Coronary Artery Disease, Questions and Answers by Jeffrey Dach MD

A young doctor sent me an email. He was reading my book on coronary artery disease, called Heart Book, and had a few questions regarding the mechanism of atherosclerosis. He writes:

What is the underlying cause or mechanism of atherosclerosis ?
Question A) Is the mechanism Vitamin C deficiency causing deficient collagen cross-linking, arterial wall weakness, cracking and a subsequent repair mechanism causing it ?

My answer to A): Vitamin C deficiency is the Linus Pauling theory of heart disease, discussed more completely this previous newsletter. In 1989, Dr Pauling published “A Unified Theory of Human Cardiovascular Disease,” which In essence, says that heart disease is a manifestation of chronic scurvy (vitamin C deficiency), and atherosclerotic plaque is a mechanism evolved to repair arteries damaged by chronic vitamin C deficiency.

B) Is the mechanism “Leaky Gut” allowing endotoxins to colonize the endothelium and form a biofilm causing it ?

My answer to B): This is the Low Level Endotoxemia (LPS) Theory of Heart Disease discussed more completely in this previous newsletter. Recent studies by Dr. Francesco Violi in 2023 lend more support for this theory.(2)

See: Violi, Francesco, et al. “Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease.” Nature Reviews Cardiology 20.1 (2023): 24-37.

LPS, also called endo toxin from the oral bactera and gut derived bacteria enter the bloodstream.  LPS in the blood stream then binds with LDL cholesterol, which is later engulfed by macrophages (white cells of the immune system). The LPS bound LDL can then infiltrate into the arterial wall and can be identified within the atherosclerotic plaque, thus inducing inflammation and oxidation of the LDL. This process forms the foam cells which are macrophages containing oxidized cholesterol, a key step in the atherosclerosis. The inflammation incited by endotoxin incites macrophages and smooth muscle cells to secrete EV’s (extracellular vesicles) which contain calcium. These vesicles then aggregate into calcium deposits within the arterial plaque. (3)(6)(81-90)

See: Hutcheson JD, et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016;15(3):335-43

C) Is the mechansim “Molecular Mimicry” from “Leaky Gut” causing the autoimmune response ?

Here is my answer to question C): Yes, this is the “Molecular Mimicry” theory of atherosclerosis in which immune response to pathogenic organisms cross-reacts with protein antigens in the arterial wall. In 2003, Dr. David Lamb suggested “molecular mimicry” could play a role in the mechanism of atherosclerosis, writing: “One possible hypothesis is that an immune response mounted against antigens on pathogenic organisms cross-react with homologous host proteins in a form of ‘molecular mimicry’.”  In 2000, Dr. Stephen Epstein made a case “for the concept that infection-induced molecular mimicry contributes to the development of atherosclerosis.” Various infections with microorganisms have been implicated in molecular mimicry such as H. Pylori gastric infection, Streptococcus infection, cytomegalovirus, periodontal pathogens HSV-1 and 2 (Herpes simplex virus),  Epstein Barr virus (EBV), Haemophilus influenzae, Chlamydia. pneumoniae, Mycoplasma pneumoniae, etc. (64-65), (66-71)

See: Epstein, Stephen E., et al. “Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry.” Arteriosclerosis, Thrombosis, and Vascular Biology 20.6 (2000): 1417-1420. (64)

And See: Lamb, David J., Wafaa El-Sankary, and Gordon AA Ferns. “Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation.” Atherosclerosis 167.2 (2003): 177-185. (65)

Above header image: SEM, Scanning Electron Microscopy of calcified vesicles within arterial plaque. Density dependent scanning electron microscopy (SEM) image of a carotid plaque showing calcifying (Orange) extracellular vesicles (Green). Magnification = 44.77K  Courtesy of wikimedia commons. (79-80)

Calcium Score Has Replaced Serum Cholesterol as Predictor of Cardiac Event

One of the main points my Heart Book, is that serum cholesterol level is not a good predictor of heart attack risk, while on the other hand, calcium score is a very accurate predictor of heart attack risk. The calcium score is measured by CAT scan imaging of the coronary arteries. A computer program calculates the calcium score as a number from zero to over 400, indicating how much  calcification is present in the coronary arteries. The below charts give an overview of how powerful the calcium score can be in predicting future cardiac events. No such charts exist for the cholesterol panel which does not correlate with calcium score. (73)

Above chart: Notice calcium scores are color coded, representing an excellent predictor of Major Adverse Cardiac Event (MACE), MI (Myocardial Infarction), and All-Cause Mortality. The higher the calcium score, the greater the cumulative increase in cardiac events over time,  courtesy of Budoff, Matthew J., et al. “When Does a Calcium Score Equates to Secondary Prevention?: Insights From the Multinational CONFIRM Registry.” JACC: Cardiovascular Imaging (2023). (72)

No such charts are available for serum cholesterol because there is no correlation between serum cholesterol and calcium score as demonstrated in 2001 by Dr. Harvey Hecht. (73)

See: Hecht, Harvey S., et al. “Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment.” The American journal of cardiology 87.4 (2001): 406-412.  (73)

Above Chart: Cumulative mortality and prognosis is based on calcium score for men and women, courtesy of Kelkar, Anita A., et al. “Long-term prognosis after coronary artery calcium scoring among low-intermediate risk women and men.” Circulation: Cardiovascular Imaging 9.4 (2016): e003742. (74)

Above chart shows cumulative mortality, MACE (major adverse cardiac event), Myocardial Infarction and Stroke, all based on calcium score, courtesy of Mitchell, Joshua D., et al. “Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the Walter Reed Cohort Study.” JACC: Cardiovascular Imaging 11.12 (2018): 1799-1806. (75)

Many of these charts can be found at the The Skeptical Cardiologist Dr. Anthony Pearson, Prevention of Heart Attack and Stroke-Early Detection of Risk Using Coronary Artery Calcium Scans in the Youngish. January 19, 2019. (76)

Calcium Score Progression, Excellent Predictor of Heart Attack Risk

Another important point is that progression of a calcium score of more than 15 percent annually on serial calcium score studies is even more predictive of future heart attack. Progression of less than 15 percent annually is protective indicating good prognosis. Calcium score annual progression above 15 percent annually indicates high risk for heart attack and poor prognosis. Thus serial calcium score testing is useful to monitor treatment. If the calcium score is increasing greater than 15 percent annually, this means the treatment is failing, and needs re-evaluation. This applies to statin drug treatment as well. All the patients in the Paolo Raggi 2004 study (below chart) were on statin drugs, yet the group with greater than 15 percent calcium score progression (right chart) all had heart attacks within 6 years of follow up. See this chart (below) from Dr. Paolo Raggi’s 2004 study, and republished by Dr. Harvey Hecht (below chart). (77-78)

Left chart shows less than 15 percent annual increase in calcium score with good prognosis and no heart attacks. Calcium scores are color coded. Notice all color coded lines on left chart share high survival rate, with good prognosis.
Right chart shows greater than 15 percent annual increase in calcium score with poor prognosis. Higher calcium scores have the worst prognosis with more rapid timing to myocardial infarction. Above chart courtesy Paolo Raggi (2004), and Hecht, Harvey S. “Coronary artery calcium scanning: past, present, and future.” JACC: Cardiovascular Imaging 8.5 (2015): 579-596. (77-78)

Calcium Score Determines Who to Treat with Statin Drug:
Joshua Mitchell at Walter Reed Hospital – Calcium Score Study

A study by Dr. Joshua Mitchell at Walter Reed Hospital showed that the calcium score, and not the serum cholesterol, should be used to determine who to treat with a statin drug. For calcium scores under 100, statin drugs have no benefit. However, above a calcium score of 100, statin drugs do show a clinical benefit. I suspect this benefit of a statin drug for high calcium scores is due to the pleiotropic effects, namely the anti-inflammatory and anti-microbial effects of statins. This idea is supported by lack of efficacy in preventing cardiovascular mortality for the non-statin cholesterol lowering drugs such as evolucamab which we discuss below. (75)

Above chart, upper panels, shows no benefit for statin drug for Calcium Score of Zero to 100 (Green Arrows) Both Statin user and non-user lines are super-imposed.  Bottom two panels: For Calcium Score over 100, statin user line is nicely separated from non-statin user (Red Arrows) indicating reduction in Major Adverse cardiac Events (MACE).  Statin users are the dotted red line.  Above charts courtesy of Mitchell, Joshua D., et al. “Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the Walter Reed Cohort Study.” JACC: Cardiovascular Imaging 11.12 (2018): 1799-1806. (75)

The Power of Zero

The Joshua Mitchell study, Coronary artery calcium myocardial infarction from JACC Card Imaging 2018, is a retrospective study.  Nine years of records were analyzed for 13,644 patients from the Walter Reed Army Medical Center (mean age 50 years; 71% men). Dr Joshua Mitchell concluded:

“the presence and severity of CAC (Coronary Artery Calcium) identified patients most likely to benefit from statins for the primary prevention of cardiovascular diseases.” (75)

Soft tissue Calcification is a Response to Infection

Xanthomas are cholesterol deposits in the soft tissues found in patients with familial hypercholesteomemia. This is a genetic disease with high serum cholesterol above 300. These xanthomas DO NOT calcify because they are not infected. Coronary arteries calcify because they are infected.

Above image: Xanthomas (red arrows) are cholesterol deposits in soft tissues. Photograph of patient’s hands showing multiple xanthomas. More specifically, these are tendinous xanthomas. Courtesy of wikimedia commons from: Kumar, Anita A., et al. “Acute myocardial infarction in an 18 year old South Indian girl with familial hypercholesterolemia: a case report.” Cases Journal 1 (2008): 1-4. (27)

In general, soft tissue calcification anywhere in the body is a response to localized infection. Calcification does not usually occur within soft tissue lipid deposits without co-existing infection or LPS in the deposit to stimulate inflammation and calcification.

Periorbital Xanthomas and Tendinous Xanthomas

For example, in fatty cholesterol deposits around the orbits (eyelids) and in deposits in tendons called Xanthomas in patients with familial hypercholesterolemia, only rarely has calcification been reported. Xanthomas are usually not calcified. Over 30 years reading CAT scans of the head and brain, I have never seen a calcified xanthoma of the eyelid. Such soft tissue cholesterol deposits do not calcify on CAT scan.

On the other hand, cholesterol deposits within atherosclerotic plaques do calcify because of the low level endotoxemia. LPS (lipo-polysacharide) and micro-organisms are engulfed by macrophages which then migrate into the atherosclerotic plaque. LPS can be picked up by LDL cholesterol which then finds its way into foam cells inside the plaque. This stimulates an inflammatory response which then creates calcifications in the arterial wall.

The arterial wall becomes infected with polymicrobial biofilm which incites an inflammatory reaction that then calcifies. The infection comes from circulating microbial organisms in the bloodstream, low-level endotoxemia from leaky gut, and periodontal disease. Recent studies show that both LDL lipoproteins and macrophages carry LPS into atheromas, creating extra cellular vesicles which then undergo calcification. (see header image).

Recent studies show a link between oral microbes in patients with periodontal disease and infection. The same oral microorgansims associated with gingivits (infection of gums) can be found in the atherosclerotic plaques in the coronary and carotid arteries.

Fourier Study Falsifies Cholesterol Theory of Coronary Artery Disease

Reducing Serum Cholesterol Alone is Ineffective

The Fourier evolocumab study by Dr Sabatini falsifies the idea that reducing serum cholesterol has any benefit for preventing or reversing coronary artery disease. The PCSK9 inhibitor drug, evolucomab, reduces LDL to low levels, yet there was no reduction in all-cause or cardiovascular mortality. Likewise the CETP inhibitor drugs, Eli Lilly’s Anacetrapib and Merc’s Evacetrapib all reduce LDL cholesterol yet fail to reduce cardiovascular mortality. I suspect the reason is because they lack the antimicrobial and anti-inflammatory effects of statins,. Because of this antimicrobial effect, statins have been proposed as a treatment for periodontal disease. Oral microorganisms found in the oral cavity in patients with periodontal disease have also been found in the coronary artery plaques. Reducing serum cholesterol alone is not effective in reducing mortality from cardiovascular mortality. It is necessary to address the underlying infection in the wall of the artery with antimicrobial and anti-inflammatory treatments, properties of statin drugs. It is also necessary to address periodontal infection and “leaky gut” representing the source of low level endotoxemia. (91-98)

Above image is Fig. 3 schematic diagram of atherosclerosis and microcalcification from Blaser, Mark C., and Elena Aikawa. (101)

What if We Had a Drug That Removes Oxidized Cholesterol from the Plaque ?

Oxidized cholesterol is an important component of the atherosclerotic plaque, and thought to play a key role in atherosclerosis. What if we had a drug that could pull this oxidized cholesterol out of the plaque, and send it back to the liver for degradation? One such agent is Cyclodextrin discussed below. Another is Tocotrienol vitamin E discussed next.

Vitamin E Prevents LDL Uptake by Macrophages

In 2000, Dr. Luigi Iuliano studied the distribution of injected radiolabeled LDL cholesterol, finding accumulation within foam cells which are macrophages containing oxidized cholesterol. Administration of 900 mg of Vitamin E in three patients for 4 weeks completed prevented radiolabeled LDL uptake by macrophages. This study is highly significant since it shows the mechanism of Vitamin E in halting progresion of the atherosclerostic process. Dr. Luigi Iuliano writes:

Autoradiographic study showed that LDL was localized prevalently in the foam cells of atherosclerotic plaques, whereas the accumulation in the lipid core was negligible. Immunohistochemistry revealed that foam cells that had accumulated radiolabeled LDL were mostly CD68 positive, whereas a small number were α-actin positive. No accumulation of the radiotracer was detected in atherosclerotic plaques after injection of radiolabeled human serum albumin. In 3 patients treated for 4 weeks with vitamin E (900 mg/d), an almost complete suppression of radiolabeled LDL uptake by macrophages was observed. (31) (40-41)

Dr. James Roberts and Cyclodextrin

Dr. James Roberts has been using such a drug called Cyclodextrin (cavadex) which actually removes oxidized cholesterol from the atherosclerotic plaque and available studies show efficacy for reducing angina symptoms and for reducing calcium scores. See this link to view Dr. Roberts’s video presentation (once there, scroll down to the bottom of the page).

A Patient with Resolution of Angina after Treatment with CycloDextrin

Mr. Smith is such a patient with calcium score progression of 46 percent annually, and a new onset of angina symptoms. His Lp(a) is markedly elevated. CAT angiogram shows significant stenosis of a branch of the LAD (left anterior descending) coronary artery, probably causing the angina. After two weeks of cyclodextrin treatment, his angina resolved. (8-26)

In 2021, Dr. Guo Chen summarized the cardiovascular benefits of and mechanism of action of cyclodextrin, writing:

1) [Cyclodextrin] enhanced cholesterol efflux from atherosclerotic plaques/macrophages (Zimmer et al. 2016),
2) [Cyclodextrin] inhibited oxidation of plasma LDL (Ao et al. 2016a; Ao and Chen 2017),
3) increased level of plasma HDL (Wang et al. 2019),
4) reduced cholesterol crystal-induced complement activation (Pilely et al. 2019), and
5) modified gut flora (for oral administration) (Sakurai et al. 2017).
6) we found that MβCD [cyclodextrin] could impair the monocyte-adhering ability of normal endothelial cells by influencing adhesion molecules and cytoskeleton (Ao et al. 2016b). (9)

Lumbrokinase and Plant Based Diet

Proteolytic enzymes have been found useful for dissolving the proteinaceaus debris within atherosclerotic plaques. Dramatic resolution of chest pain symptoms (angina), has been reported with lumbrokinase, a proteolytic enzyme taken orally, described here. (100)

See: Kasim, Manoefris, et al. “Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase: a pilot study.” The Journal of Alternative and Complementary Medicine 15.5 (2009): 539-544. (100)

Plant Based Diet

Another intervention reported to resolve angina symptoms and reverse coronary artery disease is the Plant Based Diet discussed in a previous newsletter on Plant Based Diet.

Our Calcium Score Protocol

One might put all these interventions together into a protocol along with MK-7 vitamin K, Tocotrienol vitamin E, Vitamin C, Kyolic aged Garlic, Berberine, etc. as mentioned in Heart Book, for a more robust protocol to prevent and treat coronary artery disease.

For Articles with Related Interest: Click This Link

Linus Pauling Theory of Coronary Artery Disease

LPS Endotoxemia Theory of Heart Disease

Evolocumab Are You Joking Me?

Plant Based Diet, Health Benefits for Coronary Artery Disease

If you liked this article, you might like my book, Heart Book (left cover image) at this link on Amazon.

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Florida 33314
954-792-4663

Links and References

1) Tonelli, Andrea, Evelyn N. Lumngwena, and Ntobeko AB Ntusi. “The oral microbiome in the pathophysiology of cardiovascular disease.” Nature Reviews Cardiology 20.6 (2023): 386-403.

Dysbiosis of the oral microbiome contributes to CVD through biofilm formation, endothelial dysfunction, molecular mimicry, platelet aggregation, direct arterial invasion and systemic inflammation.

••An association between the oral microbiome (or oralome) and cardiovascular inflammation and CVD is supported by a growing body of epidemiological studies, systematic reviews and basic science investigations.
••Validated links exist between oral dysbiosis and CVDs, including atherosclerotic diseases, heart failure, infective endocarditis and rheumatic heart disease.
••The mechanisms by which oral dysbiosis contributes to CVD include immunomodulation; endothelial dysfunction; molecular mimicry and antibody cross-reactivity; protein citrullination; platelet activation, aggregation and thrombogenesis; arterial invasion; and systemic inflammation.
••Targeting oral dysbiosis in a clinical setting could be an important component of CVD management.

2) Violi, Francesco, et al. “Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease.” Nature Reviews Cardiology 20.1 (2023): 24-37.

Support for the putative role of LPS in atherosclerosis has been provided by immunohistochemistry analysis of carotid atherosclerotic plaques from patients undergoing endarterectomy, which revealed the presence of LPS adjacent to plaque macrophages with high TLR4 levels85. By contrast, LPS was not detected in atherosclerosis-free thyroid arteries from the same patients85.

In humans, LPS in circulation is mostly bound to lipoproteins (80–97%)86,87, with the highest concentration in LDL (35.7%) and the lowest in VLDL (13.9%)88. However, VLDL particles carry a higher number of LPS molecules88. The observation that circulating LPS is transported by pro-atherogenic lipoproteins, such as VLDL and LDL, might be relevant in the pathogenesis of atherosclerosis. LPS could enter the arterial wall bound to these pro-atherogenic lipoproteins, which would favour LDL oxidation89 and thereby contribute to propagation of arterial inflammation. A further contributor to the pro-atherogenic process is LPS-binding protein-mediated LPS transfer from HDL to LDL26 (Fig. 3).

Low-grade endotoxaemia induces an inflammatory state in the arterial wall that ultimately leads to initiation and progression of atherosclerosis.

The central role of inflammation in the atherosclerotic process is supported by interventional studies performed in the past decade showing that the risk of cardiovascular disease can be attenuated with the use of anti-inflammatory therapies6,7
[such as colchicine]

A growing body of evidence indicates that gut dysbiosis is implicated in the atherothrombotic process via increased translocation of viable bacteria or bacterial products such as lipopolysaccharides (LPS) and trimethylamine-N-oxide (TMAO) into the systemic circulation10.

The relationship between a high-fat diet, metabolic disease and blood LPS levels was first outlined by Cani and colleagues13,20. They demonstrated in mouse models that a 4-week high-fat diet chronically increased the plasma LPS concentration two to five times, corresponding to one to two orders of magnitude lower than the levels attained with infections46

Cani and colleagues showed that chronic, experimental metabolic endotoxaemia induced by LPS infusion triggered the development of obesity, diabetes and liver insulin resistance, mimicking the negative effects elicited by a high-fat diet alone20.

The relevance of oxidative stress in atherogenesis has been supported by evidence of impaired macrophage uptake of oxLDL in patients undergoing carotid endarterectomy who received vitamin E (which has antioxidant properties) and injected with native radiolabelled LDL75.

Support for the putative role of LPS in atherosclerosis has been provided by immunohistochemistry analysis of carotid atherosclerotic plaques from patients undergoing endarterectomy, which revealed the presence of LPS adjacent to plaque macrophages with high TLR4 levels85. By contrast, LPS was not detected in atherosclerosis-free thyroid arteries from the same patients85. In humans, LPS in circulation is mostly bound to lipoproteins (80–97%)86,87, with the highest concentration in LDL (35.7%) and the lowest in VLDL (13.9%)88. However, VLDL particles carry a higher number of LPS molecules88.

The observation that circulating LPS is transported by pro-atherogenic lipoproteins, such as VLDL and LDL, might be relevant in the pathogenesis of atherosclerosis. LPS could enter the arterial wall bound to these pro-atherogenic lipoproteins, which would favour LDL oxidation89 and thereby contribute to propagation of arterial inflammation. A further contributor to the pro-atherogenic process is LPS-binding protein-mediated LPS transfer from HDL to LDL26 (Fig. 3).

Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries.
In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation.

2A) Carnevale, Roberto, et al. “Localization of lipopolysaccharide from Escherichia Coli into human atherosclerotic plaque.” Scientific Reports 8 (2018).

LPS from Escherichia Coli and Toll-like receptor 4 (TLR4) were studied in specimens from carotid and thyroid arteries of 10 patients undergoing endarterectomy and 15 controls matched for demographic and clinical characteristics. Blood LPS were significantly higher in patients compared to controls. Immunochemistry analysis revealed positivity for antibodies against LPS and TLR4 coincidentally with positivity for CD68 only in the atherosclerotic plaque of carotid arteries but not in thyroid arteries; the positivity for LPS and TLR4 was greater in the area with activated macrophages. LPS concentration similar to that detected in atherosclerotic plaque resulted in a dose-dependent TLR4-mediated Nox2 up-regulation by human monocytes. These data provide the first evidence that LPS from Escherichia Coli localizes in human plaque and may contribute to atherosclerotic damage via TLR4-mediated oxidative stress.

3) Park, Hyun-Joo, et al. “Infection of Porphyromonas gingivalis increases phosphate-induced calcification of vascular smooth muscle cells.” Cells 9.12 (2020): 2694.

Several in vitro experiments and studies using animal models have demonstrated that P. gingivalis and its virulence factors are involved in the pathogenesis at various stages of atherosclerosis, like endothelial dysfunction, intimal hyperplasia, foam cell formation, and vascular remodeling [5].

Accumulating evidence suggests a link between periodontal disease and cardiovascular diseases. Vascular calcification is the pathological precipitation of phosphate and calcium in the vasculature and is closely associated with increased cardiovascular risk and mortality. In this study, we have demonstrated that the infection with Porphyromonas gingivalis (P. gingivalis), one of the major periodontal pathogens, increases inorganic phosphate-induced vascular calcification through the phenotype transition, apoptosis, and matrix vesicle release of vascular smooth muscle cells. Moreover, P. gingivalis infection accelerated the phosphate-induced calcium deposition in cultured rat aorta ex vivo. Taken together, our findings indicate that P. gingivalis contributes to the periodontal infection-related vascular diseases associated with vascular calcification.

3A) Chistiakov, Dimitry A., Alexander N. Orekhov, and Yuri V. Bobryshev. “Links between atherosclerotic and periodontal disease.” Experimental and molecular pathology 100.1 (2016): 220-235.

4) free pdf

Violi, Francesco, et al. “Gut dysbiosis-derived low-grade endotoxemia: A common soil for liver and cardiovascular disease.” Kardiologia Polska (Polish Heart Journal) (2023).

studies in patients with severe atherosclerosis documented that LPS localizes in atherosclerotic plaque in close association with activated macrophages expressing TLR4 suggesting LPS’s role in vascular inflammation, atherosclerotic progression, and thrombosis. Finally, LPS may directly interact with myocardial cells to induce electric and functional changes leading to atrial fibrillation or heart failure.

5) Liao, Xing-Xing, et al. “Gut microbiome metabolites as key actors in atherosclerosis co-depression disease.” Frontiers in Microbiology 13 (2022): 988643.

Individuals with depression are at substantially increased risk of cardiovascular disease and death (O’Connor, 2018; Levine et al., 2021), and in particular, are strongly associated with one of the most common cardiovascular diseases–ASCVD…Given that the two are so closely related clinically, we refer to this state as atherosclerosis co-depression disease….It is now believed that depression and atherosclerosis occur by similar mechanisms, including inflammation (Chrysohoou et al., 2018), hypothalamic–pituitary–adrenal axis dysregulation (Gu et al., 2012), endothelial dysfunction (van Dooren et al., 2016; Münzel and Daiber, 2020), and other major causes, while the development of modern high-throughput technologies has provided technical support for the study of the gut microbiome, and an increasing number of studies have revealed that gut microbiome is key factors mediating the development of the host’s diseases, including depression and AS

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Genesis and Growth of arterial calcifications

Good Images

6) Hutcheson JD, Goettsch C, Bertazzo S, Maldonado N, Ruiz JL, Goh W, Yabusaki K, Faits T, Bouten C, Franck G, Quillard T, Libby P, Aikawa M, Weinbaum S, Aikawa E Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016;15(3):335-43

calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability – are interlinked.

Emerging evidence suggests that vascular calcification involves calcifying EVs released from vascular smooth muscle cells (SMCs) and macrophages^18–20, implying that atherosclerotic plaques contain continuous sources of precursors of microcalcification.

7) Rogers MA, Buffolo F, Schlotter F, Atkins SK, Lee LH, Halu A, Blaser MC, Tsolaki E, Higashi H, Luther K, Daaboul G, Bouten CVC, Body SC, Singh SA, Bertazzo S, Libby P, Aikawa M, Aikawa E Annexin A1-dependent tethering promotes extracellular vesicle aggregation revealed with single-extracellular vesicle analysis. Sci Adv. 2020;6(38):ePub –

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Cyclodextrin

8) Wu, Jiao, et al. “Cyclodextrins as therapeutic drugs for treating lipid metabolism disorders.” Obesity Reviews (2024): e13687.

9) Chen, Guo, et al. “Methyl-β-cyclodextrin suppresses the monocyte-endothelial adhesion triggered by lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL).” Pharmaceutical Biology 59.1 (2021): 1034-1042.

Atherosclerosis is a chronic cardiovascular disease characterized by the formation of atherosclerotic plaques and the narrowing of the arterial lumen. In recent years, accumulating evidence supports that cyclodextrins per se have anti-atherosclerotic efficacy (Zimmer et al. 2016; Ao et al. 2016a; Ao and Chen 2017; Sakurai et al. 2017; Pilely et al. 2019; Wang et al. 2019).
Different mechanisms have been reported, such as
1) enhanced cholesterol efflux from atherosclerotic plaques/macrophages (Zimmer et al. 2016),
2) inhibited oxidation of plasma LDL (Ao et al. 2016a; Ao and Chen 2017), increased level of plasma HDL (Wang et al. 2019),
3) reduced cholesterol crystal-induced complement activation (Pilely et al. 2019), and
4) modified gut flora (for oral administration) (Sakurai et al. 2017).
5) we found that MβCD could impair the monocyte-adhering ability of normal endothelial cells by influencing adhesion molecules and cytoskeleton (Ao et al. 2016b).

However, it is unclear whether cyclodextrins exert the anti-atherosclerotic efficacy via influencing the monocyte-endothelial adhesion during atherogenesis at which situation endothelial cells are generally activated by some stimuli, such as lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL). In this study, we sought to test this possibility by using endothelial cells stimulated with LPS or oxLDL as an in vitro cell model of atherosclerosis.

MβCD significantly suppresses the LPS/oxLDL-triggered monocyte-endothelial adhesion by downregulating adhesion molecule expression probably via LPS-IKK-NF-κB or oxLDL-Akt-NF-κB pathway. This study demonstrates a potential mechanism of the anti-atherosclerotic efficacy of cyclodextrin from the angle of monocyte-endothelial adhesion.

!!!!!!!!!!!!!!!!!! Removal of oxidized cholesterol from foam cells !!!

10) Clemens, D., et al. “Reversing atherosclerosis by the specific removal of oxidized cholesterol with cyclodextrin dimer.” Atherosclerosis 379 (2023): S34-S35.

Our data suggest that targeted removal of 7KC [7 keto cholesterol] from foam cells with UDP-003 [cyclodextrin] has the potential to prevent and reverse the formation of atherosclerotic plaques. This innovation represents the first disease-modifying therapeutic approach to treating atherosclerotic disease.

11) Mahjoubin-Tehran, Maryam, et al. “Cyclodextrins: Potential therapeutics against atherosclerosis.” Pharmacology & Therapeutics 214 (2020): 107620.

Cyclodextrins are cyclic oligosaccharides produced from many sources of starch by enzymatic degradation. The frequently used cyclodextrins are α-, β-, and γ-cyclodextrins, which are composed of six, seven, and eight glucose moieties, respectively. Especially β-cyclodextrin can entrap hydrophobic compounds, such as cholesterol, into its hydrophobic cavity and form stable inclusion complexes with cholesterol. This inherent affinity of cyclodextrins has been exploited to extract excess cholesterol from cultured cells, as well as intra- and extracellular cholesterol stores present in atherosclerotic lesions of experimental animals. Accordingly, cyclodextrins could be considered as potentially effective therapeutic agents for the treatment of atherosclerosis.

12) Gao, Cheng, et al. “Cyclodextrin-mediated conjugation of macrophage and liposomes for treatment of atherosclerosis.” Journal of Controlled Release 349 (2022): 2-15.

13) free pdf   Zhang, Lu. “Cyclodextrin related drug delivery system to promote atherosclerosis regression.” Die Pharmazie-An International Journal of Pharmaceutical Sciences 75.12 (2020): 619-625.

14) Zhang, Yan, et al. “Poly-β-cyclodextrin supramolecular nanoassembly with a pH-Sensitive switch removing lysosomal cholesterol crystals for antiatherosclerosis.” Nano Letters 21.22 (2021): 9736-9745.

15) Gluba-Brzózka, Anna, et al. “Emerging anti-atherosclerotic therapies.” International Journal of Molecular Sciences 22.22 (2021): 12109.

Cyclodextrin inhibits LPS induced macrophage activation

16) Arima, Hidetoshi, et al. “Inhibitory effects of dimethylacetyl-β-cyclodextrin on lipopolysaccharide-induced macrophage activation and endotoxin shock in mice.” Biochemical pharmacology 70.10 (2005): 1506-1517.

17) Lucia Appleton, Silvia, et al. “Cyclodextrins as anti-inflammatory agents: basis, drugs and perspectives.” Biomolecules 11.9 (2021): 1384.

18) Donida, Bruna, et al. “Nanoparticles containing β‐cyclodextrin potentially useful for the treatment of Niemann‐Pick C.” Journal of Inherited Metabolic Disease 43.3 (2020): 586-601.

19) Carradori, Dario, et al. “Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin.” bioRxiv (2020): 2020-07.

20) Feltes, McKenna, et al. “Monitoring the itinerary of lysosomal cholesterol in Niemann-Pick Type C1-deficient cells after cyclodextrin treatment [S].” Journal of lipid research 61.3 (2020): 403-412.

21) Vance, Jean E., and Barbara Karten. “Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin.” Journal of lipid research 55.8 (2014): 1609-1621.

22) Matsuo, Muneaki, et al. “Effects of cyclodextrin in two patients with Niemann–Pick type C disease.” Molecular genetics and metabolism 108.1 (2013): 76-81.

23) Davidson, Cristin D., et al. “Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.” PloS one 4.9 (2009): e6951.

24) Liu, Benny. “Therapeutic potential of cyclodextrins in the treatment of Niemann–Pick type C disease.” Clinical lipidology 7.3 (2012): 289-301.

25) Abi-Mosleh, Lina, et al. “Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells.” Proceedings of the National Academy of Sciences 106.46 (2009): 19316-19321.

26) Rosenbaum, Anton I., et al. “Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells.” Proceedings of the National Academy of Sciences 107.12 (2010): 5477-5482.

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Xanthomas. Photograph of patient’s hands showing multiple xanthomas. More specifically, these are tendinous xanthomas.

27) Kumar, Anita A., et al. “Acute myocardial infarction in an 18 year old South Indian girl with familial hypercholesterolemia: a case report.” Cases Journal 1 (2008): 1-4.

28) Orbital Xanthomas

free pdf
29) Philip, Shilpa Accamma, Swarna Sri, and Anunayi Jeshtadi. “Cutaneous Xanthoma–A Clue to Familial Hypercholesterolemia.” Journal of Evolution of Medical and Dental Sciences 9.25 (2020): 1887-1890.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!   Gingivitis  !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

30) Afzoon, Saeed, et al. “A systematic review of the impact of Porphyromonas gingivalis on foam cell formation: Implications for the role of periodontitis in atherosclerosis.” BMC Oral Health 23.1 (2023): 481.

All of the studies have reported that P. gingivalis can significantly induce foam cell formation by infecting the macrophages and induction of oxidized low-density lipoprotein (oxLDL) uptake.

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Radiolabeled LDL accumulates in macrophages in atherosclerotic plaque: Vitamin E beneficial

31) Iuliano, Luigi, et al. “Radiolabeled native low-density lipoprotein injected into patients with carotid stenosis accumulates in macrophages of atherosclerotic plaque: effect of vitamin E supplementation.” Circulation 101.11 (2000): 1249-1254.

Autoradiographic study showed that LDL was localized prevalently in the foam cells of atherosclerotic plaques, whereas the accumulation in the lipid core was negligible. Immunohistochemistry revealed that foam cells that had accumulated radiolabeled LDL were mostly CD68 positive, whereas a small number were α-actin positive. No accumulation of the radiotracer was detected in atherosclerotic plaques after injection of radiolabeled human serum albumin. In 3 patients treated for 4 weeks with vitamin E (900 mg/d), an almost complete suppression of radiolabeled LDL uptake by macrophages was observed.

Conclusions—This study shows that circulating LDL rapidly accumulates in human atherosclerotic plaque. The prevalent accumulation of LDL by macrophages provides strong support to the hypothesis that these cells play a crucial role in the pathogenesis of atherosclerosis.

A-Fib caused by Leaky Gut

32) Blöbaum, Leon, et al. “Intestinal barrier dysfunction and microbial translocation in patients with first-diagnosed atrial fibrillation.” Biomedicines 11.1 (2023): 176.

Oral bacteria in plaques

33) Jayasinghe, Thilini N., et al. “Identification of oral bacteria in the gut, atherosclerotic plaque, and cultured blood samples of patients with cardiovascular diseases–A secondary analysis of metagenomic microbiome data.” (2023).

Conclusion: Oral bacteria related to gingival and periodontal disease can be identified in the faeces, arterial plaque and blood samples of patients with CVDs.

34) Bouzid, Fériel, et al. “A potential oral microbiome signature associated with coronary artery disease in Tunisia.” Bioscience Reports 42.7 (2022): BSR20220583.

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!!!!!!!!!!!!!!!!   Vascular Calcification   !!!!!!!!!!!!!!!!!!!!

35) Neels, Jaap G., Claire Gollentz, and Giulia Chinetti. “Macrophage death in atherosclerosis: potential role in calcification.” Frontiers in Immunology 14 (2023).

36) free pdf
Lee, Sun Joo, In-Kyu Lee, and Jae-Han Jeon. “Vascular calcification—new insights into its mechanism.” International journal of molecular sciences 21.8 (2020): 2685.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Good !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Endotoxemia Ocurrs with All Fatty Meals !!!!

37) Canet-Soulas, Emmanuelle, et al. “The elusive origin of atherosclerotic plaque calcification.” Frontiers in Cell and Developmental Biology 9 (2021): 622736.

Plaques Are Calcified by Endochondral Ossification in Mice

These two articles clearly suggest that most calcium deposition in mouse plaque relies on VSMC [vascular smooth muscle cells] phenotypic change into hypertrophic chondrocytes. Many factors have been shown to stimulate VSMCs to transdifferentiate into mineralizing cells, but the vast majority are associated with inflammation and oxidative stress, which often go hand in hand (Demer and Tintut, 2011).

Plaque Ossification Appears to Be Stimulated by Inflammation in Mice

In addition, toll-like receptor (TLR)-2 and TLR-4 agonists such as lipopolysaccharide also stimulated VSMC change into chondrocytes in vitro, and ApoE–/– mice also deficient in TLR-2 developed reduced plaque calcification with reduced cartilage metaplasia (Lee et al., 2019). This effect of LPS might be relevant to plaque calcification, since endotoxemia occurs after virtually all fatty meals (Herieka and Erridge, 2014), and is associated with atherosclerosis (Wiedermann et al., 1999).

Oxidized LDL stimulated calcification in human VSMCs through TLR-4 and expression of osteochondrogenic factors (Song et al., 2017).

mouse plaques calcify through endochondral ossification, whereas human plaques more frequently develop independently of chondrocytes or osteoblasts

calcification on apoptotic debris is frequent in early plaques.

Histological examination of thousands of coronary arteries revealed that microcalcifications often form in proximity to apoptotic VSMCs, and that calcifying apoptotic macrophages are often seen in association with punctate calcifications resulting from microcalcifications (Jinnouchi et al., 2020)

These data strongly suggest that necrosis secondary to VSMC apoptosis induces or increases plaque calcification.

Calcification May Result From the Release of Extracellular Vesicles and the Activation of TNAP

Increasing data suggest that VSMCs release EVs that may initiate vascular calcification

macrophages have also been shown to release calcifying EVs (New et al., 2013; Aikawa and Blaser, 2021).

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Vitamin K

38) Vossen, Liv M., et al. “Pharmacological and nutritional modulation of vascular calcification.” Nutrients 12.1 (2019): 100.

Although statin therapy also has a proven role in the prevention and treatment of cardiovascular morbidity and mortality [15], it does not materially affect the rate of progression of coronary calcification [16]. More recently, even an accelerated increase in coronary artery calcification (CAC) was seen during statin treatment [17,18]. Altogether, the effects of conventional drug therapy on vascular calcification seem to be a bit disappointing. This has prompted several investigators to search for alternative methods to slow down the vascular calcification process. In this regard, dietary interventions with certain vitamins, notably vitamin K, have yielded promising results [19]. In addition to vitamin K, other dietary supplements (vitamin B, C, D, E, electrolytes,antioxidants)

Under normal circumstances, contractile vascular smooth muscle cells (VSMCs) which are able to take up calcium through calcium channels in their membrane regulate vessel wall tone and synthesize the calcification inhibitor matrix Gla-protein (MGP), which makes them resistant to calcification. Before being biologically active, MGP requires posttranslational carboxylation of specific protein bound glutamate-residues, a process which is catalyzed by the vitamin K dependent enzyme gamma-glutamylcarboxylase [20]. A variety of stress signals (Table 1) can induce a phenotypic switch of VSMCs towards an osteoblast-like cell type which contributes to pathological vascular
remodeling in both the media and the intima. To prevent apoptosis or calcification, VSMCs produce extracellular vesicles which are loaded with carboxylated, and hence active, MGP to prevent calcification nucleation [21]. In case of ongoing calcification pressure or, for instance, vitamin K deficiency, the extracellular vesicles may be faced with an excess of the inactive, uncarboxylated MGP, which makes them prone to support calcification. Once the extracellular matrix is calcified, VSMCs may
dierentiate into osteochrondrogenic VSMCs which produce less MGP, synthesize bone-associated proteins, and further fuel the vascular mineralization process, thus causing a vicious cycle [20]. Contrary to what was previously thought, calcification is not a passive phenomenon but a highly controlled process which involves many regulatory proteins.

Recently, Lee and coworkers reported on the results of the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) study, which is
a dynamic, multinational observational registry that prospectively collects data of patients who have undergone serial coronary computed tomography angiography [57]. Their data show that without
statin therapy, any increase in the coronary calcium score reflects progression in both previously noncalcified and already calcified plaque volumes. However, when statins are given, an increase in
calcium score indicates only progression in calcified plaques.

39) Shioi, Atsushi, et al. “The inhibitory roles of vitamin K in progression of vascular calcification.” Nutrients 12.2 (2020): 583.

Vlasschaert, Caitlyn, et al. “Vitamin K supplementation for the prevention of cardiovascular disease: where is the evidence? A systematic review of controlled trials.” Nutrients 12.10 (2020): 2909.

Vitamin E Prevents LDL Oxidation

40) Esterbauer, Herman, et al. “Role of vitamin E in preventing the oxidation of low-density lipoprotein.” The American journal of clinical nutrition 53.1 (1991): S314-S321.

41) Thomas, Shane R., and Roland Stocker. “Molecular action of vitamin E in lipoprotein oxidation: Implications for atherosclerosis.” Free Radical Biology and Medicine 28.12 (2000): 1795-1805.

42) Violi, Francesco, et al. “Interventional study with vitamin E in cardiovascular disease and meta-analysis.” Free Radical Biology and Medicine 178 (2022): 26-41.

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43) Neels, Jaap G., Claire Gollentz, and Giulia Chinetti. “Macrophage death in atherosclerosis: potential role in calcification.” Frontiers in Immunology 14 (2023).

44) Olejarz, Wioletta, Karol Sadowski, and Klaudia Radoszkiewicz. “Extracellular Vesicles in Atherosclerosis: State of the Art.” International Journal of Molecular Sciences 25.1 (2023): 388.

45) Buchet, René, et al. “Pathological biomineralization. Part I: Mineralizing extracellular vesicles in cardiovascular diseases.” Mineralizing Vesicles. Academic Press, 2024. 61-80.

46) Hashmi, Satwat, et al. “Beyond the Basics: Unraveling the Complexity of Coronary Artery Calcification.” Cells 12.24 (2023): 2822.

47) Yang, Shiqi, et al. “Vascular calcification: from the perspective of crosstalk.” Molecular Biomedicine 4.1 (2023): 35.

H. Pylori

48) Sundqvist, Martin O., et al. “Helicobacter Pylori Virulence Factor Cytotoxin-Associated Gene A (CagA) Induces Vascular Calcification in Coronary Artery Smooth Muscle Cells.” International Journal of Molecular Sciences 24.6 (2023): 5392.

49) Qiao, Kai, et al. “Roles of extracellular vesicles derived from immune cells in atherosclerosis.” Extracellular Vesicle 2 (2023): 100028.

50) Abduvalievich, Abdullaev Ikrom. “CALCIFICATION AND ATHEROSCLEROSIS OF THE CORONARY ARTERIES.” European Journal of Interdisciplinary Research and Development 15 (2023): 11-15.

51) Florea, Alexandru. “Sodium [18f] fluoride positron emission tomography for non-invasive identification of micro-calcifications as marker of atherosclerotic plaque vulnerability.” (2023).

52) Huang, Xiaofei, et al. “The Roles of Periodontal Bacteria in Atherosclerosis.” International Journal of Molecular Sciences 24.16 (2023): 12861.

53) Neels, Jaap G., Georges Leftheriotis, and Giulia Chinetti. “Atherosclerosis Calcification: Focus on Lipoproteins.” Metabolites 13.3 (2023): 457.

54) Guzman, Luis Fernando Escobar, et al. “Vascular Calcification, Insight in Its Pathophysiological Pathways, Genetics and Clinical Aspects.” (2023): 80-106.

55) Chen, Runji, et al. “Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis.” Journal of the American Heart Association 12.20 (2023): e031121.

56) Khatana, Chainika, et al. “Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis.” Oxidative medicine and cellular longevity 2020 (2020).

Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed.

Berberine

57) Ma, Shu-Rong, et al. “Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota.” Signal transduction and targeted therapy 7.1 (2022): 207.

58)  Peña-Jorquera, Humberto, et al. “Plant-based nutrition: Exploring health benefits for atherosclerosis, chronic diseases, and metabolic syndrome—A comprehensive review.” Nutrients 15.14 (2023): 3244.

59) Taylan, Gökay, et al. “The Relationship Between Premature Coronary Atherosclerosis and Helicobacter pylori Infection.” JOURNAL OF CLINICAL PRACTICE AND RESEARCH 45.1 (2023): 74-78.

Results: One hundred ninety nine patients included those with PCA [premature coronary artery disease]  [n=61 (30%)] (51% male, average age 35 years old). HPI [H Pylori infection] was detected in 70% of patients with PCA (n: 43). Statistically significant independent relationship between HPI and PCA was observed in the logistics regression analysis (p<0.001). Conclusion: HPI may be an independent risk factor for PCA.

Garlic

60) Yuristo, Eddy. “Garlic and Cardiovascular Disorders: A Current Review of Literature.” Eureka Herba Indonesia 4.1 (2023): 160-166.

61) Li, Min, et al. “Roles and mechanisms of garlic and its extracts on atherosclerosis: A review.” Frontiers in Pharmacology 13 (2022): 954938.

62) Wlosinska, Martiné, et al. “The effect of aged garlic extract on the atherosclerotic process–a randomized double-blind placebo-controlled trial.” BMC complementary medicine and therapies 20 (2020): 1-10.

One of the most serious secondary manifestations of Cardiovascular Disease (CVD) is coronary atherosclerosis. This study aimed to evaluate whether aged garlic extract (AGE) can influence coronary artery calcification (CAC) and to predict the individual effect of AGE using a standard process for data mining (CRISP–DM).
Method

This was a single-center parallel randomized controlled study in a university hospital in Europe. Patients were randomized, in a double-blind manner, through a computer-generated randomization chart. Patients with a Framingham risk score ≥ 10 after CT scan (n = 104) were randomized to an intake of placebo or AGE (2400 mg daily) for 1 year.

Main outcome measures were changes in CAC score and secondary outcome measures changes in blood pressure, fasting blood glucose, blood lipids and inflammatory biomarkers.
Result

104 patients were randomized and 46 in the active group and 47 in the placebo group were analyzed. There was a significant (p < 0.05) change in CAC progression (OR: 2.95 [1.05–8.27]), blood glucose (OR: 3.1 [1.09–8.85]) and IL-6 (OR 2.56 [1.00–6.53]) in favor of the active group. There was also a significant (p = 0.027) decrease in systolic blood pressure in the AGE group, from a mean of 148 (SD: 19) mmHg at 0 months, to 140 (SD: 15) mmHg after 12 months. The AGE Algorithm, at a selected probability cut-off value of 0.5, the accuracy score for CAC progression was 80%, precision score of 79% and recall score 83%. The score for blood pressure was 74% (accuracy, precision and recall). There were no side-effects in either group.
Conclusions

AGE inhibits CAC progression, lowers IL–6, glucose levels and blood pressure in patients at increased risk of cardiovascular events in a European cohort. An algorithm was made and was used to predict with 80% precision which patient will have a significantly reduced CAC progression using AGE. The algorithm could also predict with a 74% precision which patient will have a significant blood pressure lowering effect pressure using AGE.

63) Kravchuk, Olexandr M., et al. “Garlic supplement lowers blood pressure in 40-60 years old hypertensive individuals, regulates oxidative stress, plasma cholesterol and protrombin index.” Journal of Cardiovascular Medicine and Cardiology 8.2 (2021): 041-047.

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64) Epstein, Stephen E., et al. “Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry.” Arteriosclerosis, Thrombosis, and Vascular Biology 20.6 (2000): 1417-1420.

a case can be made for the concept that infection-induced molecular mimicry also contributes to the development of atherosclerosis.

65) Lamb, David J., Wafaa El-Sankary, and Gordon AA Ferns. “Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation.” Atherosclerosis 167.2 (2003): 177-185.

66) Chmiela, Magdalena, and Weronika Gonciarz. “Molecular mimicry in Helicobacter pylori infections.” World journal of gastroenterology 23.22 (2017): 3964.

67) Bachmaier, K., and J. M. Penninger. “Chlamydia and antigenic mimicry.” Molecular mimicry: infection-inducing autoimmune disease (2005): 153-163.

68) Binder, Christoph J., et al. “Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.” Nature medicine 9.6 (2003): 736-743.

69) Lunardi, Claudio, et al. “Induction of endothelial cell damage by hCMV molecular mimicry.” Trends in immunology 26.1 (2005): 19-24.

70) Leman, Luke J., Bruce E. Maryanoff, and M. Reza Ghadiri. “Molecules that mimic apolipoprotein AI: potential agents for treating atherosclerosis.” Journal of medicinal chemistry 57.6 (2014): 2169-2196.

Sessa, Rosa, et al. “Infectious burden and atherosclerosis: A clinical issue.” World Journal of Clinical Cases: WJCC 2.7 (2014): 240.

71) Chmiela, Magdalena, and Weronika Gonciarz. “Molecular mimicry in Helicobacter pylori infections.” World journal of gastroenterology 23.22 (2017): 3964.

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72) Budoff, Matthew J., et al. “When Does a Calcium Score Equates to Secondary Prevention?: Insights From the Multinational CONFIRM Registry.” JACC: Cardiovascular Imaging (2023).

73) Hecht, Harvey S., et al. “Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment.” The American journal of cardiology 87.4 (2001): 406-412.

74) Kelkar, Anita A., et al. “Long-term prognosis after coronary artery calcium scoring among low-intermediate risk women and men.” Circulation: Cardiovascular Imaging 9.4 (2016): e003742.

75) Mitchell, Joshua D., et al. “Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the Walter Reed Cohort Study.” JACC: Cardiovascular Imaging 11.12 (2018): 1799-1806.

76) The Skeptical Cardiologist Dr. Anthony Pearson, Prevention of Heart Attack and Stroke-Early Detection Of Risk Using Coronary Artery Calcium Scans In The Youngish January 19, 2019

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

78) Raggi, Paolo, Tracy Q. Callister, and Leslee J. Shaw. “Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy.” Arteriosclerosis, thrombosis, and vascular biology 24.7 (2004): 1272-1277.

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Header Images

79) Hutcheson JD, et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016;15(3):335-43

80) Rogers MA, et al. A1-dependent tethering promotes extracellular vesicle aggregation revealed with single-extracellular vesicle analysis. Sci Adv. 2020;6(38):ePub – PMID: 32938681

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81) Kawtharany, Lynn, et al. “Inflammation and microcalcification: A never-ending vicious cycle in atherosclerosis?.” Journal of Vascular Research 59.3 (2022): 137-150.

82) Montanaro, Manuela, et al. “The paradox effect of calcification in carotid atherosclerosis: microcalcification is correlated with plaque instability.” International Journal of Molecular Sciences 22.1 (2021): 395.

83) Vancheri, Federico, et al. “Coronary artery microcalcification: imaging and clinical implications.” Diagnostics 9.4 (2019): 125.

84) Akers, Emma J., Stephen J. Nicholls, and Belinda A. Di Bartolo. “Plaque calcification: do lipoproteins have a role?.” Arteriosclerosis, Thrombosis, and Vascular Biology 39.10 (2019): 1902-1910.

85) Ruiz, Jessica L., et al. “Zooming in on the genesis of atherosclerotic plaque microcalcifications.” The Journal of physiology 594.11 (2016): 2915-2927.

86) Hutcheson, Joshua D., et al. “Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.” Nature materials 15.3 (2016): 335-343.

87) Canet-Soulas, Emmanuelle, et al. “The elusive origin of atherosclerotic plaque calcification.” Frontiers in Cell and Developmental Biology 9 (2021): 622736.

Cardoso, Luis, and Sheldon Weinbaum. “Microcalcifications, their genesis, growth, and biomechanical stability in fibrous cap rupture.” Molecular, Cellular, and Tissue Engineering of the Vascular System (2018): 129-155.

88) Shi, Xuan, et al. “Calcification in atherosclerotic plaque vulnerability: friend or foe?.” Frontiers in physiology 11 (2020): 56.

89) Jinnouchi, Hiroyuki, et al. “Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability.” Atherosclerosis 306 (2020): 85-95.

90) New, Sophie EP, et al. “Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.” Circulation research 113.1 (2013): 72-77.

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91) Sabatine, Marc S., et al. “Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine 376.18 (2017): 1713-1722.

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92) Lindy, Otso, et al. “Statin use is associated with fewer periodontal lesions: A retrospective study.” BMC oral health 8.1 (2008): 1-7.

93) Jordan, Eboné, Yung‐Ting Hsu, and Jill Bashutski. “Do statin medications improve periodontal health and/or outcomes? A systematic review.” Clinical Advances in Periodontics 4.3 (2014): 194-202.

94) Shah, Monali, Prasad Muley, and Arti Muley. “Are statins worthy for treatment of periodontitis? A systematic review and meta-analysis.” Advances in Human Biology 7.1 (2017): 8-14.

95) Kumari, Minal, Santosh S. Martande, and Avani R. Pradeep. “Subgingivally delivered 1.2% atorvastatin in the treatment of chronic periodontitis among smokers: a randomized, controlled clinical trial.” Journal of investigative and clinical dentistry 8.2 (2017): e12213.

96) Kamel, Asem, et al. “Clinical and biochemical analysis for the adjunctive effects of simvastatin and metformin in the treatment of chronic periodontitis patients.” Egyptian Dental Journal 67.1-January (Oral Medicine, X-Ray, Oral Biology & Oral Pathology) (2021): 465-474.

97) Paju, Susanna, et al. “Is periodontal infection behind the failure of antibiotics to prevent coronary events?.” Atherosclerosis 193.1 (2007): 193-195.

98) Buhlin, Kåre, et al. “Periodontitis is associated with angiographically verified coronary artery disease.” Journal of clinical periodontology 38.11 (2011): 1007-1014.

100) Kasim, Manoefris, et al. “Improved myocardial perfusion in stable angina pectoris by oral lumbrokinase: a pilot study.” The Journal of Alternative and Complementary Medicine 15.5 (2009): 539-544.

101) Blaser, Mark C., and Elena Aikawa. “Roles and regulation of extracellular vesicles in cardiovascular mineral metabolism.” Frontiers in cardiovascular medicine 5 (2018): 187.

Figure 3. Accumulation and mineralization of calcifying EVs. (A) ALP produces inorganic phosphate (Pi) in the extravesicular space, and a mineral concentration gradient between the intra- and extra-vesicular spaces drives an influx of phosphate and calcium into EVs via suitable transporters. Hydroxyapatite nucleation is modulated by annexins and phosphatidylserines, leading to the production of calcified EVs and microcalcification; adapted from New and Aikawa (67). (B) Density-dependent color scanning electron microscopy (DDC-SEM) of calcified human atheroma (scale bar = 10 μm) reveals the accumulation of EVs as key building blocks of vascular calcification. (C) Pseudocolor transmission electron microscopy of macrophage-derived EVs reveals membrane-associated and intravesicular hydroxyapatite nucleation after calcium/phosphate treatment; adapted from New et al. (17) (scale bar = 200 nm).

Published on February 2nd, 2024 by Jeffrey Dach MD