calcium progression was 33% greater in diabetic patients than nondiabetic subjects (P<0.001) if no statin therapy was provided and 17.7% greater when statins were used (P<0.001).

Among the 49 subjects who experienced a myocardial infarction, the calcium score increased on average 20% more in diabetic than nondiabetic patients (P<0.001).

In logistic models, diabetes mellitus and systemic hypertension were the best predictors of calcium progression (odds ratio, 3.1 and 1.9, respectively), whereas baseline calcium score percentile and statin therapy were the best predictors of infarction. These findings support the notion that diabetes mellitus causes accelerated atherosclerosis, even in the presence of statin therapy, and provide evidence that coronary calcium monitoring is an effective method to assess treatment efficacy.

We considered 4 different groups:
1) subjects without CAC at baseline;
2) subjects with CAC at baseline who did not receive statin therapy after the initial EBT scan;
3) subjects with CAC at baseline who received statin therapy after the initial scan;
and
4) patients with CAC at baseline who experienced a myocardial infarction (MI) after having undergone at least 2 sequential EBT scans a minimum of 12 months apart

Statin therapy significantly slowed the progression of absolute, relative, and percentile CVS compared with no treatment among diabetic patients and nondiabetic subjects

Furthermore, among patients receiving statins, the progression of CVS was greater in patients who experienced an MI than among all others who received statins (27% versus 10 %). On the contrary, statin-untreated subjects and MI patients showed a similar CVS progression (Table 2).

Of interest, 87% of the nondiabetic subjects and 90% of the diabetic patients who experienced an MI were receiving statins during the months leading to the acute coronary event. Hence, it would appear that some patients may escape the beneficial effects of statins on the atherosclerotic plaque, with continued accumulation of disease in the vessel wall and an attendant increased risk of events.

we showed that diabetic patients accumulate CAC faster and to a larger extent than nondiabetic subjects.

The main findings support the notion that progression of atherosclerosis and effectiveness of therapy can be assessed by noninvasive imaging modalities that measure changes in CAC over time.  Additionally, they provide further evidence that treatment with statins may slow progressive CAC accumulation. Finally, our data confirm previous published evidence (21) that high baseline CVS percentiles predict the occurrence of MI, likely because they reflect the presence of an accelerated atherosclerosis process.

patients with type 2 diabetes mellitus have been reported to have a risk of
death from cardiovascular causes 2- to 4-fold higher than individuals without diabetes,
2 and the cardiovascular mortality rate among patients with type 2 diabetes without a previous history of coronary artery disease (CAD) is as high as that of nondiabetic subjects with previous CAD. 3

Patients with previous history of cardiovas-cular disease and renal failure were excluded because of the high prevalence of CAC and rapid rate of CAC accumulation in these patients.

We identified 157 diabetic patients and 1153 nondiabetic subjects with the above characteristics; of the 1310 total patients, 64% were men. The mean age for the entire cohort was 56  10. The average follow-up period was 2.2 and 2.7 years for diabetic and nondiabetic subjects, respectively.

interestingly, treatment with statins was a predictor of slower progression of CAC but also a marker of increased risk of MI. Hence, statins may reduce CAC progression, but in this observational analysis,  they were a proxy of risk, likely because they were administered to patients at higher cardiovascular risk.

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Coronary artery calcium with and without diabetes Raggi P J Amer Col Card 2004 F2.largeMore ominous significance of baseline coronary calcium in Diabetes….
see chart http://www.onlinejacc.org/content/accj/43/9/1663/F2.large.jpg

PDF
22) Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. Journal of the American College of Cardiology 2004;43(9):1663-1669.

The study was done to determine the interaction of coronary artery calcium and diabetes mellitus for prediction of all-cause death.
BACKGROUND: Diabetes is a strong risk factor for coronary artery disease (CAD) and is associated with an elevated overall mortality. Electron beam tomography (EBT) provides information on the presence of subclinical atherosclerosis and may be useful for risk stratification.
METHODS:We followed 10,377 asymptomatic individuals (903 diabetic patients) referred for EBT imaging. Primary end point was all-cause mortality, and the average follow-up was 5.0 +/- 3.5 years. Cox proportional hazard models, with and without adjustment for other risk factors, were developed to predict all-cause mortality.
RESULTS: Patients with diabetes had a higher prevalence of hypertension and smoking (p < 0.001) and were older.

The average coronary calcium score (CCS) for subjects with and for those without diabetes was 281 +/- 567 and 119 +/- 341, respectively (p < 0.0001).

Overall, the death rate was 3.5% and 2.0% for subjects with and without diabetes (p < 0.0001). In a risk-factor-adjusted model, there was a significant interaction of CCS with diabetes (p < 0.00001), indicating that, for every increase in CCS, there was a greater increase in mortality for diabetic than for nondiabetic subjects.

However, patients suffering from diabetes with no coronary artery calcium demonstrated a survival similar to that of individuals without diabetes and no detectable calcium (98.8% and 99.4%, respectively, p = 0.5).

CONCLUSIONS:Mortality from all causes is increased in asymptomatic patients with diabetes in proportion to the screening CCS. Nonetheless, subjects without coronary artery calcium have a low short-term risk of death even in the presence of diabetes mellitus.

Statin Plus PCSK9

23) Ikegami, Yuichi, et al. “The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy.” npj Aging and Mechanisms of Disease 4.1 (2018): 7.

Statins and/or PCSK9 inhibitors cause the regression of coronary atheroma and reduce clinical events. However, it currently remains unclear whether these drugs modulate coronary atheroma calcification in vivo. Coronary artery calcium (CAC) scores (Agatston Units, AUs) were estimated in 120 patients receiving coronary computed tomographic angiography (CCTA) (63% males; median age 56 years). The CAC scores were compared among the three groups: (1) neither statin nor PCSK9 inhibitor therapy, (2) statin monotherapy, and (3) statin and PCSK9 inhibitor combination therapy in an unpaired cross-sectional study. Additionally, CCTA was performed twice at an interval in 15 patients undergoing statin monotherapy to compare the previous (baseline) and subsequent (follow-up) CAC scores in a paired longitudinal study. In addition, a PCSK9 inhibitor was administered to 16 patients undergoing statin therapy. Before and after that, CCTA was performed twice to compare the previous and subsequent CAC scores in a paired longitudinal study. The unpaired cross-sectional study and paired longitudinal study consist of completely different patients. Among 120 patients, 40 (33%) had a CAC score >100 AUs. The median CAC score increased in the following order: statin group, statin and PCSK9 group, and no-statin-no-PCSK9 group. Annual CAC score progression was 29.7% by statin monotherapy and 14.3% following the addition of the PCSK9 inhibitor to statin therapy. The annual rate of CAC with the combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. CAC may be prevented with PCSK9 Inhibitor.

(PDF) The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy.

Available from: https://www.researchgate.net/publication/325931378_The_annual_rate_of_coronary_artery_calcification_with_combination_therapy_with_a_PCSK9_inhibitor_and_a_statin_is_lower_than_that_with_statin_monotherapy [accessed Dec 06 2018].

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24) Should Statins Be Banned from Dialysis? An S. De Vriese JASN June 2017, 28

Statins may also exert their procalcifying effects by affecting vitamin K metabolism. The conversion of vitamin K1 derived from dietary vegetables to vitamin K2 in the tissues requires isoprenoids derived from mevalonate.12 In vitro, statins inhibit the synthesis of vitamin K2.8,12 Vitamin K2 is essential for the activation of proteins responsible for inhibition of vascular calcification, such as matrix-Gla protein and growth arrest–specific protein 6. Vitamin K deficiency is highly prevalent in patients on dialysis and currently intensively researched as a key player and modifiable risk factor in the development of vascular calcifications in dialysis.13 It is thus tempting to bolster the hypothesis that statins may accelerate vascular calcifications in patients on dialysis by further depleting vascular vitamin K2 levels.

the insight that statins potentially accelerate vascular calcifications in patients on dialysis may persuade nephrologists to ban statins from dialysis

plaque regression in CKD with statin ezetimibe

25) Int J Cardiol. 2018 Oct 1;268:23-26. Impact of statin-ezetimibe combination on coronary atheroma plaque in patients with and without chronic kidney disease – Sub-analysis of PRECISE-IVUS trial.
Fujisue K1, Nagamatsu S1, Shimomura H2, Yamashita T3, Nakao K4, Nakamura S5, Ishihara M6, Matsui K7, Yamamoto N8, Koide S9, Matsumura T10, Fujimoto K11, Tsunoda R12, Morikami Y13, Matsuyama K14, Oshima S15, Sakamoto K1, Izumiya Y1, Kaikita K1, Hokimoto S1, Ogawa H16, Tsujita K17.

BACKGROUND:  Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD.
METHODS:  In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol < 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD.
RESULTS:  CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P < 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (-1.4 [-2.8 to -0.1]% vs. -0.2 [-1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (-2.6 [-5.6 to -0.4]% vs. -0.9 [-2.4 to 0.2]%, P = 0.04).
CONCLUSIONS:  As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy.

Review Effect of Statins on Atherosclerosis Calcium Score

26) Wan, Darryl, et al. “The effect of statin therapy on coronary atherosclerosis as assessed by computed tomography.” Current Research: Cardiology 3.4 (2016).Effect of statin therapy on coronary atherosclerosis computed tomography Wan Darryl Cur Res Card 2016

OBJECTIVES: The effect of statin therapy on coronary artery calcification is unclear. Early studies suggested a slower rate of coronary artery calcium score (CACS) progression, but recent prospective trials have failed to show this benefit. Recent studies have explored the use of Cardiac Computed Tomography Angiography (CCTA) to characterize plaque features. We provide a systematic review of available literature documenting the effects of statin therapy on the progression of CACS and non-calcium-based indices. METHODS: A systematic search was performed from January 1, 1980 to April 28, 2016 using these databases: Cochrane Database, ACP Journal Club, Health Technology Assessment, Embase, NHS Economic Evaluation Database, Ovid MEDLINE, Health and Psychosocial Instruments. English language publications that serially measured relationships between statin therapy and CACS or noncalcium- based indices were included. Case reports, reviews and meta-analyses were excluded. Data regarding progression of calcium and non-calcium-based indices were extracted and analyzed.

RESULTS: 2159 articles were retrieved for screening. Of these, 22 met pre-defined inclusion criteria; 9 were randomized controlled trials and 13 observational studies. Observational studies did not consistently demonstrate a reduction in the progression of CACS with statin therapy. No randomized trial demonstrated convincing evidence that statin therapy reduces the progression of CACS. Limited randomized trials of CCTA suggest that statin therapy may reduce non-calcified plaque volume, but increase dense calcium volume. CONCLUSION: Based on studies using statins, serial assessment of noncalcified plaque volume, but not CACS, may be useful for the assessment of medical interventions with postulated effects on progression or regression of atherosclerosis.

Coronary artery calcium (CAC) is a non-invasive marker of  atherosclerosis (1–5). In several large-scale studies, coronary artery calcium scoring (CACS) has been shown to add prognostic value in predicting cardiovascular events when added to traditional risk stratification such as the Framingham score (1,6–8). The 2010 ACCF/AHA Guidelines
have advocated selective use of CACS for cardiovascular risk assessment in
asymptomatic patients considered at intermediate risk through traditional
assessment (9).

Statin therapy is an essential tool in the primary and secondary prevention
of cardiovascular disease (10–17). Several trials have demonstrated that
statins can induce regression of coronary atherosclerosis measured by
intravascular ultrasonography (IVUS) in patients treated with high-intensity
statin therapy (18,19).

Other studies have suggested that statin therapy promotes atheroma calcification, thereby stabilizing plaque (20,21). Whether regression of atherosclerosis by statins can be assessed using serial CACS or CCTA remains controversial.

Early observational studies (22–24) suggested that statin therapy had the potential to slow CACS. However, subsequent randomized controlled trials (25–29) failed to confirm this. And more recent studies of statin effects on CACS in special populations such as Systemic Lupus Erythematosus (SLE) (30) and chronic kidney disease (CKD) patients are also controversial due to small study populations (31).

Recent studies have also investigated plaque changes as measured by non-calcium-based indices of coronary artery disease on CCTA to further characterize features of coronary plaques. Whether these measurements are useful for serial assessments remains to be seen. Accordingly, the purpose of this review is to elucidate the effect of statin therapy on CACS and non-calcium-based indices of coronary artery disease progression through a
systematic review.

OBJECTIVES: The effect of statin therapy on coronary artery calcification is unclear. Early studies suggested a slower rate of coronary artery calcium score (CACS) progression, but recent prospective trials have failed to show this benefit. Recent studies have explored the use of Cardiac Computed Tomography Angiography (CCTA) to characterize plaque features. We provide a systematic review of available literature documenting the effects of statin therapy on the progression of CACS and non-calcium-based indices. METHODS: A systematic search was performed from January 1, 1980 to April 28, 2016 using these databases: Cochrane Database, ACP Journal Club, Health Technology Assessment, Embase, NHS Economic Evaluation Database, Ovid MEDLINE, Health and Psychosocial Instruments. English language publications that serially measured relationships between statin therapy and CACS or noncalcium- based indices were included. Case reports, reviews and meta-analyses were excluded. Data regarding progression of calcium and non-calcium-based indices were extracted and analyzed. RESULTS: 2159 articles were retrieved for screening. Of these, 22 met pre-defined inclusion criteria; 9 were randomized controlled trials and 13 observational studies. Observational studies did not consistently demonstrate a reduction in the progression of CACS with statin therapy. No randomized trial demonstrated convincing evidence that statin therapy reduces the progression of CACS. Limited randomized trials of CCTA suggest that statin therapy may reduce non-calcified plaque volume, but increase dense calcium volume. CONCLUSION: Based on studies using statins, serial assessment of noncalcified plaque volume, but not CACS, may be useful for the assessment of medical interventions with postulated effects on progression or regression of atherosclerosis.
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27)  Vavlukis, Marija, and Sasko Kedev. “Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease.Current pharmaceutical design 24.4 (2018): 427-441.

METHOD: We conducted a literature review of English articles through PubMed,
RESULTS: Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention.

The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate – intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD.

CONCLUSION: Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes.

28) Statin Therapy Reduces Future Risk of Lower-Limb Amputation in Patients With Diabetes and Peripheral Artery Disease  Chien-Yi Hsu Yung-Tai Chen Yu-Wen Su Chun-Chin Chang Po-Hsun Huang Shing-Jong Lin The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 7, 1 July 2017, Pages 2373–2381,
Although there is evidence to support the beneficial effects of statins on major cardiovascular events, few studies address the protective effect of statins on limb outcome.

Objective:To investigate whether the use of statin is associated with a risk reduction in lower-extremity amputation in type 2 diabetes mellitus (DM) patients with peripheral arterial disease (PAD).
Design:Observational cohort study.
Setting:A nationwide DM database in Taiwan from 2000 to 2011.
Patients:A total of 69,332 patients aged ≥20 years with DM and PAD were identified.
Intervention:Patients were divided into three groups:
11,409 patients were statin users,
4430 patients used nonstatin lipid-lowering agents, and
53,493 patients were nonusers.
Main Outcome Measures:The primary outcome was lower-extremity amputation. Secondary outcomes were in-hospital cardiovascular death and all-cause mortality.
Results:  Compared with nonusers, statin users were associated with lower risks of
lower-extremity amputation [adjusted hazard ration (aHR), 0.75; 95% confidence interval (CI), 0.62 to 0.90],
in-hospital cardiovascular death (aHR, 0.78; 95% CI, 0.69 to 0.87),
and all-cause mortality (aHR, 0.73; 95% CI, 0.69 to 0.77).
In the propensity score matching analysis, the effect of statin on the risk of lower-extremity amputation was consistent.

Only statin users were associated with the risk reduction of lower-extremities amputation (HR, 0.77; 95% CI, 0.61 to 0.97) and cardiovascular death (HR, 0.78; 95% CI, 0.68 to 0.89) when taking competing risk of death into consideration.

Conclusions:Compared with statin nonusers who were never treated with lipid-lowering drugs, this study found that statin users had a lower risk of lower-extremity amputation and cardiovascular death in patients with DM and PAD.

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Biofilm in Atherosclerotic Plaques

29) Snow, D. E., et al. “The presence of biofilm structures in atherosclerotic plaques of arteries from legs amputated as a complication of diabetic foot ulcers.” Journal of wound care 25.Sup2 (2016): S16-S22.Bacterial Biofilm in atherosclerotic plaques of leg arteries amputated diabetic foot ulcers Snow J of wound care 2016

Atherosclerosis, rather than microcirculatory impairment caused by endothelial cell dysfunction, is the main driver of circulatory compromise in patients with diabetic limbs. The presence of atherosclerotic plaque at the trifurcation is a significant contributor to amputation of diabetic legs. The presence of bacteria and other microorganisms in atherosclerotic plaque has long been known, however, the cause of chronic inflammation and the role of bacteria/viruses in atherosclerosis have not been studied in detail. The objective of this study was to clarify the cause of the chronic inflammation within atherosclerotic plaques, and determine if any bacteria and/or viruses are involved in the inflammatory pathway.
METHOD:This study uses fluorescence microscopy and fluorescence in-situ hybridisation (FISH) to identify components of biofilm in atherosclerotic arteries. These tools are also used to identify individual bacteria, and determine the architectural spatial location within the atherosclerotic plaque where the bacteria can be found.
RESULTS:The results indicate that the presence of biofilms in grossly involved arteries may be an important factor in chronic inflammatory pathways of atherosclerotic progression, in the amputated limbs of patients with diabetic foot ulcers and vascular disease.
CONCLUSION:While the presence of bacterial biofilm structures in atherosclerotic plaque does not prove that biofilm is the proximate cause of atherosclerosis, it could contribute to the persistent inflammation associated with it. Second, the synergistic relationship between the atherosclerotic infection and the diabetic foot ulcer may ultimately contribute to higher amputation rates in diabetics.

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Pseudomonas in coronary Thrombi

30) Hansen, Gorm Mørk, et al. “Pseudomonas aeruginosa Microcolonies in Coronary Thrombi from Patients with ST-Segment Elevation Myocardial Infarction.” PloS one 11.12 (2016): e0168771.
Chronic infection is associated with an increased risk of atherothrombotic disease and direct bacterial infection of arteries has been suggested to contribute to the development of unstable atherosclerotic plaques. In this study, we examined coronary thrombi obtained in vivo from patients with ST-segment elevation myocardial infarction (STEMI) for the presence of bacterial DNA and bacteria.

Aspirated coronary thrombi from 22 patients with STEMI were collected during primary percutaneous coronary intervention and arterial blood control samples were drawn from radial or femoral artery sheaths.

Analyses were performed using 16S polymerase chain reaction and with next-generation sequencing to determine bacterial taxonomic classification. In selected thrombi with the highest relative abundance of Pseudomonas aeruginosa DNA, peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) with universal and species specific probes was performed to visualize bacteria within thrombi. From the taxonomic analysis we identified a total of 55 different bacterial species.

DNA from Pseudomonas aeruginosa represented the only species that was significantly associated with either thrombi or blood and was >30 times more abundant in thrombi than in arterial blood (p<0.0001).

Whole and intact bacteria present as biofilm microcolonies were detected in selected thrombi using universal and P. aeruginosa-specific PNA-FISH probes. P. aeruginosa and vascular biofilm infection in culprit lesions may play a role in STEMI, but causal relationships remain to be determined.

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Several samples show bacterial DNA far exceeding what would be expected by contamination, suggesting the bacteria may be propagating in the plaque.

31) Wolcott RD, Wolcott JJ, Palacio C, Rodriguez S (2012) A Possible Role of Bacterial Biofilm in the Pathogenesis of Atherosclerosis. J Bacteriol Parasitol 3:127. Bacterial Biofilm in Pathogenesis of Atherosclerosis Wolcott RD J Bact Parasit 2012

Multiple culture and molecular based studies have established the presence of bacteria in atherosclerotic plaques. Although bacteria are present within the plaque, there is no clear understanding or putative pathway as to what part bacteria might play, if any, in the pathogenesis of atherosclerosis. The current models for the pathogenesis of atherosclerotic plaque suggest that persistent infl ammation is an important factor; however, the possible sources for this sustained infl ammation are limited. The concept of biofilm infection, “a new paradigm of bacterial pathogenesis,” is introduced to show that bacteria, organized into a biofilm phenotype mode of growth, produces a sustained hyper-inflammatory host niche. Biofi lm produces an oxidative environment in a host infection. Samples of plaque from 10 patients were examined to compare 16S rDNA to 18S rDNA. Also 4 samples were evaluated in 2 separate locations to evaluate the homogeneity of bacteria within the sample. The 16S rDNA was also sequenced to identify the microorganisms present and their relative contribution to the sample. Several samples demonstrated large amounts of bacterial DNA. The spatial arrangement of bacterial DNA showed a very heterogeneous distribution of bacteria in the plaque. A heat map data analysis shows that for samples that were evaluated in 2 locations the bacteria identifi ed closely correlated. For all the samples combined, the predominant microbial species identifi ed have often been associated with the oral cavity. Several samples show bacterial DNA far exceeding what would be expected by contamination, suggesting the bacteria may be propagating in the plaque. If bacteria are propagating within the plaque, this would most likely be a biofi lm phenotype mode of growth. Biofi lm is known to produce a hyperinfl ammatory response in host environments, and therefore is a candidate for being the “engine” for the persistent infl ammation necessary for the pathogenesis of atherosclerosis.


Peri-Odontal Oral Infection

32) Chukkapalli, Sasanka S., et al. “Polymicrobial oral infection with four periodontal bacteria orchestrates a distinct inflammatory response and atherosclerosis in ApoEnull mice.” PLoS One 10.11 (2015): e0143291.
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Mouse Model of periodontal bacteria spreading to atherosclerotic plaques

33) Chukkapalli, Sasanka S., et al. “Sequential colonization of periodontal pathogens in induction of periodontal disease and atherosclerosis in LDLRnull mice.” Pathogens and disease 75.1 (2017).

Periodontal disease (PD) and atherosclerotic vascular disease (ASVD) are both chronic inflammatory diseases with a polymicrobial etiology and have been epidemiologically associated. The purpose is to examine whether periodontal bacteria that infect the periodontium can also infect vascular tissues and enhance pre-existing early aortic atherosclerotic lesions in LDLRnull mice. Mice were orally infected with intermediate bacterial colonizer Fusobacterium nucleatum for the first 12 weeks followed by late bacterial colonizers (Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia) for the remaining 12 weeks mimicking the human oral microbiota ecological colonization. Genomic DNA from all four bacterial was detected in gingival plaque by PCR, consistently demonstrating infection of mouse gingival surfaces. Infected mice had significant levels of IgG and IgM antibodies, alveolar bone resorption, and showed apical migration of junctional epithelium revealing the induction of PD. These results support the ability of oral bacteria to cause PD in mice. Detection of bacterial genomic DNA in systemic organs indicates hematogenous dissemination from the gingival pockets.

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St. Francis Heart Study. with Statin Lipitor, Vit C, E

the electron beam CT-derived coronary calcium score predicted ASCVD events, including nonfatal MI and coronary death, independently of and more accurately than standard coronary risk factors.

34) Arad, Yadon, et al. “Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study.” Journal of the American College of Cardiology 46.1 (2005): 158-165.

We sought to determine whether lipid-lowering therapy and antioxidants retard the progression of coronary calcification and prevent atherosclerotic cardiovascular disease (ASCVD) events.
BACKGROUND:  The electron beam computed tomography-derived coronary calcium score predicts coronary disease events. Small, uncontrolled studies suggest that vigorous lipid-lowering therapy slows progression of coronary calcification and prevents coronary artery disease events, but controlled, scientific demonstration of these effects is lacking.
METHODS:

We conducted a double-blind, placebo-controlled randomized clinical trial of atorvastatin 20 mg daily, vitamin C 1 g daily, and vitamin E (alpha-tocopherol) 1,000 U daily, versus matching placebos in 1,005 asymptomatic, apparently healthy men and women age 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender. All study participants also received aspirin 81 mg daily. Mean duration of treatment was 4.3 years.
RESULTS:  Treatment reduced total cholesterol by 26.5% to 30.4% (p < 0.0001), low-density lipoprotein cholesterol by 39.1% to 43.4% (p < 0.0001), and triglycerides by 11.2% to 17.0% (p < or = 0.02) but had no effect (p = 0.80) on progression of coronary calcium score (Agatston method). Treatment also failed to significantly reduce the primary end point, a composite of all ASCVD events (6.9% vs. 9.9%, p = 0.08). Event rates were related to baseline calcium score (pre-specified analysis) and may have been reduced in a subgroup of participants with baseline calcium score >400 (8.7% vs. 15.0%, p = 0.046 [not a pre-specified analysis]).
CONCLUSIONS:  Treatment with alpha-tocopherol, vitamin C, and low doses of atorvastatin (20 mg once daily) did not affect the progression of coronary calcification. Treatment may have reduced ASCVD events, especially in subjects with calcium scores >400, but these effects did not achieve conventional levels of statistical significance.

35) Waheed, Salman, et al. “Collective impact of conventional cardiovascular risk factors and coronary calcium score on clinical outcomes with or without statin therapy: The St Francis Heart Study.” Atherosclerosis 255 (2016): 193-199.

The efficacy of statin therapy remains unknown in patients eligible for statin therapy with and without elevated coronary calcium score (CAC). The study sought to evaluate how cardiovascular risk factors, expressed in terms of statin eligibility for primary prevention, and CAC modify clinical outcomes with and without statin therapy.
Methods   We conducted a post-hoc analysis of the St. Francis Heart Study treatment trial, a double-blind, placebo-controlled randomized controlled trial of atorvastatin (20 mg), vitamin C (1 g), and vitamin E (1000 U) daily, versus placebos in 990 asymptomatic individuals with CAC ≥ 80th percentile for age and gender. Primary cardiovascular outcomes included non-fatal myocardial infarction or coronary death, coronary revascularization, stroke, and peripheral arterial revascularization. We further stratified the treatment and placebo groups by eligibility (eligible when statin indicated) for statin therapy based on 2013 ACC/AHA guidelines and based on CAC categories.
Results

After a median follow-up of 4.8 years, cardiovascular events had occurred in 3.9% of the statin treated but not eligible, 4.6% of the untreated and not eligible, 8.9% of the treated and eligible and 13.4% of the untreated and eligible groups, respectively (p<0.001). Low CAC (<100) occurred infrequently in statin eligible subjects (≤4%) and was associated with low 10-year event rate (<1 per 100 person-years). In contrast, high CAC (>300) occurred frequently in more than 35% of the statin not eligible subjects and was associated with a high 10-year event rate (≥17 per 100 person-years). Risk prediction improved significantly when both clinical risk profile and CAC score were combined (net reclassification index p = 0.002).
Conclusions  Under the current statin treatment guidelines a small number of statin eligible subjects with low CAC might not benefit from statin therapy within 5 years. However, the statin not eligible subjects with high CAC have high event rate attributing to loss of opportunity for effective primary prevention.

Of the 990 participants included, mean age was 59 ± 6 years with 26.0% females. Diabetes and hypertension prevalence were 7.2% and 31.6%, respectively. T

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plaque is infected Biofilm

36) Jonsson, Annika Lindskog, et al. “Bacterial profile in human atherosclerotic plaques.” Atherosclerosis 263 (2017): 177-183.

We confirmed the presence of bacterial DNA in the atherosclerotic plaque by qPCR analysis of the 16S rRNA gene but observed no difference (n.s.) in the amount between either asymptomatic and symptomatic patients or different plaque regions A, B and C. Unweighted UniFrac distance metric analysis revealed no distinct clustering of samples by patient group or plaque region. Operational taxonomic units (OTUs) from 5 different phyla were identified, with the majority of the OTUs belonging to Proteobacteria (48.3%) and Actinobacteria (40.2%). There was no difference between asymptomatic and symptomatic patients, or plaque regions, when analyzing the origin of DNA at phylum, family or OTU level (n.s.).
Conclusions    There were no major differences in bacterial DNA amount or microbial composition between plaques from asymptomatic and symptomatic patients or between different plaque regions, suggesting that other factors are more important in determining plaque vulnerability.

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Diabetes and accelerated CAD endotoxemia

Hyperglycemia causes Leaky Gut

37) Thaiss, Christoph A., et al. “Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.” Science (2018): Hyperglycemia drives intestinal barrier dysfunction Thaiss Christoph Science 2018

In this study, we have identified glucose as an orchestrator of intestinal barrier function.

these experiments establish hyperglycemia as a direct and specific cause for intestinal barrier dysfunction and susceptibility to enteric infection

Obesity, diabetes and related manifestations are associated with an enhanced, but poorly understood risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2 -dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity.

Consequently, hyperglycemia -mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes

38) Pistrosch, Frank, Andrea Natali, and Markolf Hanefeld. “Is hyperglycemia a cardiovascular risk factor?.” Diabetes Care 34.Supplement 2 (2011): S128-S131. Is hyperglycemia a cardiovascular risk factor Pistrosch Frank Diabetes Care 2011

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Diabetes low grade endotoxemia

39) Carnevale, R., et al. “Low-grade endotoxemia, gut permeability and platelet activation in patients with impaired fasting glucose.” Nutrition, Metabolism and Cardiovascular Diseases 27.10 (2017): 890-895.

impaired fasting glucose (IFG) is associated with an increased risk of cardiovascular disease but the underlying mechanisms are still unclear. Aim of the study was to investigate the interplay between platelet activation, lipopolysaccharides (LPS) and markers of oxidative stress in patients with IFG and control subjects.
We performed a cross-sectional study including 35 patients with IFG and 35 control subjects who were well comparable for age, sex, body mass index and smoking history. Serum levels of LPS, zonulin (a marker of gut permeability), oxidized LDL and plasma levels of soluble P-selectin, were measured.

Patients with IFG had significantly higher levels of sP-selectin, LPS, zonulin and oxLDL compared to control subjects.

The IFG status (beta coefficient: 0.518, p < 0.001), higher LPS (beta coefficient: 0.352, p = 0.001) and female sex (beta coefficient: 0.179, p = 0.042) were independently associated with higher sP-selectin; in addition, oxLDL was positively associated with sP-selectin (r = 0.530, p < 0.001) and LPS (r = 0.529, p = 0.001). In IFG patients, we found a significant association between LPS and zonulin (r = 0.521, p = 0.001); this association was confirmed at multivariable analysis (beta coefficient: 0.512, p = 0.007).
Conclusion   Our study provides evidence that patients with IFG have increased platelet activation, and suggests LPS as a potential trigger for in vivo platelet activation in this patient population.

Chronic Endotoxemic in Type I Diabetes

40) Aravindhan, Vivekanandhan, et al. “Chronic endotoxemia in subjects with type-1 diabetes is seen much before the onset of microvascular complications.” PloS one 10.9 (2015): e0137618.

Lipopolysaccharide (LPS)/Endotoxin is hypothesized to play an important role in chronic inflammation associated with Type-1 diabetes (T1DM) and its complications. Endotoxin core antibodies (EndoCAb), LPS binding protein (LBP) and soluble CD14 (sCD14) act as modulators of LPS induced activation of innate immune system in vivo. For the present study we estimated the levels of LPS and its translocation markers in T1DM subjects with and without microvascular complications (MVC) and correlate them with clinical parameters of T1DM and serum inflammatory cytokine levels (TNF-α, IL-6, IL-1β and GM-CSF).
Methods  A total of 197 subjects (64 normal glucose tolerance (NGT) subjects, 97 T1DM subjects without MVC and 36 with MVC) were included in this study and the levels of serum LPS, its translocation markers and cytokines measured by immunoassays.
Results    Compared to NGT, T1DM subjects (both with and without MVC) had significantly higher levels of LPS, reduced levels of LBP and EndoCAb along with significant increase in the levels of IL-1β, IL-6, TNF-α and GM-CSF (p<0.05). No significant change was seen in the levels of these biomarkers between T1DM subjects with and without MVC.
Conclusions   Decreased levels of EndoCAb and LBP suggest sustained endotoxin activity in T1DM subjects even before the onset of microvascular complications.

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statins – effect on LPS signalling

41) Patel, Tushar R., and Siobhan A. Corbett. “Simvastatin suppresses LPS-induced Akt phosphorylation in the human monocyte cell line THP-1.” Journal of Surgical Research 116.1 (2004): 116-120.Simvastatin suppresses LPS-induced Akt phosphorylation in monocyte cell line Patel J Surg Res 2004

BACKGROUND:  Activation of the small GTPase, Rac, requires post-translational modification by isoprenylation. Statins interfere with this process by blocking the synthesis of isoprenoid intermediates. The protein kinase Akt is a multifunctional regulator of cell behavior that has been linked to Rac activation. We have shown that lipopolysaccharide (LPS) stimulation leads to Rac activation in THP-1 cells. Therefore, we hypothesized that LPS stimulation would also activate Akt, a downstream effector of Rac, and that this may be blocked by statin pretreatment.
MATERIALS AND METHODS:  THP-1 cells were maintained in 1% fetal calf serum with or without 20 microM simvastatin for 24 h, followed by LPS stimulation for increasing time. Cytoskeletal changes were observed using Alexa-Phalloidin. Akt was immunoprecipitated from total cell lysate. Activated Akt was detected by immunoblotting with a phospho-Akt antibody and was quantified by image densitometry.
RESULTS:  LPS stimulation of THP-1 cells results in membrane ruffling and cell polarization. Furthermore, LPS increased Akt activation in THP-1 cells when compared with the nonstimulated controls. Akt phosphorylation peaked after 15 min of LPS stimulation and was suppressed by pretreatment with simvastatin.
CONCLUSIONS:  These data demonstrate that LPS stimulation leads to increased Akt phosphorylation, which can be suppressed with simvastatin pretreatment. This suggests one possible mechanism through which simvastatin could modulate LPS-induced signaling events in monocytes to improve the host response to Gram-negative infections.

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Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.

42) Devaraj, Sridevi, Emily Chan, and Ishwarlal Jialal. “Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome.” The Journal of Clinical Endocrinology & Metabolism 91.11 (2006): 4489-4496.

Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS.
OBJECTIVE:  We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects.
DESIGN AND PATIENTS:  We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center.
PARTICIPANTS: Participants were subjects with MS.
INTERVENTION: imvastatin (40 mg/d) or placebo was administered for 8 wk.
METHODS AND RESULTS: The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-kappaB and increased Akt activity in MS subjects compared with placebo. T
o gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-kappaB activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation.
CONCLUSIONS:  Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.

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In Vitro Endothelial Cells Statins Inhibit NFKB

43) Hölschermann H1, Schuster D, Parviz B, Haberbosch W, Tillmanns H, Muth H.Atherosclerosis. 2006 Apr;185(2):240-5. Epub 2005 Jul 26.
Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells.
Statins have been linked to a wide range of vascular benefits, many of them are likely to be due to attenuation of chronic vascular inflammation. Nuclear factor kappaB (NF-kappaB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. Therefore, we investigated the effect of statins on TNF-alpha-induced NF-kappaB signaling in human endothelial cells (EC). ECs were pre-incubated for 16 h with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20 ng/ml TNF-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.

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45) Chaudhry, Mohammad Z., et al. “Statin (cerivastatin) protects mice against sepsis-related death via reduced proinflammatory cytokines and enhanced bacterial clearance.” Surgical infections 9.2 (2008): 183-194.

Death attributable to septic shock syndrome depends highly on the inflammatory response and cytokine production. Inhibition of inflammation is one of the many pleiotropic effects of statins. The aim of this study was to test the hypothesis that statins have a role in altering the host response to bacterial infections and thus would prove beneficial in the prevention of microbial sepsis.
METHODS:Male C57BL/6 and C3H/HeN mice received cerivastatin (4 mg/kg) or phosphate-buffered saline (PBS) intraperitoneally (i.p.), 24 and 1 h before and 24, 48, and 72 h after bacterial challenges. Sepsis was induced by i.p. injection of lipopolysaccharide (LPS) (45 mg/kg), Staphylococcus aureus (5 x 10(7) colony-forming units [CFU]/mouse), or Salmonella typhimurium (2.5 x 10(6) CFU/mouse).
RESULTS:Administration of cerivastatin improved significantly the survival rate of mice challenged with LPS (31% vs. 19% in the PBS group; p = 0.001), S. aureus (56% vs. 20% in PBS group; p = 0.01), or S. typhimurium (48% vs. 10% in PBS group; p = 0.03). Significantly reduced release of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 was evident in cerivastatin-treated mice after LPS challenge. Cerivastatin-treated mice showed insignificant reductions in serum TNF-alpha and IL-6 concentrations after bacterial challenge. However, significantly accelerated bacterial clearance was demonstrated in cerivastatin-treated mice 24 h after S. typhimurium infection and 48 h after S. aureus infection.
CONCLUSIONS:Cerivastatin protects mice against LPS- and live bacteria-induced death, an effect associated with cerivastatin-attenuated pro-inflammatory cytokine production and enhanced bacterial clearance. Hence, application of statins in the clinical setting may prove beneficial in prevention of LPS or bacterial infection-related sepsis.

Statins as Antimicrobials

46) Masadeh, Majed, et al. Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin Annals of clinical microbiology and antimicrobials 11.1 (2012): 13.

Statins have several effects beyond their well-known antihyperlipidemic activity, which include immunomodulatory, antioxidative and anticoagulant effects. In this study, we have tested the possible antimicrobial activity of statins against a range of standard bacterial strains and bacterial clinical isolates.
Methods  Minimum inhibitory concentrations (MIC) values were evaluated and compared among three members of the statins drug (atorvastatin, simvastatin, and rosuvastatin).
Results  It was revealed that statins are able to induce variable degrees of antibacterial activity with atorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE), acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, were more sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the other hand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive to atorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinical isolates were less sensitive to statins compared to their corresponding standard strains.
Conclusion  Our findings might raise the possibility of a potentially important antibacterial class effect for statins especially, atorvastatin and simvastatin.

Statins Antimicrobial effect Pseudomonas

47) Graziano, Talita Signoreti, et al. “Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.” PloS one 10.5 (2015): e0128098.

48) Emani, Shilpa, Gayathri V. Gunjiganur, and Dhoom Singh Mehta. “Determination of the antibacterial activity of simvastatin against periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans: An in vitro study.” Contemporary clinical dentistry 5.3 (2014): 377.

Conclusions:Data suggests a potent antimicrobial activity of simvastatin against both A. actinomycetemcomitans and P gingivalis. Hence simvastatin can be prescribed as a dual action drug in patients with both hyperlipidemia and periodontal disease.

49) Al-Kuraishy, Hayder M., Ali I. Al-Gareeb, and Ali K. Al-Buhadily. “Rosuvastatin as forthcoming antibiotic or as adjuvant additive agent: In vitro novel antibacterial study.” Journal of laboratory physicians 10.3 (2018): 271.

Rosuvastatin is a lipid-lowering agent that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase leading to a reduction of cholesterol biosynthesis. Many studies have shown an association between statins use and the reduction of sepsis. The aim of the present study was to evaluate the in vitro combined antibacterial activity of rosuvastatin and cefixime.
MATERIALS AND METHODS:  Five pathogenic bacteria isolates (Gram positive and Gram negative) were used for testing the antibacterial activity of rosuvastatin alone and in combination with cefixime.
RESULTS:  Rosuvastatin mainly inhibited Klebsiella pneumoniae and Escherichia coli where it caused zones of inhibition of (17.9 ± 0.6 mm) and (16.9 ± 0.3 mm), respectively; however, it moderately inhibited the growth of Staphylococcus epidermidis (12.9 ± 0.2 mm) and Staphylococcus aureus (12.76 ± 0.2) and produced less inhibition for Pseudomonas aeruginosa growth where it led to a zone of inhibition equal to (9.1 ± 0.5 mm). Minimal inhibitory concentration (μg/mL) of rosuvastatin was high compared to cefixime. Fractional inhibitory concentration (FIC) of rosuvastatin was low for E. coli and K. pneumoniae compared to the other types of bacterial strains. Rosuvastatin exhibited additive effects with cefixime against E. coli and K. pneumoniae. ΣFIC index was 0.536 and 0.734 for E. coli and K. pneumoniae, respectively.
CONCLUSION:  Rosuvastatin has a significant antibacterial activity against both Gram-negative and Gram-positive bacteria with a potential additive effect when used in combination with cefixime.

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CAT SCAN cat ANGIO

50) Finck T1, Hardenberg J1, Will A1, Hendrich E1, Haller B2, Martinoff S1, Hausleiter J3, Hadamitzky M4.JACC Cardiovasc Imaging. 2018 Oct 12.
Ten-Year Follow-Up After Coronary Computed Tomography Angiography in Patients With Suspected Coronary Artery Disease.

The aim of this study was to determine the long-term prognostic power of coronary computed tomography angiography (CTA) to predict cardiac death and nonfatal myocardial infarction.
BACKGROUND:Prognostic usefulness of coronary CTA has been confirmed for short- and intermediate-term follow-up. However, long-term data for prognostic usefulness is still lacking, but is paramount because of the slowly progressing nature of coronary artery disease (CAD).
METHODS:A total of 2,011 patients with suspected but not previously diagnosed CAD were examined by coronary CTA. Mean follow-up was 10.0 years (interquartile range [IQR]: 8.1 to 11.2 years). Cox proportional hazards analysis was used for the composite endpoint of cardiac death and nonfatal myocardial infarction. Event-free survival, which was defined as the years it took to reach a cumulative 1% risk for the composite endpoint and reclassification from clinical risk, was calculated.
RESULTS:The study endpoint was reached in 58 patients (42 cardiac deaths, 16 nonfatal myocardial infarctions). Coronary CTA-assessed CAD severity (normal, nonobstructive, or obstructive) showed the best correlation with the endpoint, with an adjusted c-index of 0.704, compared with a univariate c-index of 0.622 for the clinical risk model (Morise score) alone. The annual event rate for patients with normal coronary arteries on baseline coronary CTA was 0.04%, which translated to an event-free survival period of 10 years. The highest annual event rate of 1.33% was found in patients with 3-vessel obstructive CAD. Reclassification from clinical risk (Morise score) was possible in approximately two-thirds of all patients (68%; p < 0.0001), which led to a substantial reduction of the intermediate-risk group (reduction from 74% to 15%) in favor of the low-risk group (increase from 20% to 83%).
CONCLUSIONS: Patients with normal coronary CTA results benefitted from an event-free survival period of 10 years against cardiac death and nonfatal myocardial infarction. Risk stratification according to coronary CTA results allowed for the delineation of clearly diverging prognostic groups and reclassified approximately two-thirds of all patients from clinical risk groups.

 

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free pdf  nice illustration

Hennessy Emma Is there potential for repurposing statins as novel antimicrobials Antimicrobial agents and chemotherapy F2
FIG 2 Statins modulate bacterial growth and virulence. (A) In vitro effects of statins on bacterial species. Statins reduce in vitro bacterial growth, motility, and attachment. (B) Key antivirulence mechanisms of statins. At physiological concentrations, statin treatment can reduce bacterial invasion and translocation in addition to inhibiting lipid raft production. The inhibition of Rho GTPase activity and cholesterol production by statins contributes to reduced bacterial virulence, decreased toxicity, and impaired intracellular survival. (C) At physiological concentrations, statin treatment can reduce bacterial load and dissemination and increase bacterial clearance in mouse models of infection

https://aac.asm.org/content/aac/60/9/5111.full.pdffull pdf44)

53) Hennessy, Emma, et al. “Is there potential for repurposing statins as novel antimicrobials?.” Antimicrobial agents and chemotherapy 60.9 (2016): 5111-5121. Repurposing statins as novel antimicrobials Hennessy Emma Antimicrobial Agents 2016

It has previously been demonstrated that statins improved survival in patients who had sepsis and pneumonia

The anti-inflammatory and immunomodulatory effects of statins are mediated through the alteration of expression of transcription factors such as NFκB

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illustration of plates (already saved) statins inhibit pseudomonas

54) Hennessy, Emma, et al. “Statins inhibit in vitro virulence phenotypes of Pseudomonas aeruginosa.” The Journal of antibiotics 66.2 (2013): 99.

Motility and biofilm formation are crucial bacterial virulence factors linked to the establishment of chronic infections and are associated with successful colonization of the lungs of CF patients.16 As well as attenuating these traits, statins have also been shown to lower the levels of P. aeruginosa-induced pro-inflammatory cytokines, such as IL-817 and TNFα,18 in the host and to reduce mucin production in vivo.18 Therefore, the efficacy of using statins in the treatment of chronic P. aeruginosa infection may warrant further investigation.

Statins also have a range of cholesterol-independent effects, including anti-inflammatory functions and antimicrobial activity. These pleiotropic effects are thought to account for the improved survival observed in statin-treated patients suffering from severe bacterial infections, such as sepsis and pneumonia

These studies suggest that statins have bacteriostatic effects on the in vitro growth of clinically important bacterial species, including Staphylococcus aureus and Enterococci,5 Streptococcus pneumoniae and Moraxella catarrhalis,6 and Escherichia coli and Pseudomonas aeruginosa.7 However, the concentrations used in these in vitro studies exceed the concentration detected in human serum during statin therapy,6 suggesting the in vitro bacteriostatic effects of statins are not likely to account for the beneficial outcome of patients suffering from severe bacterial infections.

Statins modulate swarming motility of P. aeruginosa. Strains were cultured on 0.6% (w/v) Eiken agar in the presence of 100 μM SIM, LOV and MEV or an equivalent vehicle control. Statins attenuated swarming motility of (a) the model strains PAO1 and PA14, and (b) the clinical isolates CF194 (CF) and TY5010 (non-CF).

55) Statin (cerivastatin) protects mice against sepsis-related death via reduced proinflammatory cytokines and enhanced bacterial clearance.Chaudhry MZ1, Wang JH, Blankson S, Redmond HP.  Surg Infect (Larchmt). 2008 Apr;9(2):183-94.

Death attributable to septic shock syndrome depends highly on the inflammatory response and cytokine production. Inhibition of inflammation is one of the many pleiotropic effects of statins. The aim of this study was to test the hypothesis that statins have a role in altering the host response to bacterial infections and thus would prove beneficial in the prevention of microbial sepsis.
METHODS:Male C57BL/6 and C3H/HeN mice received cerivastatin (4 mg/kg) or phosphate-buffered saline (PBS) intraperitoneally (i.p.), 24 and 1 h before and 24, 48, and 72 h after bacterial challenges. Sepsis was induced by i.p. injection of lipopolysaccharide (LPS) (45 mg/kg), Staphylococcus aureus (5 x 10(7) colony-forming units [CFU]/mouse), or Salmonella typhimurium (2.5 x 10(6) CFU/mouse).
RESULTS:Administration of cerivastatin improved significantly the survival rate of mice challenged with LPS (31% vs. 19% in the PBS group; p = 0.001), S. aureus (56% vs. 20% in PBS group; p = 0.01), or S. typhimurium (48% vs. 10% in PBS group; p = 0.03). Significantly reduced release of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 was evident in cerivastatin-treated mice after LPS challenge. Cerivastatin-treated mice showed insignificant reductions in serum TNF-alpha and IL-6 concentrations after bacterial challenge. However, significantly accelerated bacterial clearance was demonstrated in cerivastatin-treated mice 24 h after S. typhimurium infection and 48 h after S. aureus infection.
CONCLUSIONS:Cerivastatin protects mice against LPS- and live bacteria-induced death, an effect associated with cerivastatin-attenuated pro-inflammatory cytokine production and enhanced bacterial clearance. Hence, application of statins in the clinical setting may prove beneficial in prevention of LPS or bacterial infection-related sepsis.

56) Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin  Majed Masadeh,corresponding author1 Nizar Mhaidat,1 Karem Alzoubi,1 Sayer Al-azzam,1 and Ziad Alnasser2  Ann Clin Microbiol Antimicrob. 2012; 11: 13.
Statins have several effects beyond their well-known antihyperlipidemic activity, which include immunomodulatory, antioxidative and anticoagulant effects. In this study, we have tested the possible antimicrobial activity of statins against a range of standard bacterial strains and bacterial clinical isolates.

Minimum inhibitory concentrations (MIC) values were evaluated and compared among three members of the statins drug (atorvastatin, simvastatin, and rosuvastatin).
Results  It was revealed that statins are able to induce variable degrees of antibacterial activity with atorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE), acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, were more sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the other hand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive to atorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinical isolates were less sensitive to statins compared to their corresponding standard strains.
Conclusion  Our findings might raise the possibility of a potentially important antibacterial class effect for statins especially, atorvastatin and simvastatin.

57) Graziano, Talita Signoreti, et al. “Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.” PloS one 10.5 (2015): e0128098.

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Leaky Gut Zonulin CAD vs Non-CAD 16s Ribosome Seqencing

intestinal bacteria in plaques may original from the intestine.

59) Li, Chuanwei, et al. “Zonulin regulates intestinal permeability and facilitates enteric bacteria permeation in coronary artery disease.” Scientific reports 6 (2016): 29142.

The detection of intestinal bacterial by 16S rRNA gene amplification in both the blood sample and atherosclerotic plaques supports the notion that intestinal bacteria in plaques may original from the intestine.

Given the fact that zonulin is significantly elevated in atherosclerosis and increase intestinal IP, it’s possible that targeting zonulin using monoclonal antibody or inhibitors maybe a provocatively new way to move forward in CAD prevention and treatment.

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4D Study 2005 Wanner NEJM Diabetics on Hemodialysis

“routine treatment with a statin to reduce the primary composite end point of death from cardiac causes, myocardial infarction,and stroke is not warranted.”

60) Wanner, Christoph, et al. “Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.” New England Journal of Medicine 353.3 (2005): 238-248. 4D Atorvastatin in type 2 diabetes mellitus on hemodialysis Wanner Christoph New Eng J Med 2005

Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus. However, the benefit of statins in such patients receiving hemodialysis, who are at high risk for cardiovascular disease and death, has not been examined.
METHODS: We conducted a multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomly assigned to receive 20 mg of atorvastatin per day or matching placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Secondary end points included death from all causes and all cardiac and cerebrovascular events combined.
RESULTS:  After four weeks of treatment, the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin, and among those receiving placebo it was reduced by 1.3 percent. During a median follow-up period of four years, 469 patients (37 percent) reached the primary end point, of whom 226 were assigned to atorvastatin and 243 to placebo (relative risk, 0.92; 95 percent confidence interval, 0.77 to 1.10; P=0.37). Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33).
CONCLUSIONS:  Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.

We conclude that in persons with type 2 diabetes mellitus who are receiving maintenance hemodialysis and have LDL cholesterol values between 80 and 190 mg per deciliter, routine treatment with a statin to reduce the primary composite end point of death from cardiac causes, myocardial infarction,and stroke is not warranted. The initiation of lipid-lowering therapy in patients with type 2 diabetes mellitus who already have end-stage renal disease may come too late to translate into consistent improvement of the cardiovascular outcome

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Type 2 diabetes mellitus, long-term Fenofibrate therapy on coronary heart disease

61) FIELD Study Investigators. “Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.” The Lancet 366.9500 (2005): 1849-1861.

In patients with type 2 diabetes mellitus, what is the effect of long-term fenofibrate therapy on coronary heart disease (CHD) events?
Methods Design: Randomized placebo-controlled trial (Fenofibrate Intervention and Event Lowering in Diabetes [FIELD]).
Blinding: Blinded clinicians, patients, and outcome assessors).*
Follow-up period: Median 5 years.
Setting: 63 centers in Australia, New Zealand, and Finland.
Patients: 9795 patients 50 to 75 years of age (mean age 62 y, 63% men) who had a World Health Organization diagnosis of type 2 diabetes, total cholesterol level 3 to 6.5 mmol/L, and a total cholesterol/high-density lipoprotein (HDL) cholesterol ratio ≥ 4 or a triglyceride level of 1 to 5 mmol/L, with no clear indication for lipid-modifying therapy. Exclusion criteria were renal impairment, chronic liver disease, symptomatic gallbladder disease, or occurrence of a cardiovascular disease (CVD) event within 3 months before study entry.
Intervention: Micronized fenofibrate, 200 mg/d (n = 4895), or matching placebo (n = 4900).
Outcomes: A composite endpoint of nonfatal myocardial infarction (MI) or CHD mortality. Secondary outcomes included a composite endpoint of major CVD events (CHD events, CVD death, and stroke), total CVD events (major CVD events, and revascularization), individual events of the composite endpoint, and all-cause mortality. The study had 80% power to detect a 22% reduction in the primary outcome.

Patient follow-up: 99% (intention-to-treat analysis).
Main results Groups did not differ for the primary outcome of nonfatal MI or CHD mortality (Table). Patients who received fenofibrate had a lower incidence of total CVD events than did patients who received placebo, mainly because of a reduction in nonfatal MI and revascularization (Table). The groups did not differ for CHD death or other secondary outcomes.

Conclusion In patients with type 2 diabetes mellitus, long-term fenofibrate therapy did not reduce major coronary events but may reduce total cardiovascular disease events.

In the FIELD study by Keech and colleagues, it is disappointing that fenofibrate did not reduce fatal MI or CHD mortality in patients with type 2 diabetes mellitus.

Such patients have greater numbers of small, dense, atherogenic particles than patients without diabetes, even with similar low-density lipoprotein (LDL) cholesterol levels. They also tend to have lower HDL cholesterol and higher triglyceride levels, 3- to 4-fold higher rates of CHD, and higher mortality associated with acute MI. Fibrates have shown beneficial effects on this pattern of lipid abnormalities. Weak evidence from post hoc analyses in the Helsinki Heart Study (1), Veterans Affairs HDL intervention trial (2), and the Bezafibrate Infarction Prevention trial (3) showed reductions in coronary events in patients receiving fibrates. The FIELD study is the first large clinical-endpoint trial of fibrate therapy in patients with diabetes.

Fenofibrate-group patients had reductions in LDL cholesterol, triglyceride, and HDL cholesterol levels. Beneficial secondary outcomes were a 25% relative risk reduction in nonfatal MI, 21% relative reduction in coronary revascularization, reduced rate of progression to albuminuria, and fewer laser treatments for retinopathy. Treatment effects appeared to be greater in patients with no previous CVD (the primary prevention group) and in those < 65 years of age, although chance variation could explain these subgroup findings.

Matthew McQueen, MD Hamilton Health Sciences Hamilton, Ontario, Canada

Fibrates for DM – no reduction in CV events

62) Naeem, Fariha, Gerard McKay, and Miles Fisher. “Cardiovascular outcomes trials with non-statin lipid-lowering drugs in diabetes.” British Journal of Diabetes 18.3 (2018): 101-105.Cardiovascular outcomes trials with statins in diabetes Naeem British J Diabetes 2018

In two dedicated studies in people with diabetes, fibrates did not significantly reduce cardiovascular events and were associated with serious side effects.

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Evacetrapib

63) CETP Inhibitor Evacetrapib’s Disappointments Extend to Diabetics Too-Cleveland Clinic

Despite significant and sustained elevations in HDL and reductions in LDL cholesterol levels, the CETP inhibitor evacetrapib failed to reduce cardiovascular events among the subgroup of 8,236 ACCELERATE trial enrollees with diabetes mellitus (DM) at baseline.

So concludes a substudy of the large multicenter ACCELERATE trial presented at the European Society of Cardiology (ESC) Congress 2017 in Barcelona on Aug. 28. The substudy results mirror findings of the primary ACCELERATE analysis, which was published in the New England Journal of Medicine this past May. The primary analysis showed that evacetrapib failed to reduce cardiovascular events relative to placebo in the overall study population — consisting of patients at high risk for cardiovascular events — despite raising HDL cholesterol levels 133 percent from baseline and reducing LDL cholesterol levels 31 percent from baseline.

“We were unpleasantly surprised,” says Cleveland Clinic cardiologist Venu Menon, MD, who presented the findings in the diabetic subset at the ESC Congress. “All genetic and epidemiological data suggested that raising HDL would reduce cardiovascular risk in this vulnerable population. The high prevalence of low HDL levels in the setting of diabetic dyslipidemia gave investigators the additional hope that the diabetic population would especially benefit from potent CETP inhibition.”

Dr. Menon is Associate Director of the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which has overseen the 543-site, 36-nation ACCELERATE trial.

ACCELERATE substudy shows no benefit of evacetrapib in patients with diabetes

64) Menon, V., et al. “3911Impact of CETP inhibition with evacetrapib in patients with diabetes mellitus: results from ACCELERATE.” European Heart Journal 38.suppl_1 (2017).

Conclusions: The presence of DM is associated with significantly higher CV event rates despite statin treatment. Favorable lipid modification with Eva did not translate into any observed clinical benefit. There is no role for additive CETP inhibition with Eva in high risk patients with DM.

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CAC Progression in DM  – progression of coronary artery calcification in type 2 diabetes  in asymptomatic type 2 diabetic subjects without prior cardiovascular disease

We found that statin therapy failed to inhibit the progression of CAC. On the contrary, statin-treated patients had a greater degree of progression.

65) Anand, Dhakshinamurthy Vijay, et al. “Determinants of progression of coronary artery calcification in type 2 diabetes: role of glycemic control and inflammatory/vascular calcification markers.” Journal of the American College of Cardiology 50.23 (2007): 2218-2225. Progression of coronary artery calcification in type 2 diabetes glycemic control inflammatory markers Anand Vijay J Amer Col Card 2007

Type 2 diabetes is associated with accelerated atherosclerosis and considered to be a coronary heart disease (CHD) equivalent (5).

We found that statin therapy failed to inhibit the progression of CAC. On the contrary, statin-treated patients had a greater degree of progression.

Three hundred ninety-eight type 2 diabetic subjects without prior coronary disease or symptoms (age 52 +/- 8 years, 61% male, glycated hemoglobin [HbA(1)c] 8 +/- 1.5) were evaluated serially by CAC imaging (mean follow-up 2.5 +/- 0.4 years). Progression/regression of CAC was defined as a change > or =2.5 between the square root transformed values of baseline and follow-up volumetric CAC scores. Demographic data, risk factors, glycemic control, medication use, serum hs-CRP, IL-6, and plasma OPG levels were measured at baseline and follow-up.

RESULTS:

Two hundred eleven patients (53%) had CAC at baseline. One hundred eighteen patients (29.6%) had CAC progression, whereas 3 patients (0.8%) had regression. Age, male gender, hypertension, baseline CAC, HbA(1)c >7, waist-hip ratio, IL-6, OPG, use of beta-blockers, calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, statins, and Framingham/UKPDS (United Kingdom Prospective Diabetes Study) risk scores were univariable predictors of CAC progression. In the multivariate model, baseline CAC (odds ratio [OR] for CAC >400 = 6.38, 95% confidence interval [CI] 2.63 to 15.5, p < 0.001), HbA(1)c >7 (OR 1.95, CI 1.08 to 3.52, p = 0.03), and statin use (OR 2.27, CI 1.38 to 3.73, p = 0.001) were independent predictors of CAC progression.

CONCLUSIONS:

Baseline CAC severity and suboptimal glycemic control are strong risk factors for CAC progression in type 2 diabetic subjects.

“We found that statin therapy failed to inhibit the progression of CAC. On the contrary, statin-treated patients had a greater degree of progression. “

Statin-treated patients in the MESA had a greater progression of coronary calcium, a finding similar to ours.

we provide the first prospective report of the progression of CAC specifically in type 2 diabetic subjects without prior CHD or symptoms at baseline

Despite achieving lower lipid levels at follow-up, statin-treated patients had a greater degree of CAC progression (% of patients with progression 38% [n 85],absolute CAC score change/year 25 [SD: 55] mm3) in comparison with untreated patients (% of patients with progression 19% [n33], absolute CAC change/year 6 [SD: 23] mm3).

In the final multivariate analysis, baseline CAC (OR for CAC 400 mm 3 6.38, 95% CI 2.63 to 15.5,p0.001), HbA1c 7 (OR 1.95, 95% CI 1.08 to 3.52, p0.03), and statin use (OR 2.27, 95% CI 1.38 to 3.73, p 0.001) were independent predictors of CAC progression Fig. 3)

Neither hs-CRP nor IL-6 were predictive of prevalent CAC (baseline CAC score). In contrast,
plasma OPG was a powerful predictor of prevalent CAC (OR 3.08, 95% CI 2.42 to 3.92, p0.001)

OBJECTIVES: This study prospectively evaluated the relationship between cardiovascular risk factors, selected biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, and osteoprotegerin [OPG]), and the progression of coronary artery calcification (CAC) in type 2 diabetic subjects.

BACKGROUND: Coronary artery calcification is pathognomonic of coronary atherosclerosis. Osteoprotegerin is a signaling molecule involved in bone remodeling that has been implicated in the regulation of vascular calcification and atherogenesis.

METHODS: Three hundred ninety-eight type 2 diabetic subjects without prior coronary disease or symptoms (age 52 +/- 8 years, 61% male, glycated hemoglobin [HbA(1)c] 8 +/- 1.5) were evaluated serially by CAC imaging (mean follow-up 2.5 +/- 0.4 years). Progression/regression of CAC was defined as a change > or =2.5 between the square root transformed values of baseline and follow-up volumetric CAC scores. Demographic data, risk factors, glycemic control, medication use, serum hs-CRP, IL-6, and plasma OPG levels were measured at baseline and follow-up.

RESULTS: Two hundred eleven patients (53%) had CAC at baseline. One hundred eighteen patients (29.6%) had CAC progression, whereas 3 patients (0.8%) had regression. Age, male gender, hypertension, baseline CAC, HbA(1)c >7, waist-hip ratio, IL-6, OPG, use of beta-blockers, calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, statins, and Framingham/UKPDS (United Kingdom Prospective Diabetes Study) risk scores were univariable predictors of CAC progression. In the multivariate model, baseline CAC (odds ratio [OR] for CAC >400 = 6.38, 95% confidence interval [CI] 2.63 to 15.5, p < 0.001), HbA(1)c >7 (OR 1.95, CI 1.08 to 3.52, p = 0.03), and statin use (OR 2.27, CI 1.38 to 3.73, p = 0.001) were independent predictors of CAC progression.

CONCLUSIONS: Baseline CAC severity and suboptimal glycemic control are strong risk factors for CAC progression in type 2 diabetic subjects.

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Statin therapy induced a 50% reduction in the rate of CAC progression in Asymptomatic Diabetics.

66) Budoff, M. J., et al. “Diabetes and progression of coronary calcium under the influence of statin therapy.” American heart journal 149.4 (2005): 695.

We sought to evaluate the progression of atherosclerosis in asymptomatic persons with type 2 diabetes and measure the influence of statin therapy on CAC progression.
Methods  We evaluated 163 asymptomatic patients with type 2 diabetes (120 men, 43 women). Patients were physician referred and underwent 2 consecutive EBT scans at least 1 year apart. Demographic data, risk factors for CHD, and medication use were collected. Patients with symptoms or known CHD were excluded.
Results   The mean age was 65 ± 10 years. The mean CAC score at baseline was 651 ± 414. Only 9 (6%) of 163 of participants had scores of 0 at baseline. The time between scans averaged 27 ± 15 months. Patients not treated with statins demonstrated a median annual increase in CAC progression of 20% (4%-44%), whereas statin-treated patients demonstrated increase of 10% (4%-25%) (P = .0001). Hemoglobin A1c was weakly associated with CAC progression.
Conclusions:  Asymptomatic diabetic patients show a high prevalence of atherosclerosis based on high frequency of coronary calcification. Statin therapy induced a 50% reduction in the rate of CAC progression. As rapid CAC progression has been associated with coronary events, EBT may serve as a noninvasive method for following atherosclerosis and response to therapy.

Insulin Resistance Predicts Progression of CAC

67) Am Heart J. 2009 May;157(5):939-45. Insulin resistance independently predicts the progression of coronary artery calcification. Lee KK1, Fortmann SP, Fair JM, Iribarren C, Rubin GD, Varady A, Go AS, Quertermous T, Hlatky MA.

Change in coronary artery calcification is a surrogate marker of subclinical coronary artery disease (CAD). In the only large prospective study, CAD risk factors predicted progression of coronary artery calcium (CAC).

METHODS:We measured CAC at enrollment and after 24 months in a community-based sample of 869 healthy adults aged 60 to 72 years who were free of clinical CAD. We assessed predictors of the progression of CAC using univariate and multivariate models after square root transformation of the Agatston scores. Predictors tested included age, sex, race/ethnicity, smoking status, body mass index, family history of CAD, C-reactive protein and several measures of diabetes, insulin levels, blood pressure, and lipids.
RESULTS:The mean age of the cohort was 66 years, and 62% were male. The median CAC at entry was 38.6 Agatston units and increased to 53.3 Agatston units over 24 months (P < .01). The CAC progression was associated with white race, diabetes, dyslipidemia, hypertension, lower diastolic blood pressure, and higher pulse pressure. After controlling for these variables, higher fasting insulin levels independently predicted CAC progression.
CONCLUSIONS:Insulin resistance, in addition to the traditional cardiac risk factors, independently predicts progression of CAC in a community-based population without clinical CAD.

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Randomized trials of Statins in Diabetes 20-30% reduction in Mortality

Statins in Diabetics Review Article All Trials 2018

68) Naeem, Fariha, Gerard McKay, and Miles Fisher. “Cardiovascular outcomes trials with statins in diabetes.” British Journal of Diabetes 18.1 (2018): 7-13.Cardiovascular outcomes trials with statins in diabetes Naeem British J Diabetes 2018

Treatment with statins is one of the most effective ways of reducing cardiovascular events in those with diabetes. Many studies containing thousands of subjects with diabetes have demonstrated that statins reduce cardiovascular events when there is no known cardiovascular disease (primary prevention) and in those with confirmed atherosclerotic disease (secondary prevention). High-dose statins appear to be even more effective in established cardiovascular disease, but at the expense of increased drug side effects.

Diabetics on Hemodialysis- No Benefit for Statins

The 4D study is worthy of mention, however, as it included only patients with T2DM on maintenance haemodialysis.21 Most of the patients in the 4D study had some form of vascular disease at baseline. No benefit on major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke) was found comparing atorvastatin 20 mg to placebo over the 4 years of the study. The authors postulated that initiating lipid-lowering therapy in this group of patients might be too late to observe beneficial effects. They also suggested that the pathogenesis of vascular
events might be different in people with T2DM and nephropathy compared to people with T2DM and no renal complications. Additional factors in patients with renal failure such as sympathetic overactivity, left ventricular hypertrophy and cardiac fibrosis may
contribute to CVD rather than the more traditional factors leading to atherosclerotic disease. A recent post-hoc analysis followed subjects up for a median of 11.5 years, and although MACE was not reduced, the risk of all cardiac events combined and the risk of
cardiovascular death was significantly lower in the original atorvastatin group compared with the placebo group.22

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Statins reduced mortality 27% in Diabetics without high cholesterol Primary Prevention

69) Colhoun, Helen M., et al. “Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.” The Lancet 364.9435 (2004): 685-696. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes CARDS Colhoun Helen Lancet 2004

Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol.
METHODS:  2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat.
FINDINGS:  The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7).

127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001).

Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group.
INTERPRETATION:  Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.

70) COLLINS, R. “MRC BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people wirh diabetes: a randomised placebo-controlled trial.” Lancet 361 (2003): 2005-2016.

Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk.
METHODS:  5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period.
FINDINGS: Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period.
INTERPRETATION:  The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.

HgbA1C  risk factor for CAD and all cause mortality

71) Cavero-Redondo, Iván, et al. “Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis.” BMJ open 7.7 (2017): e015949.

Leaky Gut – Endotoxemia

72)  Fukui, H. ” Endotoxin and Other Microbial Translocation Markers in the Blood: A Clue to Understand Leaky Gut SyndromeCell Mol Med 2 (2016): 3.  Endotoxin and microbial translocation markers in blood leaky gut syndrome Fukui Cell Mol Med 2016

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bacteria colonize Aortic Aneurysms

A wide variety of bacteria, including oral bacteria, was found to colonize aortic aneurysms and may play a role in their development.

73) da Silva, Rafael Marques, et al. “Bacterial diversity in aortic aneurysms determined by 16S ribosomal RNA gene analysis.Journal of vascular surgery 44.5 (2006): 1055-1060.

A wide variety of bacteria, including oral bacteria, was found to colonize aortic aneurysms and may play a role in their development.
Aortic aneurysms are common vascular conditions that cause considerable morbidity and mortality. Understanding of the mechanisms involved in the pathogenesis of the condition remains limited. Recently, infection has been suggested as possible contributor in the development of the disease. The aim of the present study was to examine aortic aneurysms for the presence of bacterial DNA using polymerase chain reaction (PCR) targeting the 16S ribosomal RNA (rRNA) gene, followed by cloning and sequencing.

METHODS:Universal eubacterial primers were used to amplify 16S rRNA bacterial genes in 10 specimens from arterial walls of aortic aneurysms. Subsequently, PCR amplicons were cloned into Escherichia coli and sequencing of the cloned inserts was used to determine species identity or closest relatives by comparison with known sequences in GenBank.
RESULTS:Sequences of Stenotrophomonas spp., including S. maltophilia (formerly Pseudomonas homology group V) were detected in six aneurysm samples. Propionibacterium acnes was identified in five samples, and Brevundimonas diminuta (formerly P. diminuta) in four samples. Other species previously assigned to the Pseudomonas genus such as Comamonas testosteroni, Delftia acidovorans, Burkholderia cepacia, Herbaspirillum sp., and Acidovorax sp. were also detected. Some clones fell into other environmental species, including Methylobacterium sp. and Bradyrhizobium elkanii, and others represented bacteria that have not yet been cultivated. DNA sequences from oral bacteria, including Streptococcus sanguinis, Tannerella forsythia, and Leptotrichia buccalis were detected. Sequences from Prevotella melaninogenica and Lactobacillus delbrueckii, which are commonly found in both mouth and gastrointestinal tract, were also detected. Additional species included Dermacoccus spp. and Corynebacterium vitaeruminis.
CONCLUSIONS:A wide variety of bacteria, including oral bacteria, was found to colonize aortic aneurysms and may play a role in their development. Several of these microorganisms have not yet been cultivated.
CLINICAL RELEVANCE:Although Chlamydophila pneumoniae has been detected in aneurysmal walls, its exact role in the condition remains inconclusive. Overall, there is scarce information about the role of microorganisms in aneurysmal disease. In the present study, we used molecular genetics to detect a diversity of bacteria in arterial walls of aortic aneurysms. The presence of multiple microorganisms in aneurysmal disease may have implications for chemoprophylaxis and antibiotic treatment if directed only at C.pneumoniae.

74) Armingohar, Zahra, et al. “Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis.” Journal of oral microbiology 6.1 (2014): 23408.

75) Renko, Jaana, et al. “Bacterial signatures in atherosclerotic lesions represent human commensals and pathogens.” Atherosclerosis 201.1 (2008): 192-197.we defined bacterial DNA signatures in surgically removed sterile abdominal aorta samples of patients with aortic atherosclerosis.

76) Renko, Jaana, et al. “Bacterial DNA signatures in carotid atherosclerosis represent both commensals and pathogens of skin origin.” European Journal of Dermatology 23.1 (2013): 53-58.nearly all (94%) of the sequences were associated with the human skin microbiome.

77) Curran, Samuel A., et al. “Bacteria in the adventitia of cardiovascular disease patients with and without rheumatoid arthritis.” PloS one 9.5 (2014): e98627.

The incidence of atherosclerosis is significantly increased in rheumatoid arthritis (RA). Infection is one factor that may be involved in the pathogenesis of both diseases. The cause of RA and atherosclerosis is unknown, and infection is one of the factors that may be involved in the pathogenesis of both diseases. The aims of this study were to identify bacteria in the aortic adventitia of patients with cardiovascular disease (CVD) in the presence and absence of RA, and to determine the effect of identified candidate pathogens on Toll-like receptor (TLR)-dependent signalling and the proinflammatory response. The aortic adventitia of 11 CVD patients with RA (RA+CVD) and 11 CVD patients without RA (CVD) were collected during coronary artery bypass graft surgery. Bacteria were detected in four samples from CVD patients and three samples from RA+CVD patients and identified by 16S rRNA gene sequencing. Methylobacterium oryzae was identified in all three RA+CVD samples, representing 44.1% of the bacterial flora. The effect of M. oryzae on TLR-dependent signalling was determined by transfection of HEK-293 cells. Although mild TLR2 signalling was observed, TLR4 was insensitive to M. oryzae. Human primary macrophages were infected with M. oryzae, and a TLDA qPCR array targeting 90 genes involved in inflammation and immune regulation was used to profile the transcriptional response. A significant proinflammatory response was observed, with many of the up-regulated genes encoding proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) and chemokines (CCR7, IL-8). The aortic adventitia of CVD patients contains a wide range of bacterial species, and the bacterial flora is significantly less diverse in RA+CVD than CVD patients. M. oryzae may stimulate an proinflammatory response that may aggravate and perpetuate the pathological processes underlying atherosclerosis in RA patients.

78) Paraskevas, K. I., D. P. Mikhailidis, and A. D. Giannoukas.Periodontitis and abdominal aortic aneurysms: a random association or a pathogenetic link?International angiology: a journal of the International Union of Angiology 28.6 (2009): 431.

A number of micro-organisms have been implicated in the development/progression of abdominal aortic aneurysms (AAAs), thus suggesting an infective theory of AAA pathogenesis. Periodontitis may be involved in the development of AAAs by means of introduction of subgingival plaque periodontal bacteria into the bloodstream and degeneration of the aortic wall. A different theory supports that the findings of periodontal pathogens in AAA biopsies are a secondary phenomenon with transient bacteremia leading to invasion of already formed AAAs. It is not yet clear whether the periodontopathic bacteria accelerate the growth/weakening of the aortic wall or whether they are secondary colonizers of AAAs. Clarification of the association between periodontal disease and AAAs in large-scale studies holds implications for a role for chemoprophylaxis/antibiotic treatment in the management of AAAs.

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LPS CAD

79) Liljestrand, John M., et al. “Lipopolysaccharide, a possible molecular mediator between periodontitis and coronary artery disease.” Journal of clinical periodontology 44.8 (2017): 784-792. Lipopolysaccharide mediator between periodontitis and coronary artery disease Liljestrand J clin periodontology 2017

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Systemic Review DM Endotoxemia

80) Gomes, Júnia Maria Geraldo, Jorge de Assis Costa, and Rita de Cássia Gonçalves Alfenas. “Metabolic endotoxemia and diabetes mellitus: a systematic review.” Metabolism 68 (2017): 133-144.Metabolic endotoxemia and diabetes mellitus systematic review Gomes Metabolism 2017

>Higher LPS or LBP concentrations in diabetic subjects compared with healthy controls (Table 1) were observed in most studies.

In summary, DM and its metabolic abnormalities characterized by insulin resistance, hyperinsulinemia, and hyperglycemia, lead to increased intestinal permeability and higher LPS absorption, increasing plasma LPS concentrations

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Diabetics  exposure to Pseudomonal bacteria

81) Peräneva, Lina, et al. “Systemic exposure to Pseudomonal bacteria: a potential link between type 1 diabetes and chronic inflammation.” Acta diabetologica 50.3 (2013): 351-361.

Bacterial endotoxins have been associated with chronic inflammation and the development and progression of diabetic nephropathy. We hypothesized that subjects with high serum lipopolysaccharide activity also carry remains of bacterial DNA in their system. Serum-derived bacterial DNA clones were isolated and identified from 10 healthy controls and 14 patients with type 1 diabetes (T1D) using universal primers targeted to bacterial 16S rDNA. A total of 240 clones representing 35 unique bacterial species were isolated and identified. A significant proportion of the isolated bacteria could be assigned to our living environment. Proteobacteria was by far the most prevalent phylum among the samples. Notably, the patients had significantly higher frequencies of Stenotrophomonas maltophilia clones in their sera compared to the healthy controls. Real-time PCR analysis of S. maltophilia and Pseudomonas aeruginosa flagellin gene copy number in the human leukocyte DNA fraction revealed that the overall Pseudomonal bacterial load was higher in older patients with T1D. Serum IgA- and IgG-antibody levels against Pseudomonal bacteria Delftia acidovorans, P. aeruginosa, and S. maltophilia were also determined in 200 healthy controls and 200 patients with T1D. The patients had significantly higher serum levels of IgA antibodies against all three Pseudomonal bacteria. Additionally, the IgA antibodies against Pseudomonal bacteria correlated significantly with serum C-reactive protein. These findings indicate that recurrent or chronic Pseudomonal exposure may increase susceptibility to chronic inflammation in patients with T1D.

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82) PATENT 2012:  Bacterial DNA as Markers of Cardiovascular and/or Metabolic Disease

he present invention relates to an in vitro method for predicting and/or diagnosing a cardiovascular and/or metabolic disease in a subject, which method comprises determining the concentration of bacterial DNA in a biological sample of said subject, together with degenerated primers for predicting and/or diagnosing a cardiovascular and/or metabolic disease in a subject.

There is thus a need for new methods and new markers for predicting metabolic and/or cardiovascular diseases, which could be used routinely, in a large scale and at a low cost.The present inventors have demonstrated that change in bacterial lipopolysaccharides (LPS) blood concentration, the main components of the outer wall of Gram-negative bacteria and the natural ligands of Toll-like receptor 4 which has been identified as central in the atherosclerosis process, was a causative triggering factor of weight intake and diabetes
(Cani et al. (2007) Diabetes 56:1761-1772, Cani et al. (2008) Diabetes 57:1470-1481).

Thus, the present invention relates to an in vitro method for predicting and/or diagnosing a cardiovascular and/or metabolic disease in a subject, which method comprises determining the concentration of bacterial DNA in a biological sample of said subject.
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83) deleted

LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-α, IL-6, and negatively correlated with HDL cholesterol.

increased LPS levels were significantly associated with type 2 diabetes

84) Jayashree, B., et al. “Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes.” Molecular and cellular biochemistry 388.1-2 (2014): 203-210.

Emerging data indicate that gut-derived endotoxin (metabolic endotoxemia) may contribute to low-grade systemic inflammation in insulin-resistant states. Specific gut bacteria seem to serve as lipopolysaccharide (LPS) sources and several reports claim a role for increased intestinal permeability in the genesis of metabolic disorders. Therefore, we investigated the serum levels of LPS and zonulin (ZO-1, a marker of gut permeability) along with systemic levels of tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) in patients with type 2 diabetes mellitus (T2DM) compared to control subjects. Study subjects were recruited from the Chennai Urban Rural Epidemiology Study [CURES], Chennai, India. Study group (n = 45 each) comprised of a) subjects with normal glucose tolerance (NGT) and (b) patients with T2DM. LPS, ZO-1, TNF-α, and IL-6 levels were measured by ELISA. Serum levels of LPS [p < 0.05], LPS activity [p < 0.001], ZO-1 [p < 0.001], TNFα [p < 0.001], and IL-6 [p < 0.001] were significantly increased in patients with T2DM compared to control subjects. Pearson correlation analysis revealed that LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-α, IL-6, and negatively correlated with HDL cholesterol. Regression analysis showed that increased LPS levels were significantly associated with type 2 diabetes [odds ratio (OR) 13.43, 95 % CI 1.998-18.9; p = 0.003]. In Asian Indians who are considered highly insulin resistant, the circulatory LPS levels, LPS activity, and ZO-1 were significantly increased in patients with type 2 diabetes and showed positive correlation with inflammatory markers and poor glycemic/lipid control.

85) Carrera-Bastos, Pedro, et al. “Serum Zonulin and Endotoxin Levels in Exceptional Longevity versus Precocious Myocardial Infarction. Aging and disease 9.2 (2018): 317.
Endotoxemia-induced inflammation has been associated with insulin resistance and atherosclerosis, ultimately increasing the risk of coronary heart disease. Increased intestinal permeability is an important event leading to endotoxemia. This study aims to elucidate the possible association between endotoxin (lipopolysaccharide) and zonulin (a biomarker of intestinal permeability) levels and the risk of coronary heart disease, and thus healthy aging. Serum levels of zonulin, lipopolysaccharide and soluble CD14 (a protein that binds lipopolysaccharide) were measured in disease-free centenarians, young healthy controls and patients with precocious acute myocardial infarction.

Disease-free centenarians had significantly lower levels of serum zonulin (P<0.01) and lipopolysaccharide (P<0.001) than young patients with acute myocardial infarction, and had significantly lower concentrations of serum lipopolysaccharide than young healthy controls (P<0.05). No significant differences were found for soluble CD14 between groups. Our findings may stimulate further research into the role played by intestinal permeability and endotoxemia not only in coronary heart disease but also in lifespan modulation.

HgbA1c

86) Zhao, Wenhui, et al. “HbA1c and coronary heart disease risk among diabetic patients.Diabetes Care 37.2 (2014): 428-435.
The current study in a low-income population suggests a graded positive association between HbA1c at baseline and during follow-up with the risk of CHD among both African American and white diabetic patients with low socioeconomic status.

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Colchicine reduces MI by 50%

88) Crittenden, Daria B., et al. “Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout.The Journal of rheumatology (2012): jrheum-111533. Prevalence of MI was 1.2% in the colchicine versus 2.6% in the no-colchicine group

89) Nidorf, Stefan M., et al. “Low-dose colchicine for secondary prevention of cardiovascular disease.” Journal of the American College of Cardiology 61.4 (2013): 404-410. Low-dose colchicine for secondary prevention of cardiovascular disease Nidorf Stefan J Amer Col Card 2013

The objective of this study was to determine whether colchicine 0.5 mg/day can reduce the risk of cardiovascular events in patients with clinically stable coronary disease.
BACKGROUND:The presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable coronary disease raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve clinical outcomes in patients with stable coronary disease.
METHODS:In a clinical trial with a prospective, randomized, observer-blinded endpoint design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. The primary analysis was by intention-to-treat.
RESULTS: The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine and 40 of 250 patients (16.0%) assigned no colchicine (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59; p < 0.001; number needed to treat: 11).

In a pre-specified secondary on-treatment analysis that excluded 32 patients (11%) assigned to colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 4.5% versus 16.0% (hazard ratio: 0.29; 95% CI: 0.15 to 0.56; p < 0.001).
CONCLUSIONS:  Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.

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St Francis Heart Study

90) Arad, Yadon, et al. “Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study.” Journal of the American College of Cardiology 46.1 (2005): 158-165. Coronary calcification risk factors C-reactive protein and events St Francis Heart Study Arad, Yadon J Amer Col Card 2005

In a prospective, population-based study, 4,903 asymptomatic persons age 50 to 70 years underwent electron beam CT scanning of the coronary arteries.
RESULTS:  At 4.3 years, follow-up was available in 4,613 participants (94%), and 119 had sustained at least one ASCVD event. Subjects with ASCVD events had higher baseline coronary calcium scores (median [interquartile range], Agatston method) than those without events: 384 (127, 800) versus 10 (0, 86) (p < 0.0001). For coronary calcium score threshold > or = 100 versus < 100, relative risk (95% confidence interval) was 9.6 (6.7 to 13.9) for all ASCVD events, 11.1 (7.3 to 16.7) for all CAD events, and 9.2 (4.9 to 17.3) for non-fatal myocardial infarction and death. The coronary calcium score predicted CAD events independently of standard risk factors and CRP (p = 0.004), was superior to the Framingham risk index in the prediction of events (area under the receiver-operating characteristic curve of 0.79 +/- 0.03 vs. 0.69 +/- 0.03, p = 0.0006), and enhanced stratification of those falling into the Framingham categories of low, intermediate, and high risk (p < 0.0001).
CONCLUSIONS:  The electron beam CT coronary calcium score predicts CAD events independent of standard risk factors, more accurately than standard risk factors and CRP, and refines Framingham risk stratification.

91) De Lorgeril, Michel, et al. “Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.” The Lancet 343.8911 (1994): 1454-1459.

In a prospective, randomised single-blinded secondary prevention trial we compared the effect of a Mediterranean alpha-linolenic acid-rich diet to the usual post-infarct prudent diet. After a first myocardial infarction, patients were randomly assigned to the experimental (n = 302) or control group (n = 303). Patients were seen again 8 weeks after randomisation, and each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linolenic acids confirmed by measurements in plasma. Serum lipids, blood pressure, and body mass index remained similar in the 2 groups. In the experimental group, plasma levels of albumin, vitamin E, and vitamin C were increased, and granulocyte count decreased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control and 3 in the experimental group; 17 non-fatal myocardial infarction in the control and 5 in the experimental groups: a risk ratio for these two main endpoints combined of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables. Overall mortality was 20 in the control, 8 in the experimental group, an adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.

92) Hu, T., and L. A. Bazzano. “The low-carbohydrate diet and cardiovascular risk factors: evidence from epidemiologic studies.” Nutrition, Metabolism and Cardiovascular Diseases 24.4 (2014): 337-343.

93) Hu, Tian, et al. “Adherence to low‐carbohydrate and low‐fat diets in relation to weight loss and cardiovascular risk factors.” Obesity science & practice 2.1 (2016): 24-31.

94) Francois, Monique E., Jenna B. Gillen, and Jonathan P. Little. “Carbohydrate-restriction with High-intensity interval training: an optimal Combination for treating Metabolic diseases?.” Frontiers in nutrition 4 (2017): 49.

95) Youssef, George, and Matthew J. Budoff. “Coronary artery calcium scoring, what is answered and what questions remain.” Cardiovascular diagnosis and therapy 2.2 (2012): 94.

St Francis Heart Study is a double blinded, placebo controlled, randomized clinical trial where 1,005 asymptomatic men and women aged 50-70 years with CAC score ≥80th percentile for age and gender were randomized to receive either Atorvastatin 20 mg daily and vitamin E (α-Tocopherol) 1,000 units daily or placebo (45) with mean duration of treatment of 4.3 years. Treatment reduced total cholesterol by 26.5-30.4%, LDL-cholesterol by 39-43% and triglycerides by 11.2-17%, but had no effect on progression of CAC score. More importantly, the treatment with statins did reduce CV events by 42% (P<0.05) in those persons taking statins as compared to the placebo group, demonstrating definitively that persons with CAC benefit by treatment with statins.

Interestingly, in the overall study cohort of 4,609 patients, change in calcium score was a robust predictor of subsequent coronary disease events. Median score increased by 4 [0, 38] from baseline to the year two scan in subjects who did not sustain a coronary event at any time during the study. In contrast, median (interquartile range) increased by 247 [40, 471] U between the baseline and two-year examinations in subjects who first experienced a CAD event after the year two scan (P<0.0001). In multiple logistic regression, only age (P=0.03), male gender (P=0.04), LDL cholesterol (P=0.01), HDL cholesterol (P=0.04), and two-year change in calcium score (P=0.0001) were significantly associated with subsequent CAD events. Thus, progression of CAC was the strongest predictor of future CV events. It was nevertheless disappointing to find no effect of LDL-cholesterol lowering on CAC score progression.

Infection

96)  Chhibber-Goel, Jyoti, et al. “Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients.” NPJ biofilms and microbiomes 2.1 (2016): 7.

Our literature search resulted in the selection of 63 studies and the identification of 23 bacteria that individually or otherwise co-existed in the studied human atherosclerotic plaque samples.

Data were collated from 63 studies covering 1791 patients spread over a decade. Our analysis confirms the presence of 23 oral commensal bacteria, either individually or in co-existence, within atherosclerotic plaques in patients undergoing carotid endarterectomy, catheter-based atherectomy, or similar procedures. Of these 23 bacteria, 5 (Campylobacter rectus, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Prevotella nigrescens) are unique to coronary plaques, while the other 18 are additionally present in non-cardiac organs, and associate with over 30 non-cardiac disorders.

Proteins secreted by the atherosclerotic plaque-associated bacteria. a Histogram representing the number of secretory protein/peptides and proteases from atherosclerotic plaque-associated bacteria. b The gingival crevice is a habitat to many oral microbes that secrete proteins, peptides and proteases. (1) Secretory peptides and proteases are likely responsible for altering the host actin cytoskeleton in the gingival epithelium leading to microbial entry into the system. (2) These secreted proteins can also activate the immune system causing inflammation. Primarily, cytokine-mediated (IL-6 and IL-8) inflammation is associated with atherosclerotic plaque formation. Certain proteases cause inflammatory response by activating the complement system

When in blood, commensal bacteria can invade the endothelial layer of the blood vessels with help of secretory proteins, and stimulate the production of pro-inflammatory cytokines such as monocyte chemo-attractant protein 1, IL-6, and IL-8.49, 50 These inflammatory cytokines can result in recruitment of DC, which then phagocytose oral bacteria and carry them through the blood stream until they are deposited in the vascular sites.51\

Thus, these atherosclerotic plaque-associated bacteria may form mutually beneficial poly-microbial communities

97) Rosenfeld, Michael E., and Lee Ann Campbell. “Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis.” Thrombosis and haemostasis 105.05 (2011): 858-867.

We also conclude that the failure of the anti-biotic trials should not lead to
the dismissal of the potential role of pathogens in the pathogenesis of atherosclerosis because there are a number of considerations such as lack of susceptibility to antibiotic treatment due to persistent infection in the plaque and pathogen burden that would require simultaneous treatment with multiple antibiotics and anti viral agents.

1) poly -cicbriobial

2) biofilm

98) Ravnskov, Uffe, and Kilmer S. McCully. “Biofilms, lipoprotein aggregates, homocysteine, and arterial plaque rupture.” MBio 5.5 (2014): e01717-14. Biofilms Arterial Plaque Rupture Ravnskov Uffe Kilmer McCully 2014

99) Fry, Stephen Eugene, et al. “Putative biofilm-forming organisms in the human vasculature: expanded case reports and review of the literature.” Phlebological Review 22.1 (2014): 24-37. Biofilm_forming organisms human vasculature Stephen Eugene Fry Phlebological Review 2014

Statins as Antimicrobials

100) Kozarov, Emil, Teresa Padro, and Lina Badimon. “View of statins as antimicrobials in cardiovascular risk modification.” Cardiovascular research 102.3 (2014): 362-374.

In the USA alone, approximately 32 million individuals take statins to lower plasma cholesterol levels.

101)  Lanter, B. B., and D. G. Davies. “Propionibacterium acnes Recovered from Atherosclerotic Human Carotid Arteries Undergoes Biofilm Dispersion and Releases Lipolytic and Proteolytic Enzymes in Response to Norepinephrine Challenge In Vitro.” Infection and immunity 83.10 (2015): 3960-3971.

In the present study, human atherosclerotic carotid arteries were examined following endarterectomy for the presence of the Gram-positive bacterium Propionibacterium acnes and its potential association with biofilm structures within the arterial wall. The P. acnes 16S rRNA gene was detectable in 4 of 15 carotid artery samples, and viable P. acnes was one among 10 different bacterial species recoverable in culture. Fluorescence in situ hybridization analysis of 5 additional atherosclerotic carotid arteries demonstrated biofilm bacteria within all samples, with P. acnes detectable in 4 samples. We also demonstrated that laboratory-grown cultures of P. acnes biofilms were susceptible to induction of a biofilm dispersion response when challenged with physiologically relevant levels of norepinephrine in the presence of iron-bound transferrin or with free iron. The production and release of lipolytic and proteolytic extracellular enzymes by P. acnes were shown to increase in iron-induced dispersed biofilms, and these dispersion-induced P. acnes VP1 biofilms showed increased expression of mRNAs for the triacylglycerol lipases PPA2105 and PPA1796 and the hyaluronate lyase PPA380 compared to that in untreated biofilms. These results demonstrate that P. acnes can infect the carotid arteries of humans with atherosclerosis as a component of multispecies biofilms and that dispersion is inducible for this organism, at least in vitro, with physiologically relevant levels of norepinephrine resulting in the production and release of degradative enzymes.

Metabolic Endotoxemia and Diabetes Mellitus:

102)  Gomes, Júnia Maria Geraldo, Jorge de Assis Costa, and Rita de Cássia Gonçalves Alfenas. “Metabolic endotoxemia and diabetes mellitus: a systematic review.” Metabolism 68 (2017): 133-144. Metabolic endotoxemia and diabetes mellitus systematic review Gomes Júnia Metabolism 2017

we observed that diabetic subjects presented higher fasting and postprandial LPS concentrations compared to lean non-diabetic subjects and/or obese subjects.
LPS was more elevated in diabetic patients with advanced complications, such as macroalbuminuria [17] ,and those treated with insulin

diabetics seem to have increased intestinal permeability [28]  and higher LPS absorption after a high-fat meal [20,25]

diabetic subjects seem to have lower clearance of LPS and consequently, increased LPS concentrations.

103) Abedin, Moeen, Yin Tintut, and Linda L. Demer. “Vascular calcification: mechanisms and clinical ramifications.” Arteriosclerosis, thrombosis, and vascular biology 24.7 (2004): 1161-1170.

104)  Doherty, Terence M., et al. “Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads.” Proceedings of the National Academy of Sciences 100.20 (2003): 11201-11206.

105) Valenti, Valentina, et al. “Absence of coronary artery calcium identifies asymptomatic diabetic individuals at low near-term but not long-term risk of mortality: a 15-year follow-up study of 9715 patients.” Circulation: Cardiovascular Imaging 9.2 (2016): e003528.Absence of coronary calcium identifies diabetic at low near term risk of mortality Valenti Circulation 2016

106) Dykun, Iryna, et al. “Statin medication enhances progression of coronary artery calcification: the Heinz Nixdorf Recall Study.” Journal of the American College of Cardiology 68.19 (2016): 2123-2125. Statin medication enhances progression of coronary artery calcification Heinz Nixdorf Dykun J Amer Coll Card 2016

 

Summary
Diabetes, Arterial Calcification and Statin Drugs
Article Name
Diabetes, Arterial Calcification and Statin Drugs
Description
Diabetics have rapid progression of coronary artery disease. Statins are beneficial in Diabetic because of pleotrophic effects, not from reduction in cholesterol.
Author
publisher
jeffrey dach md
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Last updated on by Jeffrey Dach MD

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