Cardiovascular diseases

Heart disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels (arteries and veins). While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to arteriosclerosis (hardening of the arteries).

Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. in the arterial wall.

Excess 25-hydroxyvitamin D3 exacerbates tubulointerstitial injury in mice by modulating macrophage phenotype. 1)

According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., cardiovascular diseases result from the combined effects of communities of microbes that people gradually accumulate over time via the process of successive infectionAn infectious cascade of pathogens in which initial infectious agents slow the immune response and make it easier for subsequent infections to proliferate.. In fact, there is some evidence that arterial plaque may at least be partly composed of biofilm A structured community of microorganisms encapsulated within a self-developed protective matrix and living together., a community of diverse microbes that work together.

While many more pathogens will likely be identified in patients with cardiovascular diseases, certain easily cultured and readily identifiable microbes have been repeatedly identified in people with such conditions including H. pylori, cytomegalovirus, and Chlamydia pneumoniae.2) 3)

One of the best known links between two different inflammatory diseases – and a prototypical illustration of successive infection – is the relationship between cardiovascular diseases such as heart attack and stroke, and periodontal disease.

OlmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. , the most essential component of the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis., has several benefits for patients with cardiovascular disease, beyond its role in activating the innate immune system.

Types of cardiovascular disease

  • anginaPain felt in the chest due to insufficient blood supply to the heart, generally as the result of arteriosclerosis of the coronary arteries, usually experienced during exercise or stress
  • arrhythmia – A disruption of the regular rhythmic beating of the heart.
  • atherosclerosis – A process in which the blood vessels narrow and harden through build-up of plaque in the walls of arteries. Note that atherosclerosis is a more specific type of arteriosclerosis, which refers in a more general sense to the hardening of the arteries.
  • congestive heart failure – Develops when the heart’s pumping ability diminishes due to blockages or restriction of blood flow. With heart failure, the weakened heart can’t supply the cells with enough blood. This results in fatigue and shortness of breath.
  • coronary artery disease (CAD) – Refers to atherosclerosis in the coronary arteries, which supply the heart muscle with blood.
  • heart attack (coronary thrombosis, myocardial infarction [MI]) – When the heart muscle, or myocardium, stops functioning due to loss of blood flow, nutrients, or electric signal. 4)
  • high blood pressure (hypertension) – Besides being a measure of poor cardiovascular health, high blood pressure forces your heart and arteries to work harder, and your major organs are affected. You can live for a long time with no signs of high blood pressure, until the whole system begins to collapse under the workload. Reviewed in Hypertension (high blood pressure)
  • hypercholesterolemia (hyperlipidemia) – Chronic high levels of cholesterol in the blood. Reviewed in Tests: cholesterol and triglycerides (lipids).
  • stroke (cerebrovascular accident) – Strokes occur when blood vessels that carry oxygen and nutrients to the brain are either blocked by a clot (thrombosis or embolism) or burst. Blood (and oxygen) is no longer able to reach the brain, and the brain starts to die. Affects the arteries leading to and within the brain.
In samples collected from patients with coronary artery disease, more than 50+ species were found in coronary artery plaque. The arrows point to groups of bacteria emitting a fluorescent signal. Source: Ott et al.

Evidence of infectious cause

Immunoinflammatory processes due to chronic infection are thought to be one of the definitive atherogenetic processes.

K. Ayada et al.5)

According to the Marshall Pathogenesis, cardiovascular diseases result from the combined effects of communities of microbes that people gradually accumulate over time via the process of successive infection.

Role of infectious burden in cardiovascular disease

Chronic and acute infections have been implicated as risk factors that increase the risk of stroke, myocardial infarction and other vascular events. The lack of consistency among studies attempting to link exposure to infectious pathogens and cardiovascular disease risk is evidence that a single pathogen is likely not responsible for these diseases. However:

Reconsidering exposure as an “infectious burden” (IB) aligns with our understanding that the totality of pro-inflammatory agents can contribute to atherosclerosis and vascular risk. We define IB as the cumulative life-course exposure to infectious agents that elicit strong inflammatory responses….

Elkind et al.6)

Arterial plaque may contain biofilm

Arterial plaque may contain and/or be caused by biofilm, that is, a community of diverse microbes that work together. Ott et al.'s work which showed a diverse groups of bacterial “signatures” in atherosclerotic lesions of patients with coronary heart disease. Using 16S rDNA sequencing, the team was able to identify over 50 different species including Staphylococcus species, Proteus vulgaris, Klebsiella pneumoniae, and Streptococcus species in plaque. The team concluded, “Detection of a broad variety of molecular signatures in all [coronary heart disease] specimens suggests that diverse bacterial colonization may be more important than a single pathogen.”7)

In a commentary following Ott's paper, Katz and Shannon concluded that his work suggested that atherosclerotic plaques are composed of “functional biofilm.” The team noted that the characteristics of a “mature” arterial wall make it well-suited for biofilm formation. These findings further suggest:

A “conspiracy” of bacterial pathogens as opposed to a single infection is involved in atherogenesis, which may help to explain the inefficacy of antibiotics, such as macrolides or fluoroquinolones, in clinical trials.

Joel T. Katz, MD and Richard P. Shannon, MD 8)

Immune cells are abundant in the walls of the arteries even during the initial stages of plaque formation.9) Macrophages have been shown to infiltrate arterial plaque and express a variety of matrix-degrading enzymes that weaken and sometimes break apart the fibrous caps which holds the plaque intact.10) 11) A portion of arterial plaque consists of apoptized (dead) macrophages.

Individual pathogens already implicated in cardiovascular disease

While many more pathogens will likely be identified in patients with cardiovascular diseases, certain easily cultured and readily identifiable microbes have been repeatedly identified in people with such conditions. These include:

  • Chlamydia pneumoniaeC. pnuemonia can readily switch between reproductive and latent forms12) – and, as an intracellular gram-negative bacterium, has been shown to infect macrophages responsible for degrading plaque.13) Mycoplasma pneumoniae, another intracellular pathogen, has also been associated with atherosclerosis.14) A number of studies have been conducted to determine the specific association between C. pneumoniae and the development of atherosclerotic plaque. This association was first suggested in 1988, when it was discovered that patients with cardiovascular disease or acute myocardial infarction (AMI) were more likely to have antibodies to C. pneumoniae in their blood.15) Arcari et al.16) studied the link between C. pneumoniae seropositivity and AMI in males aged 30 to 50. The authors found a significantly higher risk of AMI in patients who had high titers to C. pneumoniae immunoglobulin A (IgA) within the previous one to 5-year period. This risk persisted after adjusting for other cardiovascular risk factors. C. pneumoniae has been detected in more than 40% of atherosclerotic plaques,17) 18) and has been shown (along with cytomegalovirus) to directly disseminate into the arterial vessel walls.19) Smoking, an independent risk factor for cardiovascular disease, has also been shown to be an independent risk factor for C. pneumoniae seropositivity. It has also been suggested that an exacerbation of C. pneumoniae infection through smoking cigarettes may increase the potential for a systemic infection and therefore increase the chance for development of atherosclerosis.20)

Taken together [the large variety of demonstrated proatherogenic changes set into motion by Chlamydia pneumoniae] suggested that Cpn infections could contribute to the initiation and progression of atherosclerosis leading to atherosclerotic plaque growth and increased arterial stenosis. Moreover, Cpn infection may also play a role in the development of an unstable atherosclerotic plaque leading to acute cardio- and/or cerebrovascular events.

Frank R. Stassen 21)

  • Cytomegalovirus – Cytomegaloviruses (CMV) can cause acute, persistent and latent infections in both humans and animals. Of all herpes viruses, CMV has been most frequently associated with atherosclerosis in epidemiological, experimental and clinical studies.22) First evidence for a role for CMV in cardiovascular disease comes from studies demonstrating the presence of CMV antigens or nucleic acids in the diseased vascular wall.23) Likewise, CMV nucleic acids have repeatedly been detected in arteries obtained from atherosclerotic patients. More importantly, viral presence was higher in arterial biopsies of patients undergoing reconstructive vascular surgery as compared to patients with early atherosclerosis.24) 25) Also, a positive correlation between CMV and cardiovascular disease has been demonstrated in a variety of studies examining blood markers in diseases.26) Several studies showed the level of CMV antibodies to be gradually related to increased intimal-medial thickening (a measure of the thickness of artery walls). No association were found between low CMV antibody titers and cardiovascular disease, but a clear association was found when the height of the titers was taken into account. Stassen et al. conclude, “In summary, a large variety of data support the hypothesis that CMV contribute to atherogenesis.”27)
  • Helicobacter pyloriH. pylori is a known causal agent of several gastrointestinal diseases and has also been implicated in ischemic heart disease (reduced blood supply to the heart muscle). Researchers have proposed a number of mechanisms by which H. pylori may accelerate cardiovascular disease. Ayada states that local inflammatory and immune responses against H. pylori in the stomach can induce systemic (including atherosclerotic lesions) immune reactions due to the chronic nature of the infection.28) There is also speculation that H. pylori may act directly on atherosclerotic plaques, because studies have found its DNA in arterial plaque.29) Other studies suggest that H. pylori may induce platelet aggregation, and thereby play a role in the acute phase of ischemic heart disease.30) A recent meta-analysis indicates that infection with certain more virulent strains of H. pylori may provoke an intense immune response and precipitate coronary events.31)
  • Porphyromonas gingivalisP. gingivalis appears to have an important role in the initiation and progression of atherosclerosis.32) Gibson et al. showed that immunizing mice against P. gingivalis prevents acceleration of atherosclerosis.33) For more on P. gingivalis and other known periodontal pathogens, see below.

Other evidence

  • Common infections predispose a person to stroke and heart attack – In a prospective cohort study, a composite measure of Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2 infection, were associated with a higher risk of stroke and other vascular events.34) Diarrhea as an infant (the primary cause of which is microbial infection) has been associated with later cardiovascular disease.35) Further, influenza vaccination was associated with a 50% reduction in the incidence of sudden cardiac death, acute myocardial infarction (heart attack), and ischemic stroke. Both heart attack and stroke have their peak incidence in winter months, which correspond to the time of year when cases of influenza also peak.36)
  • Common infections and cardiovascular diseases share the same inflammatory markers – As Costa et al. have pointed out,37) inflammatory markers that are risk factors for heart attack and stroke are also elevated during lower respiratory tract infections as well as during infections such as rheumatic fever, syphilis, diarrhea, malaria, and tuberculosis.38) 39) 40) 41)
  • prenatal exposure to influenza and cardiovascular disease – Prenatal exposure to the 1918 influenza pandemic (Influenza A, H1N1 subtype) is associated with >/=20% excess cardiovascular disease at 60 to 82 years of age, relative to cohorts born without exposure to the influenza epidemic, either prenatally or postnatally. These findings suggest novel roles for maternal infections in the fetal programming of cardiovascular risk factors that are independent of maternal malnutrition.42)
  • evolutionary analysis suggests cardiovascular disease is not caused by lifestyle or genetic factors – Atherosclerosis has been identified in Egyptian mummies.43) This suggests that whatever factors cause atherosclerosis has existed for at least several millenia. If it were true that a factor such as a harmful allele for a gene or the consumption of fatty foods caused atherosclerosis, the human species would have had several millenia to evolve a defense for this vulnerability to disease or, at the very least, to weed this trait out of the population.44)

Infections May be Causal in the Pathogenesis of Atherosclerosis

A causal relationship between periodontal disease and cardiovascular disease?

One of the best known links between two different inflammatory diseases – and a prototypical illustration of successive infection – is the relationship between cardiovascular diseases such as heart attack and stroke, and periodontal disease. A BMJ paper showed a correlation between dental disease and systemic disease (stroke, heart disease, diabetes). After correcting for age, exercise, diet, smoking, weight, blood cholesterol level, alcohol use and health care, people who had periodontal disease had a significantly higher incidence of heart disease, stroke and premature death. More recently, these results were confirmed in studies in the United States, Canada, Great Britain, Sweden, and Germany. The magnitude of the association is striking: one study found that people with periodontal disease had a two times higher risk of dying from cardiovascular disease.45)

A 2010 study using pyrosequencing compared the bacterial diversity of atherosclerotic plaque, oral, and gut samples of 15 patients with atherosclerosis, and oral and gut samples of healthy controls.46) The team concluded that there was a high degree of correlation between the presence of certain bacteria in the oral cavity (and to a somewhat lesser extent the gut) with bacteria in the gastrointestinal tract. Interestingly, several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels. A 2011 study that compared heart attack victims to healthy volunteers found the heart patients had higher numbers of bacteria in their mouths.47) Their tests on 386 men and women who had suffered heart attacks and 840 people free of heart trouble showed two types – Tannerella forsynthesis and Prevotella intermedia – were more common among the heart attack patients. Interestingly, the total number of species that could be identified in the saliva was the best indicator that somebody was likely to have had a heart attack.

Successive infection dictates that as a person accumulates pathogens in one area of the body, those pathogens likely have mechanisms that allow them to slow the immune response. So, if people harbor greater number of pathogens in their mouths, the immune response may slow in the heart and arteries, making it easier for microbes to spread their as well. The same can be said for the opposite scenario. Also, it may be possible that microbes in the mouth spread toward the heart and arteries, although this has yet to be completely confirmed. However, some of the same bacteria identified in the salivary microbiome, such as Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis - both of which cause tooth decay48) - have also been identified in atherosclerotic plaque.49) 50)

Work by Kozarov et al. strongly suggests that “the key step [towards systemic infection] is the persistence of intracellular bacteria in phagocytes.” Bacterial strains, they conclude, “once in the circulation, are internalized by phagocytic cells, at which stage selected species avoid immediate killing and spread and colonize distant sites.”51) The group also showed that older patients, when compared to younger controls, have atheromas (plaques) which contain greater proportions of pathogens traditionally associated with periodontitis.52)

Our data demonstrate that the elderly individuals (mean age 67 years) have higher incidence of periodontopathogens in their plaques than the younger individuals…. Species from the Bacteroides family were found in about 17% of the young but in about 80% of the elderly patients, as expected given the association of this family with adult and refractory periodontitis.

Kozarov et al.53)

Given these similarities between the two disease states, along with the evidence presented above, it would be surprising if cardiovascular disease were not also definitively shown to be caused by the communities of microbes.


C-reactive protein

Main article: C-reactive protein

C-reactive protein (CRP) is an important and evolutionarily ancient component of the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease..54) CRP has been described as “the prototypical acute-phase reactant to infections and inflammation in human beings.” In the clinical setting, CRP is used “as a clinical indicator of acute infections and response to treatment, and to assess inflammatory status in chronic diseases.”55) Initially it was thought that CRP might be a pathogenic secretion as it was elevated in people with a variety of illnesses including cancer.56) However, discovery of synthesis in the liver demonstrated that it is manufactured by the human body.

The fact that CRP is an independent predictor of stroke and coronary artery disease but also a key contributor to effective bacterial clearance,57) underscores the importance of microbes in the pathogenesis of these diseases. Some patients on the Marshall Protocol (MP) have reported temporary increases in CRP, an observation which is consistent with a heightened immune response.

CRP's name comes from its capacity to bind the C-polysaccharide of Streptococcus pneumoniae, which provides innate defense against pneumococcal infection.58)

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The lipid profile is a group of tests that are often ordered together to determine risk of coronary heart disease such as heart attack or atherosclerosis. The lipid profile typically includes:

  • high density lipoprotein cholesterol (HDL-C) — often called “good” cholesterol
  • low density lipoprotein cholesterol (LDL-C) — often called “bad” cholesterol
  • total cholesterol
  • triglycerides

In many of the diseases the Marshall Protocol (MP) treats, patients may present with elevated cholesterol. Traditionally, it has been assumed that the elevated cholesterol is causing or contributing to the disease process. However, the alternate hypothesis is no less plausible; in certain inflammatory diseases, the body may be deliberately upregulating levels of cholesterol in order to better manage the disease process. Increasing evidence suggests that this alternative explanation may be true.59) 60) For example, a 2010 study found that several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels61), and another study found that high cholesterol protects against endotoxemia.62)

Both “good” and “bad” forms of cholesterol play pivotal roles in fighting infection, for example, scavenging endotoxins that are released during destruction of pathogenic bacterial forms. While higher levels of total cholesterol are associated with some forms of cardiovascular disease in some patient populations, a number of statistically significant inverse correlations have been found between total cholesterol and various diseases including chronic heart failure, respiratory and gastrointestinal diseases, and various acute infections.

Correlations between the abundances of different genera and disease markers in oral and fecal samples. Pearson correlation coefficients are represented by color ranging from blue, negative correlation (−1), to red, positive correlation (1). (A) Oral samples; (B) Fecal samples. Significant correlations are noted by *P < 0.05; <html></html>P < 0.01, and <html>*</html>P < 0.001. Source: Koren et al.

Thus, high cholesterol levels among patients on the MP are not seen as a problem but as a sign of the inflammatory response to infection. This means that MP patients do not need to take any measures to lower cholesterol. Over time, as the MP medications work to gradually lower infectious agents causing inflammation, it is expected that cholesterol will return to a normal range. In this same vein, statins, in particular, should not be used to lower cholesterol, because they have effects on the same receptors as olmesartan, which may prevent the drug from working effectively.

<html><!– Most researchers today consider that a high intake of saturated fat and elevated LDL cholesterol are the most important causes of atherosclerosis and coronary heart disease. This lipid hypothesis has dominated cardiovascular research and prevention for almost half a century although the number of contradictory studies may exceed those that are supportive.63)

Both “good” and “bad” form of cholesterol play pivotal roles in fighting infection, for example, scavenging endotoxins that are released during destruction of pathogenic bacterial forms. While higher levels of total cholesterol are associated with some forms of cardiovascular disease in some patient populations, a number of statistically significant inverse correlations have been found between total cholesterol and various diseases including chronic heart failure, respiratory and gastrointestinal diseases, and various chronic infections as well.

There is also broad evidence that cholesterol does not promote plaque as evidenced by studies that show therapies which directly lower cholesterol may make patients sicker. The article devoted to statins reviews the evidence that statins offer mild protection against disease not through its effect on cholesterol but through their underreported immunomodulatory properties.

Some patients on the Marshall Protocol (MP) have reported temporary increases in cholesterol and triglycerides, an observation which is consistent with a heightened immune response.


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The cumulative evidence suggests that infections may induce or promote atherosclerosis.64) 65) 66) 67) 68) 69) 70) From our point of view, scientists might readily explain the correlation between infections and atherosclerosis on the basis of the double-edged sword property of the anti-infective immune effects of lipoproteins, and might be able to design more rational and systemic experiments to test this correlation.

R. Han 71)

much confusion has arisen from unclear nomenclature with regard to polyunsaturated fatty acids and the lack of reporting of food sources in prospective cohorts. Data from prospective cohort studies and randomized controlled trials generally support the replacement of saturated fats with mixed polyunsaturated fatty acids to reduce the risk of death from coronary artery disease. However, it is unclear whether oils rich in omega-6 linoleic acid but low in omega-3 α-linolenic acid also reduce this risk.

Richard P. Bazinet, PhD and Michael W.A. Chu, MD MEd 72)

Key points

  • The replacement of dietary saturated fats with some, but not all polyunsaturated fatty acids reduces serum cholesterol levels and the risk of heart disease.
  • New analyses suggest that replacing saturated animal fats with linoleic acid, an omega-6 polyunsaturated fatty acid, lowers serum cholesterol levels but increases the risk of death from coronary artery disease.
  • Health Canada’s Food Directorate should reconsider the health claim that omega-6 polyunsaturated fatty acids reduce the risk of heart disease by lowering blood cholesterol levels.

Richard P. Bazinet, PhD and Michael W.A. Chu, MD MEd


Related article: Folic acid and folate

A high level of blood serum homocysteine (known as “homocysteinemia”) is a strong risk factor for cardiovascular disease,73) This has led some to conclude homocysteine “has many deleterious cardiovascular effects.”74) However the amino acid does not appear to cause disease.

Because supplementation of the B vitamins lower levels of homocysteine, one common intervention for altering this risk factor is to supplement patients at risk for cardiovascular disease with folic acid (B9), pyridoxine (B6), and cyanocobalamin (B12). In fact, interventions designed to lower levels of homocysteine with high-dose supplementation of the B vitamins been equivocal, in some cases, seeming to exacerbate disease.

  • A 2010 study by House et al. has shown substantial adverse outcomes associated with high-dose B vitamins in patients with advanced diabetic nephropathy.75) These side effects included myocardial infarction, stroke, revascularization, and all-cause mortality. According to one commentator, unless other explanations come to light in further analyses of the study, these findings make repetition of a similar trial in this high-risk patient group unethical.
  • The Heart Outcomes Prevention Evaluation (HOPE-2) study, involved 5,522 patients with vascular disease or diabetes mellitus and found no effect of high-dose B6, B9 and B12 cosupplementation on death from cardiovascular disease, whereas the risk of stroke was decreased and the risk of unstable angina requiring hospitalization was increased.76)

Marino et al. showed that eradication of Helicobacter pylori associated with gastritis reduced abnormally high levels of homocysteine.77)

The role of hyperhomocysteinemia in coronary artery disease (CAD) patients remains unclear. 78)

Effect of olmesartan on cardiovascular diseases

As is the case with the antivirals,79) antibiotics such as clarithomycin have consistently failed to reduce the rate of cardiovascular disease.80) However, these failures are not conclusive evidence that cardiovascular diseases are not caused by infections nor do they show that these diseases cannot be treated as a chronic infection. These trials did not induce immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed. and they did not use high dose olmesartan, which has several benefits beyond its role in activating the innate immune system.

Several prospective, randomized studies show vascular benefits with olmesartan medoxomil: reduced progression of coronary atherosclerosis in patients with stable angina pectoris (OLIVUS); decreased vascular inflammatory markers in patients with hypertension and micro- (pre-clinical) inflammation (EUTOPIA); improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis (MORE); and resistance vessel remodeling in patients with stage 1 hypertension (VIOS).

R. Preston Mason81)

Olmesartan and other ARBs have been used to block various bad effects of Angiotensin II, including heart failure. In this regard, olmesartan has been shown to:-

  • protect the heart from damage from inflammation in myocarditis82)
  • ameliorate acute experimental autoimmune myocarditis, in rats, suppressing cytotoxic myocardial injury 83)
  • prevent acute left ventricular dysfunction84)
  • lower C-reactive protein, one of the acute phase proteins that increase during systemic inflammation85)
  • act as an antiarrhythmic86)
  • block the production of Angiotensin II, thus improving mortality rates in heart failure patients87)
  • This study demonstrated that olmesartan reduced angiotensin II and aldosterone levels more effectively than azilsartan, resulting in a stable antihypertensive effect. Olmesartan also had an inhibitory effect on cardiac hypertrophy. Accordingly, it may be effective for patients with increased RAAS activity after cardiac surgery or patients with severe cardiac hypertrophy. 88)

Pharmacotherapy targeting the renin-angiotensin system [the mechanism of the ARBs] is one of the most effective means of reducing hypertension and cardiovascular morbidity.89) 90)

Nien-Chen Li et al.91)

Olmesartan has also been shown to

  • prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes 92)
  • reduce the volume of atherosclerotic plaques93) 94)
  • mildly reduce the risk of stroke in people at high risk for strokes (cerebrovascular events).95)
  • significantly remodel and destiffen the arterial wall material during long-term treatment 96).

Jigsaw wrote Since Elizabeth Blackburn won a Nobel prize for telomerase in 2009, I have wondered what effect olmesartan might have on it. Are our telomeres getting shorter and shorter, so we just go POP? while getting healthier and healthier in other respects. This report 97) is re-assuring. Olmesartan raises ACE2 which converts angII to Ang 1-7

Other treatments

  • statins – As the 2008 ENHANCE trial illustrates, while high cholesterol is correlated with increased incidence of diseases, lowering cholesterol does not appear to improve human health.98) Indeed, there is some evidence this type of intervention does the opposite.99) The statins have a range of documented negative effects, some of which may be immunopathological. Because statins may interfere with the Marshall Protocol, these drugs are contraindicated.
  • diuretics – A diuretic is any drug that elevates the rate of urination and thus provides a means of forced diuresis. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class of diuretic does so in a distinct way. Some diuretics are contraindicated for MP patients.
  • diet and exercise – It has been widely hypothesized that a poor diet and a lack of exercise are driving the recent surge in obesity and cardiovascular disease – diseases which are closely linked. But, even the most ambitious intervention programs, which have gone to great lengths to increase rates of exercise and improve eating habits of a population, have failed. One 1999 $200,000 NIH-funded intervention, known as the Pathways program, was performed on two groups of children. Pathways involved a substantial increase in physical education programs, classes about nutrition, significant reduction in fat and calorie content of all school meals, and several other health related measures - and all as part of a randomized controlled trial, the gold standard in studies. The primary goal of the study was to reduce the rate of body fat (a risk factor for cardiovascular disease) in the intervention group, but after the three-year intervention the percent of body fat in both groups was essentially identical. The researchers were unable to explain the failure of their intervention.100) Other such trials for obesity have been equally unsuccessful.101)
  • beta-blockers – In the aftermath of a heart attack, a beta-blocker will reduce consumption of limited oxygen supplies by slowing a straining heart. This intervention appears to be a sensible one in light of the assumption that heart failure is caused by the heart over-exerting itself. Yet the best study to date has shown that this routinely prescribed class of drugs increases heart failure and overall death.102) 103)
  • anti-arrhythmics – Ventricular arrhythmia is correlated with an almost 400% increase in the risk of death from cardiac complications, but a large randomized controlled trial showed that the drugs encainide and flecainide tripled the risk of death from other causes when compared with placebo.104)
  • vitamin D – According to results shared at a 2012 conference, patients with 25-DThe vitamin D metabolite widely (and erroneously) considered best indicator of vitamin D "deficiency." Inactivates the Vitamin D Nuclear Receptor. Produced by hydroxylation of vitamin D3 in the liver. levels above 100 nanograms per 100ml, were 2.5 times more likely to have atrial fibrillation as those with more moderate levels (41-80ng/100ml). A 2012 randomized controlled trial conducted over four months showed that daily doses of 2500 IU of vitamin D do not protect against cardiovascular disease risk.105)

The level of vitamin D in our blood should neither be too high nor to low. Scientists have now shown that there is a connection between high levels of vitamin D and cardiovascular deaths. vitamin D is suspected of increasing mortality rate

According to a 2006 estimate, 18% of the global cancer burden is attributable to infectious agents, but almost every indication is that this figure is far too conservative.106) Researchers confined by the logic of Koch's postulatesCentury-old criteria designed to establish a causal relationship between a causative microbe and a disease. Koch's belief that only one pathogen causes one disease has now been called into question as multiple postulates are increasingly considered out of date. have looked for a single microbe causing a single disease. Evidence suggests, however, that it is communities of microbes that are responsible for cancer. According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., chronic microbes persist, in large part, by dysregulating the Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.), a key nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. with a well-characterized role in both the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. and metastasis suppression. Indeed one of the hallmarks of cancer is a disruption in the vitamin D endocrine system including high 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol. and slowed activity of the receptor. As they progressively multiply through a process known as successive infectionAn infectious cascade of pathogens in which initial infectious agents slow the immune response and make it easier for subsequent infections to proliferate., microbes elicit an inflammatory response, a response which has been shown to increase over time the risk of metastasis.

Several patients have worked with their doctors to treat their cancer with the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis.. However, the MP appears to be most effective as a preventative measure.

It may be particularly important for MP patients with cancer in the family to avoid caffeine as far as possible.

“It is difficult to assess the practical significance of phagocytic suppression, but our previous work (unpublished) has shown that cancer cells can suppress phagocytosis in a similar manner. If this is the case, caffeine may be aiding in the suppression of immune response in the tumor microenvironment.” 107)

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Vitamin D supplementation is ineffective in improving cardiovascular health among various patient populations, including in the presence or absence of vitamin D deficiency. 108)

Patient interviews

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neurosarcoidosis, systemic sarcoidosis; spasticity, myasthenia, CNS dysfunction, joint pain, pulmonary, splenic and cardiac involvement

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sarcoidosis of the heart, coronary artery disease, atrial fibrillation

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Interviews of patients with other diseases are also available.

Patients experiences

I am happy to report that on the MP, my cardiac symptoms [including angina, cardiac arrhythmias] have been reduced at this point to almost nil.

Even with a good size dose of Verapamil daily and nitroglycerine, pre-MP, I was experiencing cardiac symptoms and events. Once I started the Benicar, they stopped. :) I haven't had to pop sub-lingual nitroglycerine tabs since starting! (Prior to starting the Benicar, I was taking 3 nitro tabs during an event, and then sometimes that wasn't enough.)

Hrts, MarshallProtocol.com

My heart inflammation over the past year has diminished considerably and so I no longer have the pain levels that I once suffered. That to me verifies that I am improving and I am on the right track. I still get heart herxes but they are controllable, and the pressure and arrhythmia, although are very irritating, no longer cause me such concern. I have been through the cycles enough times to have a good feel for what is going on and I can regulate them without too much distress.

CelticLadee, MarshallProtocol.com

When I was diagnosed with MVP [mitral valve prolapse], I was told I might also have dysautonomia, an imbalance of the central nervous system. This is part of something called MVP Syndrome, and the imbalance can cause jittery anxiety, irritable bowel syndrome, headaches, physical sensations that mimic low blood sugar, etc. So I decided that I must have this syndrome, because I had all these symptoms. Now I realize it probably all goes back to the sarcoidosis.

If you look at the symptoms list, you'll be amazed at how many of them are Th1 inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. disease symptoms. There's also a link to anxiety/depression. When I found this site 10 years ago I was relieved to find that I wasn't the only MVP person suffering with odd things. At different times, I've suffered from about 90% of the MVP Syndrome symptoms listed, but then I found the MP site and it all began to click.

Jen Hicks, MarshallProtocol.com

More information

Hyperuricaemia was associated with an unfavourable cardiovascular risk profile in HF patients. Treatment with low doses of allopurinol did not improve the prognosis of HF patients. 109)

Increased risks per 10 000 person-years found in estrogen plus progestin therapy for 16608 healthy postmenopausal women (studied over 5 years) were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers. 110)

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Sallie Q 08.25.2017 removed broken links

Sallie Q 06.04.2017 adding uTube on smart meter effect


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Benicar and cardiovascular events: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789932/?tool=pubmed https://clinicaltrials.gov/ct2/show/NCT00185159?term=ROADMAP&rank=2 https://clinicaltrials.gov/ct2/show/NCT00141453?term=ORIENT+olmesartan&rank=1 https://www.biosciencetechnology.com/News/Feeds/2010/06/sections-regulatory-news-fda-drug-safety-communication-ongoing-safety-revi/

FDA Drug Safety Communication: Ongoing safety review of Benicar and cardiovascular events

[Cardiovascular effects of VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. and CaSR activation.] Brancaccio D, Cozzolino M G Ital Nefrol ; 26(S-49) :18-22 Download citation Affiliation Cattedra di Nefrologia, Universita' degli Studi, Milano and Unita' di Nefrologia e Centro Dialisi Simone Martini, Milano - Italy. Abstract Cardiovascular complications are the most common cause of death in uremic patients, especially those on chronic dialysis. One of the major findings is massive calcium deposition in the vessel walls. There is general consensus about the correlation between the distribution of vascular calcification and increased risk of death due to cardiovascular disease. An emerging issue is the possible beneficial role of vitamin D receptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDR) activation in reducing the morbidity and mortality rates in patients on chronic dialysis, as shown in large, although retrospective, studies. Still open is the possible role of CaSR activators in ameliorating the clinical course of patients on dialysis, although calcimimetics are able to improve the Ca-P-PTH serum profile and increase the number of patients within the international guidelines parameters. This review has been structured to give the readers an updated opinion on the possible positive impact of VDR and CaSR activators in terms of all-cause and cardiovascular morbidity and mortality in dialysis patients.

See this too: https://www.theheart.org/article/1024539.do

Lancet. 2009 Nov 28;374(9704):1840-8. Epub 2009 Nov 16. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.111)

Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, Riegger GA, Malbecq W, Smith RD, Guptha S, Poole-Wilson PA; HEAAL Investigators. Collaborators (293) Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. mkonstam@tuftsmedicalcenter.org Erratum in: Lancet. 2009 Dec 5;374(9705):1888. Comment in: Lancet. 2009 Nov 28;374(9704):1808-9. Lancet. 2010 Mar 27;375(9720):1079; author reply 1079-80. Expert Opin Pharmacother. 2010 Aug;11(12):2117-9. Lancet. 2010 Mar 27;375(9720):1079; author reply 1079-80. Evid Based Med. 2010 Apr;15(2):51-2. Abstract BACKGROUND: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS: This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS: Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION: Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. doses to confer clinical benefit. FUNDING: Merck (USA). PMID: 19922995

Need to put this in Science Behind Olmesartan, etc. also

Heart Vessels. 2010 Nov 10. [Epub ahead of print]

Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients.

Miyoshi T, Doi M, Hirohata S, Kamikawa S, Usui S, Ogawa H, Sakane K, Izumi R, Ninomiya Y, Kusachi S. Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan, miyoshit@cc.okayama-u.ac.jp. Abstract

Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P < 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.

PMID: 21063874

Expression of the vitamin d receptor is increased in the hypertrophic heart. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690395/?tool=pubmed

The liganded vitamin D receptor is thought to play an important role in controlling cardiac function. Specifically this system has been implicated as playing an anti-hypertrophic role in the heart. Despite this, studies of the VDR in the heart have been limited in number and scope. In the present study we use a combination of real time PCR, Western blot analysis, immunofluorescence and transient transfection analysis to document the presence of functional VDR in both the myocytes and fibroblasts of the heart, as well as in the intact ventricular myocardium. We also demonstrate the presence of 1-α-hydroxylase and 24-hydroxylase in the heart, two enzymes involved in the synthesis and metabolism of 1,25 dihydroxyvitamin D (VD3). VDR is shown to interact directly with the human B-type natriuretic peptide (hBNP) gene promoter, a surrogate marker of the transcriptional response to hypertrophy. Of note, induction of myocyte hypertrophy either in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory. or in vivoA type of scientific study that analyzes an organism in its natural living environment. leads to an increase in VDR mRNA and protein levels. Collectively, these findings suggest that the key components required for a functional VD3-dependent signaling system are present in the heart and that this putatively anti-hypertrophic system is amplified in the setting of cardiac hypertrophy.

Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients.


Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P < 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.

Body's Bacteria Affect Atherosclerosis https://www.sciencedaily.com/releases/2010/10/101018074538.htm

“The causes of atherosclerosis have recently become clearer, but we know less about why the plaque in the arteries ruptures and contributes to clot formation,” says Fredrik Bäckhed, researcher at the Sahlgrenska Academy's Department of Molecular and Clinical Medicine.

Inflammation increases the risk of the plaque rupture in the arteries, but the underlying mechanisms for inflammation are not clear. Our bodies are home to ten times more bacteria than cells, and research in recent years has shown that our gut flora is altered in obesity , which over time may lead to cardiovascular disease. Poor dental health and periodontitis have also been linked to atherosclerosis, which would indicate that the bacteria in the mouth or gut could affect the condition.

“We tested the hypothesis that bacteria from the mouth and/or the gut could end up in the atherosclerotic plaque and thus contribute to the development of cardiovascular disease.”

The researchers initially found that the number of bacteria in the plaque correlated with the number of white blood cells, a measure of inflammation. Next they used modern sequencing methods to determine the composition of the bacteria in the mouth, gut and arterial plaque of 15 patients, and in the mouth and gut of 15 healthy control subjects. They found that several bacteria were found in the atherosclerotic plaques and, primarily, the mouth, but also the gut, of the same patient and that the bacteria Pseudomonas luteola and Chlamydia pneumoniae were present in all atherosclerotic plaques. These results would suggest that the bacteria can enter the body from the mouth and gut and end up min the plaque where they ultimately may contribute toinflammation and rupture of the plaque. The researchers also found that some of the bacteria in the mouth and gut correlated with biomarkers associated with cardiovascular disease.

“Finding the same bacteria in atherosclerotic plaque as in the mouth and gut of the same individual paves the way for new diagnosis and treatment strategies that work on the body's bacteria,” says Bäckhed. “However, our findings must be backed up by larger studies, and a direct causal relationship established between the bacteria identified and atherosclerosis.”

Med Hypotheses. 2011 Jan 7. [Epub ahead of print] Infectious atherosclerosis: Is the hypothesis still alive? A clinically based approach to the dilemma.

Alviar CL, Echeverri JG, Jaramillo NI, Figueroa CJ, Cordova JP, Korniyenko A, Suh J, Paniz-Mondolfi A.

St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.


Among the multiple factors involved in the pathophysiology of heart disease, infections have been proposed to play a role in atherosclerosis with most of the available evidence implicating Chlamydia pneumonia, influenza virus and Mycoplasma pneumoniae. Based on a model case presentation, we speculate that in the absence of traditional risk factors and in the context of an ongoing respiratory infection caused by a pro-inflammatory pathogen (M. pneumoniae) along with a past positive serologic history for potentially proven atherogenic microorganism (C. pneumoniae) and infection may elicit potentially pathogenic events on vascular wall cells and leukocytes of atheromatous lesions, supporting the hypothesis that such infections may potentiate atherosclerotic cardiovascular disease (CVD).

Copyright © 2010 Elsevier Ltd. All rights reserved. PMID: 21216537

Old but interesting:

Br Med J. 1974 Sep 14;3(5932):647-50. Vitamin D and myocardial infarction. Lindén V. Abstract A detailed investigation was carried out into the consumption of vitamin D from different sources in patients who had suffered from myocardial infarction, angina pectoris, and degenerative joint diseases. Randomly selected controls of the same ages and sex were drawn from the Central Bureau of Statistics. The consumption was significantly higher in infarction patients. A daily intake of 30 mug may be the critical level. Student's t test for trend showed increasing probability of myocardial infarction with increasing intake of vitamin D, and more infarction patients than controls had a history of kidney stone. Long-term high consumption of vitamin D may be a precipitating cause of myocardial infarction. PMID: 4425790

Bacteria Eyed for Possible Role in Atherosclerosis ScienceDaily (Jan. 6, 2011) — Dr. Emil Kozarov and a team of researchers at the Columbia University College of Dental Medicine have identified specific bacteria that may have a key role in vascular pathogenesis, specifically atherosclerosis, or what is commonly referred to as “hardening of the arteries” – the number one cause of death in the United States. See Also: Health & Medicine Heart Disease Stroke Prevention Dentistry Infectious Diseases Diseases and Conditions Wounds and Healing Reference Inflammation Ulcer Coronary heart disease Biological tissue Fully understanding the role of infections in cardiovascular diseases has been challenging because researchers have previously been unable to isolate live bacteria from atherosclerotic tissue. Using tissue specimens from the Department of Surgery and the Herbert Irving Comprehensive Cancer Center at Columbia University, Dr. Kozarov and his team, however, were able to isolate plaques from a 78-year-old male who had previously suffered a heart attack. Their findings are explained in the latest Journal of Atherosclerosis and Thrombosis. In the paper, researchers describe processing the tissue using cell cultures and genomic analysis to look for the presence of culturable bacteria. In addition, they looked at five pairs of diseased and healthy arterial tissue. The use of cell cultures aided in the isolation of the bacillus Enterobacter hormaechei from the patient's tissue. Implicated in bloodstream infections and other life-threatening conditions, the isolated bacteria were resistant to multiple antibiotics. Surprisingly, using quantitative methods, this microbe was further identified in very high numbers in diseased but not in healthy arterial tissues. The data suggest that a chronic infection may underlie the process of atherosclerosis, an infection that can be initiated by the systemic dissemination of bacteria though different “gates” in the vascular wall – as in the case of a septic patient, through intestinal infection. The data support Dr. Kozarov's previous studies, where his team identified periodontal bacteria in carotid artery, thus pointing to tissue-destructing periodontal infections as one possible gate to the circulation. Bacteria can gain access to the circulation through different avenues, and then penetrate the vascular walls where they can create secondary infections that have been shown to lead to atherosclerotic plaque formation, the researchers continued. “In order to test the idea that bacteria are involved in vascular pathogenesis, we must be able not only to detect bacterial DNA, but first of all to isolate the bacterial strains from the vascular wall from the patient,” Dr. Kozarov said. One specific avenue of infection the researchers studied involved bacteria getting access to the circulatory system via internalization in white blood cells (phagocytes) designed to ingest harmful foreign particles. The model that Dr. Kozarov's team was able to demonstrate showed an intermediate step where Enterobacter hormaechei is internalized by the phagocytic cells, but a step wherein bacteria are able to avoid immediate death in phagocytes. Once in circulation, Dr. Kozarov said, bacteria using this “Trojan horse” approach can persist in the organism for extended periods of time while traveling to and colonizing distant sites. This can lead to multitude of problems for the patients and for the clinicians: failure of antibiotic treatment, vascular tissue colonization and initiation of an inflammatory process, or atherosclerosis, which ultimately can lead to heart attack or stroke. “Our findings warrant further studies of bacterial infections as a contributing factor to cardiovascular disease, and of the concept that 'bacterial persistence' in phagocytic cells likely contributes to systemic dissemination,” said Dr. Kozarov, an associate professor of oral biology at the College of Dental Medicine. Dr. Jingyue Ju, co-author and director of the Columbia Center for Genome Technology & Bio-molecular Engineering, also contributed to this research, which was supported in part by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health and by the Columbia University Section of Oral and Diagnostic Sciences.

The JUPITER lipid lowering trial and vitamin D: Is there a connection? Ware WR Dermatoendocrinol Apr 2010; 2(2) :50-4 Free full text via publisher | Download citation Affiliation Faculty of Science (Emeritus); University of Western Ontario; London, ON CA. Abstract There is growing evidence that vitamin D deficiency significantly increases the risk of adverse cardiovascular events and that a vitamin D status representing sufficiency or optimum is protective. Unfortunately, in clinical trials that address interventions for reducing risk of adverse cardiovascular events, vitamin D status is not generally measured. Failure to do this has now assumed greater importance with the report of a study that found rosuvastatin at doses at the level used in a recent large randomized lipid lowering trial (JUPITER) had a large and significant impact on vitamin D levels as measured by the metabolite 25-hydroxyvitamin D. The statin alone appears to have increased this marker such that the participants on average went from deficient to sufficient in two months. The difference in cardiovascular risk between those deficient and sufficient in vitamin D in observational studies was similar to the risk reduction found in JUPITER. Thus it appears that this pleiotropic effect of rosuvastatin may be responsible for part of its unusual effectiveness in reducing the risk of various cardiovascular endpoints found in JUPITER and calls into question the interpretation based only on LDL cholesterol and CRP changes. In addition, vitamin D status is a cardiovascular risk factor which up until now has not been considered in adjusting study results or in multivariate analysis, and even statistical analysis using only baseline values may be inadequate.

J Hypertens. 2006 Nov;24(11):2255-61. Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil. Faure S, Oudart N, Javellaud J, Fournier A, Warnock DG, Achard JM. Source Division of Nephrology & Department of Pharmacology and Physiology, University of Limoges, France. Abstract OBJECTIVES: Treatment with erythropoietin and AT1 blockers is protective in experimental acute cerebral ischemia, with promising results in pilot clinical studies in human stroke. This paper examines the effects of using both agents as combination therapy in acute ischemic stroke. METHODS: We used the single carotid ligation stroke model in the gerbil. Six groups of 50 gerbils were treated either with placebo, erythropoietin (intraperitoneally, 5000 IU/kg, 2 and 48 h after stroke), olmesartan (10 mg/kg per day in drinking water started 36 h after stroke), ramipril (2.5 mg/kg per day in drinking water started 36 h after stroke), erythropoietin + olmesartan, or erythropoietin + ramipril. Long-term (1 month) Kaplan-Meyer survival curves were obtained, and survivors were submitted at day 30 to immediate (object recognition test) and spatial (Morris water maze) memory function tests. RESULTS: Erythropoietin alone and olmesartan alone, but not ramipril, significantly increased survival at day 30 compared with untreated controls (38, 30 and 6% versus 12%, respectively). Combined treatment with erythropoietin and olmesartan further increased the survival rate to 56%, whereas combined therapy with erythropoietin and ramipril decreased 30-day survival to 24% (P < 0.0001, erythropoietin + olmesartan versus erythropoietin + ramipril). Untreated stroke survivors had markedly altered performances in both the object recognition test (P = 0.0007) and the Morris water maze (P < 0.0001) tests at day 30 compared with normal gerbils. In erythropoietin-treated animals, ramipril therapy had no beneficial effect whereas olmesartan fully restored normal response to the memory tests. CONCLUSION: Post-infarct treatment with olmesartan combined with early erythropoietin therapy has a protective effect on survival, and markedly improves long-term memory dysfunction in this experimental model. PMID: 17053548

Arterioscler Thromb Vasc Biol. 2011 May 19. [Epub ahead of print] Endothelial Microparticle Formation by Angiotensin II Is Mediated via AT1R/NADPH Oxidase/Rho Kinase Pathways Targeted to Lipid Rafts.

Burger D, Montezano AC, Nishigaki N, He Y, Carter A, Touyz RM. Source

Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.



Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs).


Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O(2)(-) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (AT(1)R blocker) and fasudil (Rho kinase inhibitor). Methyl-β-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O(2)(-) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E(-/-) mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin.


We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles.

PMID: 21597004

cardiac cardiac_disease cardiovascular_disease

Infect Immun. 2011 Jun;79(6):2277-84. Epub 2011 Mar 21.The Collagen-Binding Protein Cnm Is Required for Streptococcus mutans Adherence to and Intracellular Invasion of Human Coronary Artery Endothelial Cells. Abranches J, Miller JH, Martinez AR, Simpson-Haidaris PJ, Burne RA, Lemos JA. Source Center for Oral Biology, University of Rochester Medical Center, Box 611, 601 Elmwood Ave., Rochester, NY 14642. jacqueline_abranches@urmc.rochester.edu. Abstract Streptococcus mutans is considered the primary etiologic agent of dental caries, a global health problem that affects 60 to 90% of the population, and a leading causative agent of infective endocarditis. It can be divided into four different serotypes (c, e, f, and k), with serotype c strains being the most common in the oral cavity. In this study, we demonstrate that in addition to OMZ175 and B14, three other strains (NCTC11060, LM7, and OM50E) of the less prevalent serotypes e and f are able to invade primary human coronary artery endothelial cells (HCAEC). Invasive strains were also significantly more virulent than noninvasive strains in the Galleria mellonella (greater wax worm) model of systemic disease. Interestingly, the invasive strains carried an additional gene, cnm, which was previously shown to bind to collagen and laminin in vitro. Inactivation of cnm rendered the organisms unable to invade HCAEC and attenuated their virulence in G. mellonella. Notably, the cnm knockout strains did not adhere to HCAEC as efficiently as the parental strains did, indicating that the loss of the invasion phenotype observed for the mutants was linked to an adhesion defect. Comparisons of the invasive strains and their respective cnm mutants did not support a correlation between biofilm formation and invasion. Thus, Cnm is required for S. mutans invasion of endothelial cells and possibly represents an important virulence factor of S. mutans that may contribute to cardiovascular infections and pathologies.

PMID: 21422186

J Inflamm (Lond). 2011 Apr 28;8:9.Innate immunityThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. and monocyte-macrophage activation in atherosclerosis. Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C. Source CytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. Biology of Atherosclerosis, Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, UK. c.monaco@imperial.ac.uk. Abstract ABSTRACT: Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.

PMID: 21526997

Vitamin D in synthetic form was introduced into the human food chain in the 1920’s, coincidentally with the beginning of what was called the ‘epidemic’ of coronary heart disease. It had, at that time, been shown to prevent rickets in laboratory animals.

For decades, vitamin D has been used experimentally to create coronary heart disease in animals like the dog and the rat where it is not otherwise possible to simulate the forms of disease seen in man.

In 1936, obstetrician Dr. Wayne Brehm of Columbus, OH, showed the maternal and neonatal toxic effects of Viosterol, a synthetic form of Vitamin D, in his patients. This noteworthy study, unknown and unheralded to this day, deserves a place in the annals of medicine as one of the first randomized prospective clinical trials.

In 1972, Swedish and German researchers published striking pictures of heavy calcification in the arteries of ‘normal’ newborns killed in automobile accidents. Vitamin D supplementation of the mothers’ diet was considered as a cause, and no better reason has since been suggested. From South America in the 1970’s came news of a rapidly fatal calcific disease of naturally grazing animals caused by consuming large quantities of Vitamin D in the leaves of Solanum malacoxylon, a shrub of the potato family. In Europe the same occurred in animals eating vitamin D-rich golden oat grass, Trisetum flavescens.

As a practising cardiologist concerned with the calcification of arteries, especially the coronaries, I have long been deeply skeptical of widespread supplementation of the human diet with Vitamin D. The idea that there is wide deficiency is based on a threshold of 30 ng/ml. This is in fact the average value found in the US (admittedly by dubious measurement techniques), but has served to define half the population as being in need of medical attention and supplementation.

The threshold is largely arbitrary, and ‘deficiency’ has been said to cause cancer, multiple sclerosis, hypertension and atherosclerosis. A key assertion in these arguments is that prevalence is related to latitude –for example, the notion that the further north in the US that you go, the more colorectal cancer you see. Examination of the official cancer statistics shows that this again is untrue, and that much of the other supportive evidence is unacceptable.

Sporadic deficiency does exist and must be treated, but this applies to identifiable groups such as older people in institutions. The relationship of Vitamin D metabolism jointly to atherosclerosis and osteoporosis requires further examination. I have expressed these views and the reasoning behind them in some detail in a small book available from a publisher called Lulu.com. It is entitled “Vitamin D in Disarray.” They will also appear in more extended form in the wider context of coronary heart disease and its causes in a book which is about to be published in England entitled “Medicine sans Statistics.”

Hywel Davies MD

Vitamin D and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.Elamin MB, Abu Elnour NO, Elamin KB, Fatourechi MM, Alkatib AA, Almandoz JP, Liu H, Lane MA, Mullan RJ, Hazem A, Erwin PJ, Hensrud DD, Murad MH,Montori VM J Clin Endocrinol Metab Jun 2011; Download citation Affiliation Knowledge and Evaluation Research Unit (M.B.E., N.O.A.E., M.M.F., A.A.A., M.A.L., R.J.M., A.H., P.J.E., M.H.M., V.M.M.), Mayo Clinic, Rochester, Minnesota 55905; Department of Medicine (K.B.E.), Case Western Reserve University, Metrohealth Medical Center, Cleveland, Ohio 44109; Division of Endocrinology, Diabetes, Metabolism, Nutrition (J.P.A., V.M.M.), Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology and Metabolism (H.L.), Santa Clara Valley Medical Center, San Jose, California 95128; and Division of Preventive, Occupational, and Aerospace Medicine (A.H., D.D.H., M.H.M.), Mayo Clinic, Rochester, Minnesota 55905. Abstract Context: Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. Objective: The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. Design and Methods: We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. Results: We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. Conclusions: Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.

PMID: 21677037

Controversies in Vitamin D Supplementation https://escholarship.org/uc/item/4m84d4fn

Concurrent with this rise in vitamin D ingestion in Canada, United States, Sweden, Israel, and England were the epidemic onsets of atherosclerosis and osteoporosis, which led Moon et al. to hypothesize that chronic vitamin D excess contributes to the development of these two illnesses (1). Moon and colleagues supported their postulate by citing 37 studies, some dated as early as 1945, which documented cardiovascular and skeletal effects similar to atherosclerosis and osteoporosis in humans and laboratory animals after high vitamin D intake. Subsequently, Haddad et al. showed in seven healthy human volunteers that while endogenously synthesized dermal vitamin D is transported on vitamin D binding protein and causes a more sustained increase in serum 25-hydroxy vitamin D, the orally administered vitamin D is absorbed from the intestinal tract via chylomicrons and carried in the circulation by lipoproteins such as VLDL and LDL, which may end up in the artery wall (3, 4). This finding supports Fraser’s earlier speculation that the toxicity of orally acquired vitamin D might be due to its unnatural route through the body and, consequently, it is less finely regulated than endogenously synthesized dermal vitamin D (5).

A recent study by Rebsamen and colleagues found that vitamin D induced a dose-dependent increase in vascular smooth muscle cell migration in rat aorta, suggesting a possible mechanism of vitamin D in atherosclerosis and vascular remodeling (6). They showed that vitamin D- induced migration is a rapid, non-transcriptional response that requires the activation of phosphatidylinositol 3-kinase pathway, which concurs with the role of phosphatidylinositol 3- kinase in cell migration processes previously shown in numerous cell types including vascular smooth muscle cells. The validity of these results is enhanced by the fact that Rebsamen et al. performed all the experiments in triplicates and obtained comparable results each time. Moreover, the investigators reported statistically significant differences (P<0.05) between the vitamin D and control groups, using the unpaired, 2-tailed Student’s t test. The major limitation of this study, however, is that it was performed in vitro on rat aortic smooth muscle cell cultures, which may not be translatable to human subjects in vivo.

In another study, nine breeding pairs of Sprague–Dawley rats and their offsprings were fed either normal chow (control), modified chow supplemented with low-dose vitamin D, or modified chow supplemented with high-dose vitamin D (7). Norman et al. found that increased exposure to vitamin D during gestation and early life significantly reduced the aortic elastin content and force generation in these rats. This result is alarming since prior studies have indicated that reduction in the elastin content and increased aortic wall stiffness might be predispositions to aneurysm and hypertension (8, 9). Based on the fact that reduced elastin expression was associated with an increase in elastic lamellae in the aorta (10), Norman et al. proposed that the reduction in elastic lamellae associated with vitamin D was mostly likely due to vitamin D’s effect on proteins involved in the synthesis and/or catabolism of elastic fibrils, rather than fetal or neonatal elastin gene expression. The graded reduction in aortic force generation with increasing exposure to vitamin D found in this study was consistent with the findings of Weishaar et al. who previously demonstrated that chronically vitamin-D deficient rats had increased aortic force generation (11). Since there is evidence that vitamin D crosses the placenta (12, 13), excessive maternal vitamin D intake also means excessive fetal exposure. Norman et al. found this to be disturbing because they believe that Western countries have been consuming excessive vitamin D since the discovery of preventive effect of cod liver oil in rickets in 1919 (14). The validity of these results have been most strongly questioned by Reinhold Veith, who believes that Norman et al. have supplemented the rats’ diet with the more potent, vitamin D-derived hormone, 1,25(OH)2D, instead of vitamin D (15). Furthermore, he contends that “modern adults are not consuming physiologically meaningful amounts of vitamin D through foods or vitamin pills.”

1. Moon J, Bandy B, Davison AJ. Hypothesis: etiology of atherosclerosis and osteoporosis: are imbalances in the calciferol endocrine system implicated? J Am Coll Nutr. 1992;11:567-83. 2. Norman AW. Vitamin D and milk, Department of Biochemistry & Biomedical Sciences at the University of California, Riverside website https://vitamind.ucr.edu/milk.html December 12, 2000. Comment: Highly respected institution. Anthony Norman is a professor in the Department of Biochemistry & Biomedical Sciences at the University of California, Riverside. 3. Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J. Human plasma transport of vitamin D after its endogenous synthesis. J Clin Invest. 1993;91:2552–5. 4. Demer LL. Vitamin D supplementation and atherosclerosis, Personal communication. 2003. Comment: Dr. Demer is a professor in the Departments of Medicine and Physiology at the David Geffen School of Medicine at UCLA, a highly respected institution. 5. Fraser DR. The physiological economy of vitamin D. Lancet. 1983;1:969–72. 6. Rebsamen MC, Sun J, Norman AW, Liao JK. 1 ,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase. Circ Res. 2002;91:17-24. 7. Norman P, Moss I, Sian M, Gosling M, Powell J. Maternal and postnatal vitamin D ingestion influences rat aortic structure, function and elastin content. Cardiovasc Res. 2002;55:369-74. 8. Martyn C, Greenwald S. Impaired synthesis of elastin in walls of aorta and large conduit arteries during development as an initiating event in pathogenesis of hypertension. Lancet. 1997;350:953–955. 9. He CM, Roach MR. The composition and mechanical properties of abdominal aortic aneurysms. J Vasc Surg. 1994;20:6–13. 10. Li D, Faury G, Taylor D, et al.Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest. 1998;102:1783–7. 11. Weishaar R, Kim SN, Saunders D, Simpson R. Involvement of vitamin D3Form of vitamin D made in the skin when exposed to light. Also available in fish and meat. This secosteroid is sometimes converted into 25-D. Also known as cholecalciferol and activated 7-dehydrocholesterol. with cardiovascular function. Effects on physical and morphological properties. Am J Physiol. 1990;258:E134-42. 12. Toda T, Toda Y, Kummerow F. Coronary arterial lesions in piglets from sows fed moderate excesses of vitamin D. Tohoku J Exp Med. 1985;145:303-10. 13. Clements MR, Fraser DR. Vitamin D supply to the rat fetus and neonate. J Clin Invest. 1988;81:1768–73. 14. Holmes R, Kummerow F. The relationship of adequate and excessive intake of vitamin D to health and disease. J Am Coll Nutr. 1983;2:173–99.

===== References =====

Morris HA. Vitamin D: can you have too much of a good thing in chronic kidney disease?. Kidney Int. 2015 Nov;88(5):936-8. doi: 10.1038/ki.2015.257.
[PMID: 26579677] [DOI: 10.1038/ki.2015.257]
Lindholt JS, Fasting H, Henneberg EW, Ostergaard L. A review of Chlamydia pneumoniae and atherosclerosis. Eur J Vasc Endovasc Surg. 1999 Apr;17(4):283-9. doi: 10.1053/ejvs.1998.0757.
[PMID: 10204048] [DOI: 10.1053/ejvs.1998.0757]
3) , 7) , 65)
Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, Kühbacher T, Nikolaus S, Namsolleck P, Blaut M, Hampe J, Sahly H, Reinecke A, Haake N, Günther R, Krüger D, Lins M, Herrmann G, Fölsch UR, Simon R, Schreiber S. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation. 2006 Feb 21;113(7):929-37. doi: 10.1161/CIRCULATIONAHA.105.579979.
[PMID: 16490835] [DOI: 10.1161/CIRCULATIONAHA.105.579979]
Aleksova A, Beltrami AP, Belfiore R, Barbati G, Di Nucci M, Scapol S, De Paris V, Carriere C, Sinagra G. U-shaped relationship between vitamin D levels and long-term outcome in large cohort of survivors of acute myocardial infarction. Int J Cardiol. 2016 Nov 15;223:962-966. doi: 10.1016/j.ijcard.2016.08.322. Epub 2016 Aug 24.
[PMID: 27589046] [DOI: 10.1016/j.ijcard.2016.08.322]
5) , 28)
Ayada K, Yokota K, Kobayashi K, Shoenfeld Y, Matsuura E, Oguma K. Chronic infections and atherosclerosis. Ann N Y Acad Sci. 2007 Jun;1108:594-602. doi: 10.1196/annals.1422.062.
[PMID: 17894024] [DOI: 10.1196/annals.1422.062]
Mitchell S.V. Elkind et al. "'Infectious Burden' – New Insights into Stroke Prevention." European Neurological Review, 2010;5(1):34–38.
Katz JT, Shannon RP. Bacteria and coronary atheroma: more fingerprints but no smoking gun. Circulation. 2006 Feb 21;113(7):920-2. doi: 10.1161/CIRCULATIONAHA.105.607358.
[PMID: 16490832] [DOI: 10.1161/CIRCULATIONAHA.105.607358]
9) , 21) , 22) , 27) , 79)
Stassen FR, Vainas T, Bruggeman CA. Infection and atherosclerosis. An alternative view on an outdated hypothesis. Pharmacol Rep. 2008 Jan-Feb;60(1):85-92.
[PMID: 18276989]
Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991 Mar;87(1):87-90. doi: 10.1016/0021-9150(91)90235-u.
[PMID: 1872926] [DOI: 10.1016/0021-9150(91)90235-u]
MacNeill BD, Jang I, Bouma BE, Iftimia N, Takano M, Yabushita H, Shishkov M, Kauffman CR, Houser SL, Aretz HT, DeJoseph D, Halpern EF, Tearney GJ. Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease. J Am Coll Cardiol. 2004 Sep 1;44(5):972-9. doi: 10.1016/j.jacc.2004.05.066.
[PMID: 15337206] [DOI: 10.1016/j.jacc.2004.05.066]
Kern JM, Maass V, Maass M. Molecular pathogenesis of chronic Chlamydia pneumoniae infection: a brief overview. Clin Microbiol Infect. 2009 Jan;15(1):36-41. doi: 10.1111/j.1469-0691.2008.02631.x.
[PMID: 19220338] [DOI: 10.1111/j.1469-0691.2008.02631.x]
May AE, Redecke V, Grüner S, Schmidt R, Massberg S, Miethke T, Ryba B, Prazeres da Costa C, Schömig A, Neumann F. Recruitment of Chlamydia pneumoniae-infected macrophages to the carotid artery wall in noninfected, nonatherosclerotic mice. Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):789-94. doi: 10.1161/01.ATV.0000068645.60805.7C. Epub 2003 Mar 27.
[PMID: 12663369] [DOI: 10.1161/01.ATV.0000068645.60805.7C]
Góis J, Higuchi M, Reis M, Diament J, Sousa J, Ramires J, Oliveira S. Infectious agents, inflammation, and growth factors: how do they interact in the progression or stabilization of mild human atherosclerotic lesions?. Ann Vasc Surg. 2006 Sep;20(5):638-45. doi: 10.1007/s10016-006-9076-1. Epub 2006 Sep 17.
[PMID: 16983590] [DOI: 10.1007/s10016-006-9076-1]
Saikku P, Leinonen M, Mattila K, Ekman MR, Nieminen MS, Mäkelä PH, Huttunen JK, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet. 1988 Oct 29;2(8618):983-6. doi: 10.1016/s0140-6736(88)90741-6.
[PMID: 2902492] [DOI: 10.1016/s0140-6736(88)90741-6]
Arcari CM, Gaydos CA, Nieto FJ, Krauss M, Nelson KE. Association between Chlamydia pneumoniae and acute myocardial infarction in young men in the United States military: the importance of timing of exposure measurement. Clin Infect Dis. 2005 Apr 15;40(8):1123-30. doi: 10.1086/428730. Epub 2005 Mar 14.
[PMID: 15791511] [DOI: 10.1086/428730]
Taylor-Robinson D, Thomas BJ. Chlamydia pneumoniae in arteries: the facts, their interpretation, and future studies. J Clin Pathol. 1998 Nov;51(11):793-7. doi: 10.1136/jcp.51.11.793.
[PMID: 10193317] [PMCID: 500968] [DOI: 10.1136/jcp.51.11.793]
Campbell LA, Kuo CC, Grayston JT. Chlamydia pneumoniae and cardiovascular disease. Emerg Infect Dis. 1998 Oct-Dec;4(4):571-9. doi: 10.3201/eid0404.980407.
[PMID: 9866733] [PMCID: 2640250] [DOI: 10.3201/eid0404.980407]
Zhu J, Katz RJ, Quyyumi AA, Canos DA, Rott D, Csako G, Zalles-Ganley A, Ogunmakinwa J, Wasserman AG, Epstein SE. Association of serum antibodies to heat-shock protein 65 with coronary calcification levels: suggestion of pathogen-triggered autoimmunity in early atherosclerosis. Circulation. 2004 Jan 6;109(1):36-41. doi: 10.1161/01.CIR.0000105513.37677.B3. Epub 2003 Dec 8.
[PMID: 14662717] [DOI: 10.1161/01.CIR.0000105513.37677.B3]
20) , 44)
Ewald PW, Cochran GM. Chlamydia pneumoniae and cardiovascular disease: an evolutionary perspective on infectious causation and antibiotic treatment. J Infect Dis. 2000 Jun;181 Suppl 3:S394-401. doi: 10.1086/315602.
[PMID: 10839723] [DOI: 10.1086/315602]
Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum CH, DeBakey ME. Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet. 1983 Sep 17;2(8351):644-7. doi: 10.1016/s0140-6736(83)92529-1.
[PMID: 6136795] [DOI: 10.1016/s0140-6736(83)92529-1]
Hendrix MG, Dormans PH, Kitslaar P, Bosman F, Bruggeman CA. The presence of cytomegalovirus nucleic acids in arterial walls of atherosclerotic and nonatherosclerotic patients. Am J Pathol. 1989 May;134(5):1151-7.
[PMID: 2541613] [PMCID: 1879908]
Hendrix MG, Salimans MM, van Boven CP, Bruggeman CA. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol. 1990 Jan;136(1):23-8.
[PMID: 2153348] [PMCID: 1877468]
Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?. Lancet. 1997 Aug 9;350(9075):430-6. doi: 10.1016/S0140-6736(97)03079-1.
[PMID: 9259669] [DOI: 10.1016/S0140-6736(97)03079-1]
Pellicano R, Peyre S, Astegiano M, Oliaro E, Fagoonee S, Rizzetto M. Updated review (2006) on Helicobacter pylori as a potential target for the therapy of ischemic heart disease. Panminerva Med. 2006 Dec;48(4):241-6.
[PMID: 17215796]
Berrutti M, Pellicano R, Fagoonee S, Astegiano M, Smedile A, Saracco G, Repici A, Leone N, Rizzetto M. Potential relationship between Helicobacter pylori and ischemic heart disease: any pathogenic model?. Panminerva Med. 2008 Jun;50(2):161-3.
[PMID: 18607339]
Franceschi F, Niccoli G, Ferrante G, Gasbarrini A, Baldi A, Candelli M, Feroce F, Saulnier N, Conte M, Roccarina D, Lanza GA, Gasbarrini G, Gentiloni SN, Crea F. CagA antigen of Helicobacter pylori and coronary instability: insight from a clinico-pathological study and a meta-analysis of 4241 cases. Atherosclerosis. 2009 Feb;202(2):535-42. doi: 10.1016/j.atherosclerosis.2008.04.051. Epub 2008 Jul 3.
[PMID: 18599062] [DOI: 10.1016/j.atherosclerosis.2008.04.051]
Wang Q, Zhou X, Huang D. Role for Porphyromonas gingivalis in the progression of atherosclerosis. Med Hypotheses. 2009 Jan;72(1):71-3. doi: 10.1016/j.mehy.2008.04.030. Epub 2008 Sep 30.
[PMID: 18829178] [DOI: 10.1016/j.mehy.2008.04.030]
Gibson FC3, Genco CA. Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: disparate diseases with commonalities in pathogenesis through TLRs. Curr Pharm Des. 2007;13(36):3665-75. doi: 10.2174/138161207783018554.
[PMID: 18220804] [DOI: 10.2174/138161207783018554]
Elkind MSV, Ramakrishnan P, Moon YP, Boden-Albala B, Liu KM, Spitalnik SL, Rundek T, Sacco RL, Paik MC. Infectious burden and risk of stroke: the northern Manhattan study. Arch Neurol. 2010 Jan;67(1):33-8. doi: 10.1001/archneurol.2009.271. Epub 2009 Nov 9.
[PMID: 19901154] [PMCID: 2830860] [DOI: 10.1001/archneurol.2009.271]
Blackwell DL, Hayward MD, Crimmins EM. Does childhood health affect chronic morbidity in later life?. Soc Sci Med. 2001 Apr;52(8):1269-84. doi: 10.1016/s0277-9536(00)00230-6.
[PMID: 11281409] [DOI: 10.1016/s0277-9536(00)00230-6]
Meyers DG. Myocardial infarction, stroke, and sudden cardiac death may be prevented by influenza vaccination. Curr Atheroscler Rep. 2003 Mar;5(2):146-9. doi: 10.1007/s11883-003-0087-x.
[PMID: 12573201] [DOI: 10.1007/s11883-003-0087-x]
Costa DL, Helmchen LA, Wilson S. Economics of health and mortality special feature: race, infection, and arteriosclerosis in the past. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13219-24. doi: 10.1073/pnas.0611077104. Epub 2007 Aug 8.
[PMID: 17686992] [PMCID: 1948925] [DOI: 10.1073/pnas.0611077104]
Finch CE, Crimmins EM. Inflammatory exposure and historical changes in human life-spans. Science. 2004 Sep 17;305(5691):1736-9. doi: 10.1126/science.1092556.
[PMID: 15375259] [DOI: 10.1126/science.1092556]
De Luca M, Rossi A. [Findings and considerations on the behavior of C reactive protein in various stages of syphilitic infection]. G Ital Dermatol Minerva Dermatol. 1968 Mar-Apr;109(3):109-16.
[PMID: 5755517]
Prat C, Domínguez J, Rodrigo C, Giménez M, Azuara M, Jiménez O, Galí N, Ausina V. Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J. 2003 Nov;22(11):963-8. doi: 10.1097/01.inf.0000095197.72976.4f.
[PMID: 14614368] [DOI: 10.1097/01.inf.0000095197.72976.4f]
Gölbasi Z, Uçar O, Keles T, Sahin A, Cagli K, Camsari A, Diker E, Aydogdu S. Increased levels of high sensitive C-reactive protein in patients with chronic rheumatic valve disease: evidence of ongoing inflammation. Eur J Heart Fail. 2002 Oct;4(5):593-5. doi: 10.1016/s1388-9842(02)00102-2.
[PMID: 12413502] [DOI: 10.1016/s1388-9842(02)00102-2]
Mazumder B, Almond D, Park K, Crimmins EM, Finch CE. Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease. J Dev Orig Health Dis. 2010 Feb;1(1):26-34. doi: 10.1017/S2040174409990031.
[PMID: 20198106] [PMCID: 2826837] [DOI: 10.1017/S2040174409990031]
Azer SA. Arterial disease in antiquity. Med J Aust. 1999 Sep 6;171(5):280.
[PMID: 10495769]
Morrison HI, Ellison LF, Taylor GW. Periodontal disease and risk of fatal coronary heart and cerebrovascular diseases. J Cardiovasc Risk. 1999 Feb;6(1):7-11. doi: 10.1177/204748739900600102.
[PMID: 10197286] [DOI: 10.1177/204748739900600102]
46) , 61)
Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE, Bäckhed F. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4592-8. doi: 10.1073/pnas.1011383107. Epub 2010 Oct 11.
[PMID: 20937873] [PMCID: 3063583] [DOI: 10.1073/pnas.1011383107]
Andriankaja O, Trevisan M, Falkner K, Dorn J, Hovey K, Sarikonda S, Mendoza T, Genco R. Association between periodontal pathogens and risk of nonfatal myocardial infarction. Community Dent Oral Epidemiol. 2011 Apr;39(2):177-85. doi: 10.1111/j.1600-0528.2010.00582.x.
[PMID: 21375559] [DOI: 10.1111/j.1600-0528.2010.00582.x]
Lamell CW, Griffen AL, McClellan DL, Leys EJ. Acquisition and colonization stability of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in children. J Clin Microbiol. 2000 Mar;38(3):1196-9. doi: 10.1128/JCM.38.3.1196-1199.2000.
[PMID: 10699021] [PMCID: 86374] [DOI: 10.1128/JCM.38.3.1196-1199.2000]
Kozarov EV, Dorn BR, Shelburne CE, Dunn WAJ, Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):e17-8. doi: 10.1161/01.ATV.0000155018.67835.1a. Epub 2005 Jan 20.
[PMID: 15662025] [DOI: 10.1161/01.ATV.0000155018.67835.1a]
Gibson FC3, Ukai T, Genco CA. Engagement of specific innate immune signaling pathways during Porphyromonas gingivalis induced chronic inflammation and atherosclerosis. Front Biosci. 2008 Jan 1;13:2041-59. doi: 10.2741/2822.
[PMID: 17981690] [DOI: 10.2741/2822]
Rafferty B, Dolgilevich S, Kalachikov S, Morozova I, Ju J, Whittier S, Nowygrod R, Kozarov E. Cultivation of Enterobacter hormaechei from human atherosclerotic tissue. J Atheroscler Thromb. 2011;18(1):72-81. doi: 10.5551/jat.5207. Epub 2010 Oct 20.
[PMID: 20972353] [DOI: 10.5551/jat.5207]
52) , 53)
Kozarov E, Sweier D, Shelburne C, Progulske-Fox A, Lopatin D. Detection of bacterial DNA in atheromatous plaques by quantitative PCR. Microbes Infect. 2006 Mar;8(3):687-93. doi: 10.1016/j.micinf.2005.09.004. Epub 2006 Jan 13.
[PMID: 16513386] [DOI: 10.1016/j.micinf.2005.09.004]
Ng PML, Jin Z, Tan SSH, Ho B, Ding JL. C-reactive protein: a predominant LPS-binding acute phase protein responsive to Pseudomonas infection. J Endotoxin Res. 2004;10(3):163-74. doi: 10.1179/096805104225004833.
[PMID: 15198851] [DOI: 10.1179/096805104225004833]
Liu AH. Innate microbial sensors and their relevance to allergy. J Allergy Clin Immunol. 2008 Nov;122(5):846-58; quiz 858-60. doi: 10.1016/j.jaci.2008.10.002.
[PMID: 19000576] [DOI: 10.1016/j.jaci.2008.10.002]
56) , 58)
Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003 Jun;111(12):1805-12. doi: 10.1172/JCI18921.
[PMID: 12813013] [PMCID: 161431] [DOI: 10.1172/JCI18921]
Tan SSH, Ng PML, Ho B, Ding JL. The antimicrobial properties of C-reactive protein (CRP). J Endotoxin Res. 2005;11(4):249-56. doi: 10.1179/096805105X37402.
[PMID: 16176663] [DOI: 10.1179/096805105X37402]
59) , 99)
Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003 Dec;96(12):927-34. doi: 10.1093/qjmed/hcg150.
[PMID: 14631060] [DOI: 10.1093/qjmed/hcg150]
60) , 71)
Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010 Apr;54(4):246-53. doi: 10.1111/j.1348-0421.2010.00203.x.
[PMID: 20377753] [DOI: 10.1111/j.1348-0421.2010.00203.x]
Levels JH, Geurts P, Karlsson H, Marée R, Ljunggren S, Fornander L, Wehenkel L, Lindahl M, Stroes ES, Kuivenhoven JA, Meijers JC. High-density lipoprotein proteome dynamics in human endotoxemia. Proteome Sci. 2011 Jun 28;9(1):34. doi: 10.1186/1477-5956-9-34.
[PMID: 21711511] [PMCID: 3146904] [DOI: 10.1186/1477-5956-9-34]
Ravnskov U. The fallacies of the lipid hypothesis. Scand Cardiovasc J. 2008 Aug;42(4):236-9. doi: 10.1080/14017430801983082.
[PMID: 18615352] [DOI: 10.1080/14017430801983082]
Van Lenten BJ, Wagner AC, Anantharamaiah GM, Garber DW, Fishbein MC, Adhikary L, Nayak DP, Hama S, Navab M, Fogelman AM. Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation. 2002 Aug 27;106(9):1127-32. doi: 10.1161/01.cir.0000030182.35880.3e.
[PMID: 12196340] [DOI: 10.1161/01.cir.0000030182.35880.3e]
Buyukhatipoglu H, Tiryaki O, Tahta K, Usalan C. Inflammation as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis in haemodialysis patients: the role of chlamydia and cytomegalovirus infection. Nephrology (Carlton). 2007 Feb;12(1):25-32. doi: 10.1111/j.1440-1797.2006.00742.x.
[PMID: 17295657] [DOI: 10.1111/j.1440-1797.2006.00742.x]
Westerterp M, Berbée JFP, Pires NMM, van Mierlo GJD, Kleemann R, Romijn JA, Havekes LM, Rensen PCN. Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice. Circulation. 2007 Nov 6;116(19):2173-81. doi: 10.1161/CIRCULATIONAHA.107.693382. Epub 2007 Oct 22.
[PMID: 17967778] [DOI: 10.1161/CIRCULATIONAHA.107.693382]
Milioti N, Bermudez-Fajardo A, Penichet ML, Oviedo-Orta E. Antigen-induced immunomodulation in the pathogenesis of atherosclerosis. Clin Dev Immunol. 2008;2008:723539. doi: 10.1155/2008/723539.
[PMID: 18551190] [PMCID: 2423423] [DOI: 10.1155/2008/723539]
Mayr M, Kiechl S, Tsimikas S, Miller E, Sheldon J, Willeit J, Witztum JL, Xu Q. Oxidized low-density lipoprotein autoantibodies, chronic infections, and carotid atherosclerosis in a population-based study. J Am Coll Cardiol. 2006 Jun 20;47(12):2436-43. doi: 10.1016/j.jacc.2006.03.024. Epub 2006 May 30.
[PMID: 16781371] [DOI: 10.1016/j.jacc.2006.03.024]
Mattila KJ, Pussinen PJ, Paju S. Dental infections and cardiovascular diseases: a review. J Periodontol. 2005 Nov;76(11 Suppl):2085-8. doi: 10.1902/jop.2005.76.11-S.2085.
[PMID: 16277580] [DOI: 10.1902/jop.2005.76.11-S.2085]
Bazinet RP, Chu MWA. Omega-6 polyunsaturated fatty acids: is a broad cholesterol-lowering health claim appropriate?. CMAJ. 2014 Apr 1;186(6):434-9. doi: 10.1503/cmaj.130253. Epub 2013 Nov 11.
[PMID: 24218530] [PMCID: 3971029] [DOI: 10.1503/cmaj.130253]
Mangoni AA, Jackson SHD. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. 2002 May;112(7):556-65. doi: 10.1016/s0002-9343(02)01021-5.
[PMID: 12015248] [DOI: 10.1016/s0002-9343(02)01021-5]
Warren CJ. Emergent cardiovascular risk factor: homocysteine. Prog Cardiovasc Nurs. 2002 Winter;17(1):35-41. doi: 10.1111/j.0889-7204.2002.00620.x.
[PMID: 11872979] [DOI: 10.1111/j.0889-7204.2002.00620.x]
House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, Dresser GK, Spence JD. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010 Apr 28;303(16):1603-9. doi: 10.1001/jama.2010.490.
[PMID: 20424250] [DOI: 10.1001/jama.2010.490]
Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest JJ, Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77. doi: 10.1056/NEJMoa060900. Epub 2006 Mar 12.
[PMID: 16531613] [DOI: 10.1056/NEJMoa060900]
Marino MCA, de Oliveira CA, Rocha AMC, Rocha GA, Clementino NCD, Antunes LF, Oliveira RA, Martins AS, Del Puerto HL, D'Almeida V, Galdieri L, Pedroso ERP, Cabral MMDA, Nogueira AMMF, Queiroz DMM. Long-term effect of Helicobacter pylori eradication on plasma homocysteine in elderly patients with cobalamin deficiency. Gut. 2007 Apr;56(4):469-74. doi: 10.1136/gut.2006.095125. Epub 2006 Sep 27.
[PMID: 17005765] [PMCID: 1856853] [DOI: 10.1136/gut.2006.095125]
Fromonot J, Deharo P, Bruzzese L, Cuisset T, Quilici J, Bonatti S, Fenouillet E, Mottola G, Ruf J, Guieu R. Adenosine plasma level correlates with homocysteine and uric acid concentrations in patients with coronary artery disease. Can J Physiol Pharmacol. 2016 Mar;94(3):272-7. doi: 10.1139/cjpp-2015-0193. Epub 2015 Aug 28.
[PMID: 26762617] [DOI: 10.1139/cjpp-2015-0193]
Taylor-Robinson D, Boman J. The failure of antibiotics to prevent heart attacks. BMJ. 2005 Aug 13;331(7513):361-2. doi: 10.1136/bmj.331.7513.361.
[PMID: 16096289] [PMCID: 1184236] [DOI: 10.1136/bmj.331.7513.361]
Mason RP. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. Vasc Health Risk Manag. 2011;7:405-16. doi: 10.2147/VHRM.S20737. Epub 2011 Jun 24.
[PMID: 21796255] [PMCID: 3141913] [DOI: 10.2147/VHRM.S20737]
Seko Y. Effect of the angiotensin II receptor blocker olmesartan on the development of murine acute myocarditis caused by coxsackievirus B3. Clin Sci (Lond). 2006 Mar;110(3):379-86. doi: 10.1042/CS20050299.
[PMID: 16336207] [DOI: 10.1042/CS20050299]
Yuan Z, Nimata M, Okabe T, Shioji K, Hasegawa K, Kita T, Kishimoto C. Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure. Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1147-52. doi: 10.1152/ajpheart.00078.2005. Epub 2005 May 6.
[PMID: 15879491] [DOI: 10.1152/ajpheart.00078.2005]
Ohta T, Hasebe N, Tsuji S, Izawa K, Jin Y, Kido S, Natori S, Sato M, Kikuchi K. Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol. Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2914-21. doi: 10.1152/ajpheart.00221.2004. Epub 2004 Aug 5.
[PMID: 15297251] [DOI: 10.1152/ajpheart.00221.2004]
Prasad K. C-reactive protein (CRP)-lowering agents. Cardiovasc Drug Rev. 2006 Spring;24(1):33-50. doi: 10.1111/j.1527-3466.2006.00033.x.
[PMID: 16939632] [DOI: 10.1111/j.1527-3466.2006.00033.x]
Boos CJ, Lip GYH. Targeting the renin-angiotensin-aldosterone system in atrial fibrillation: from pathophysiology to clinical trials. J Hum Hypertens. 2005 Nov;19(11):855-9. doi: 10.1038/sj.jhh.1001933.
[PMID: 16094406] [DOI: 10.1038/sj.jhh.1001933]
Schulz R, Heusch G. Angiotensin II in the failing heart. Short communication. Kidney Blood Press Res. 2005;28(5-6):349-52. doi: 10.1159/000090189. Epub 2006 Mar 7.
[PMID: 16534230] [DOI: 10.1159/000090189]
Sezai A, Osaka S, Yaoita H, Arimoto M, Hata H, Shiono M, Sakino H. Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study). Ann Thorac Cardiovasc Surg. 2016 Jun 20;22(3):161-7. doi: 10.5761/atcs.oa.16-00054. Epub 2016 Apr 18.
[PMID: 27086671] [PMCID: 4909997] [DOI: 10.5761/atcs.oa.16-00054]
Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL, PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004 Nov 11;351(20):2058-68. doi: 10.1056/NEJMoa042739. Epub 2004 Nov 7.
[PMID: 15531767] [PMCID: 2556374] [DOI: 10.1056/NEJMoa042739]
Matchar DB, McCrory DC, Orlando LA, Patel MR, Patel UD, Patwardhan MB, Powers B, Samsa GP, Gray RN. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008 Jan 1;148(1):16-29. doi: 10.7326/0003-4819-148-1-200801010-00189. Epub 2007 Nov 5.
[PMID: 17984484] [DOI: 10.7326/0003-4819-148-1-200801010-00189]
Li N, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010 Jan 12;340:b5465. doi: 10.1136/bmj.b5465.
[PMID: 20068258] [PMCID: 2806632] [DOI: 10.1136/bmj.b5465]
Raff U, Ott C, Ruilope LM, Menne J, Haller H, Schmieder RE. Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes. J Hypertens. 2014 Nov;32(11):2267-76; discussion 2276. doi: 10.1097/HJH.0000000000000313.
[PMID: 25275251] [DOI: 10.1097/HJH.0000000000000313]
Stumpe KO, Agabiti-Rosei E, Zielinski T, Schremmer D, Scholze J, Laeis P, Schwandt P, Ludwig M, MORE study investigators. Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study. Ther Adv Cardiovasc Dis. 2007 Dec;1(2):97-106. doi: 10.1177/1753944707085982.
[PMID: 19124398] [DOI: 10.1177/1753944707085982]
Hirohata A, Yamamoto K, Miyoshi T, Hatanaka K, Hirohata S, Yamawaki H, Komatsubara I, Murakami M, Hirose E, Sato S, Ohkawa K, Ishizawa M, Yamaji H, Kawamura H, Kusachi S, Murakami T, Hina K, Ohe T. Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial. J Am Coll Cardiol. 2010 Mar 9;55(10):976-82. doi: 10.1016/j.jacc.2009.09.062.
[PMID: 20202514] [DOI: 10.1016/j.jacc.2009.09.062]
Lu G, Cheng J, Zhu K, Ma X, Shen F, Su D. A systematic review of angiotensin receptor blockers in preventing stroke. Stroke. 2009 Dec;40(12):3876-8. doi: 10.1161/STROKEAHA.109.559989. Epub 2009 Nov 5.
[PMID: 19892999] [DOI: 10.1161/STROKEAHA.109.559989]
Laurent S, Boutouyrie P, Vascular Mechanism Collaboration. Dose-dependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Hypertension. 2014 Oct;64(4):709-16. doi: 10.1161/HYPERTENSIONAHA.114.03282. Epub 2014 Jul 7.
[PMID: 25001274] [DOI: 10.1161/HYPERTENSIONAHA.114.03282]
Durand MJ, Zinkevich NS, Riedel M, Gutterman DD, Nasci VL, Salato VK, Hijjawi JB, Reuben CF, North PE, Beyer AM. Vascular Actions of Angiotensin 1-7 in the Human Microcirculation: Novel Role for Telomerase. Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1254-62. doi: 10.1161/ATVBAHA.116.307518. Epub 2016 Apr 14.
[PMID: 27079876] [PMCID: 4882242] [DOI: 10.1161/ATVBAHA.116.307518]
Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH, Visseren FLJ, Sijbrands EJG, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3;358(14):1431-43. doi: 10.1056/NEJMoa0800742. Epub 2008 Mar 30.
[PMID: 18376000] [DOI: 10.1056/NEJMoa0800742]
Caballero B, Clay T, Davis SM, Ethelbah B, Rock BH, Lohman T, Norman J, Story M, Stone EJ, Stephenson L, Stevens J, Pathways Study Research Group. Pathways: a school-based, randomized controlled trial for the prevention of obesity in American Indian schoolchildren. Am J Clin Nutr. 2003 Nov;78(5):1030-8. doi: 10.1093/ajcn/78.5.1030.
[PMID: 14594792] [PMCID: 4863237] [DOI: 10.1093/ajcn/78.5.1030]
Reilly JJ, Kelly L, Montgomery C, Williamson A, Fisher A, McColl JH, Lo Conte R, Paton JY, Grant S. Physical activity to prevent obesity in young children: cluster randomised controlled trial. BMJ. 2006 Nov 18;333(7577):1041. doi: 10.1136/bmj.38979.623773.55. Epub 2006 Oct 6.
[PMID: 17028105] [PMCID: 1647320] [DOI: 10.1136/bmj.38979.623773.55]
Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS, COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32. doi: 10.1016/S0140-6736(05)67661-1.
[PMID: 16271643] [DOI: 10.1016/S0140-6736(05)67661-1]
Newman, D. H. (2008). Hippocrates' shadow: secrets from the house of medicine. New York, NY, Scribner.
Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol. 2005 May;105(5 Pt 1):1114-8. doi: 10.1097/01.AOG.0000157445.67309.19.
[PMID: 15863552] [DOI: 10.1097/01.AOG.0000157445.67309.19]
Gepner AD, Ramamurthy R, Krueger DC, Korcarz CE, Binkley N, Stein JH. A prospective randomized controlled trial of the effects of vitamin D supplementation on cardiovascular disease risk. PLoS One. 2012;7(5):e36617. doi: 10.1371/journal.pone.0036617. Epub 2012 May 7.
[PMID: 22586483] [PMCID: 3346736] [DOI: 10.1371/journal.pone.0036617]
Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clin Microbiol Rev. 2010 Oct;23(4):837-57. doi: 10.1128/CMR.00012-10.
[PMID: 20930075] [PMCID: 2952975] [DOI: 10.1128/CMR.00012-10]
Steck RP, Hill SL, Weagel EG, Weber KS, Robison RA, O'Neill KL. Pharmacologic immunosuppression of mononuclear phagocyte phagocytosis by caffeine. Pharmacol Res Perspect. 2015 Oct 25;3(6):e00180. doi: 10.1002/prp2.180. eCollection 2015 Dec.
[PMID: 27022462] [PMCID: 4777255] [DOI: 10.1002/prp2.180]
Veloudi P, Jones G, Sharman JE. Effectiveness of Vitamin D Supplementation for Cardiovascular Health Outcomes. Pulse (Basel). 2017 Jan;4(4):193-207. doi: 10.1159/000452742. Epub 2016 Dec 9.
[PMID: 28229054] [PMCID: 5290441] [DOI: 10.1159/000452742]
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Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SAA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. doi: 10.1001/jama.288.3.321.
[PMID: 12117397] [DOI: 10.1001/jama.288.3.321]
Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, Riegger GAJ, Malbecq W, Smith RD, Guptha S, Poole-Wilson PA, HEAAL Investigators. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009 Nov 28;374(9704):1840-8. doi: 10.1016/S0140-6736(09)61913-9. Epub 2009 Nov 16.
[PMID: 19922995] [DOI: 10.1016/S0140-6736(09)61913-9]
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