Insulin resistance increases cardiovascular disease

Insulin resistance (IR), resistance of the insulin receptor due to overstimulation, elicits a rise of insulin levels to overcome the reduced receptor sensitivity. The resulting elevated insulin levels damage tissues throughout the body, and are a major contributing cause of cardiovascular disease. This is well known to many practitioners, so it was disturbing to read an article in the New York Times describing endocrinologists who are baffled by the fact that medications for type 2 diabetes that increase insulin levels worsen the risk for cardiovascular disease. The wealth of scientific evidence has been accumulating for a long time.

Insulin resistance and coronary artery disease

Insulin resistance and CADA study published in 1996 in the journal Diabetologia described the strong connection between CAD (coronary artery disease) and insulin resistance with its consequent hyperinsulinemia.

“The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance.”

Of particular interest is that all the study subjects, both those with CAD and controls, had a normal oral glucose tolerance test. HOWEVER…

Fasting plasma insulin concentration and area under the plasma insulin curve following glucose ingestion were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal. The magnitude of insulin resistance was positively correlated with the severity of CAD.”

It is hard to over emphasize the importance to clinicians of being vigilant in recognizing insulin resistance in the presence of normal glucose levels.

“In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X’.

Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease

In 1991 a paper published in Diabetes Care described how insulin resistance promotes multiple factors that cause atherosclerosis.

“Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found.”


“…insulin resistance…correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells.”

It is also well-known that IR with its hyperinsulinemia cause elevated lipid levels.

Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic.”

And elevated insulin directly fosters atherosclerosis:

“Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.”


Controlling insulin resistance more important than glucose or LDLA more recent study in Diabetes Care presents striking data demonstrating the massive impact reduction in heart attacks that would occur by preventing insulin resistance. In setting out to determine what portion of coronary artery disease is caused by IR, the authors used data from the National Health and Nutrition Examination Survey 1998–2004 to simulate a population representative of young adults in the U.S. They applied the Archimedes model was to estimate the proportion of heart attacks that would be prevented by maintaining insulin resistance at healthy levels. Their data painted a dramatic picture:

“In young adults, preventing insulin resistance would prevent ∼42% of myocardial infarctions. The next most important determinant of CAD is systolic hypertension, prevention of which would reduce myocardial infarctions by ∼36%. Following systolic blood pressure, the most important determinants are HDL cholesterol (31%), BMI (21%), LDL cholesterol (16%), triglycerides (10%), fasting plasma glucose and smoking (both ∼9%), and family history (4%).”

Preventing insulin resistance beat the pants off controlling LDL cholesterol and smoking! Interestingly, they found that the effects were especially important for women:

“The effects of insulin resistance are also affected by sex. Today’s young men face a higher rate of myocardial infarctions than today’s young women: 55 vs. 32%. However, insulin resistance plays a larger relative role in women than in men, with normalization of insulin resistance reducing the myocardial infarction rate ∼57% for women (from 32 to 14%), compared with ∼29% (from 55 to 39%) for men.”

Preventing insulin resistance carries more weight than controlling glucose

In their conclusion the authors make points that are crucial for clinicians to bear in mind:

“Of the risk factors that we believe are sufficiently well studied to permit quantitative analysis, insulin resistance is the most important single risk factor for CAD. Our results indicate that insulin resistance is responsible for approximately 42% of myocardial infarctions. Its effect on CAD is indirect, mediated through its effects on other variables such as SBP, HDL cholesterol, triglycerides, glucose, and apoB.”

Effect of insulin resistance on myocardial infarction

In comparing their results with other research, the authors highlight the critical error made by depending on medications that increase insulin to control glucose:

“Our results are not directly comparable with those of clinical trials, where the effects of glucose lowering on CAD were either much smaller or null. The reason is that in the clinical trials, the focus was on lowering blood glucose—not preventing or curing insulin resistance. The drugs used in the trials either lowered glucose without affecting insulin resistance (e.g., sulfonylureas and insulin) or lowered insulin resistance to some extent but did not eliminate it (e.g., metformin and rosiglitazone). Furthermore, we normalized insulin resistance over the entire lifetimes of the subjects, whereas the treatments in the trials were given only after individuals had developed diabetes and were given only for the limited durations of the studies. Thus, the results of the trials do not represent the full eff

ect of normalizing insulin resistance and are actually consistent with our results.”

Note the implication that cardiovascular damage by IR occurs long before losing glucose control and crossing the border into diabetes territory.

Insulin resistance without diabetes causes cardiovascular disease

Investigators publishing in PLoS One make the same point about cardiovascular damage caused by IR well before diabetes sets in.

“To enable a comparison between cardiovascular disease risks for glucose, insulin and HOMA-IR, we calculated pooled relative risks per increase of one standard deviation…We included 65 studies (involving 516,325 participants) in this meta-analysis. In a random-effect meta-analysis the pooled relative risk of CHD (95% CI; I2) comparing high to low concentrations was 1.52 (1.31, 1.76; 62.4%) for glucose, 1.12 (0.92, 1.37; 41.0%) for insulin and 1.64 (1.35, 2.00; 0%) for HOMA-IR. The pooled relative risk of CHD per one standard deviation increase was 1.21 (1.13, 1.30; 64.9%) for glucose, 1.04 (0.96, 1.12; 43.0%) for insulin and 1.46 (1.26, 1.69; 0.0%) for HOMA-IR.”

They concluded that insulin resistance (HOMA-IR) was the leading culprit:

“The relative risk of cardiovascular disease was higher for an increase of one standard deviation in HOMA-IR compared to an increase of one standard deviation in fasting glucose or fasting insulin concentration.”

The authors also demonstrate that IR is a much better biomarker than fasting insulin:

 “The present meta-analyses showed that fasting glucose, fasting insulin and HOMA-IR were all associated with incident cardiovascular disease in individuals without diabetes. In a standardized meta-analysis we found that coronary heart disease risk increased with 46% for an increase of one standard deviation in HOMA-IR concentration compared to an increase of 21% for fasting glucose concentration and an increase of 4% for fasting insulin concentration.”

Insulin resistance causes fat expansion and vascular endothelial damage

An excellent paper published in Arteriosclerosis, Thrombosis, and Vascular Biology details how IR causes cardiovascular disease beyond abnormal glucose, lipids, hypertension, and its proinflammatory effects.

“…insulin’s action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications.”

The authors describe how IR causes vascular inflammation and atherosclerosis:

“Insulin action directly on vascular endothelial cells affects endothelial function beyond regulating blood flow or capillary recruitment. Conditional knockout of the insulin receptor in endothelial cells causes a 2- to 3-fold increase in the atherosclerotic lesion size in apolipoprotein E–null mice…the increased atherogenesis in this model can be attributed to insulin action directly on endothelial cells rather than effects mediated through systemic parameters. The accelerated atherosclerosis in mice with endothelial cell insulin receptor knockout is preceded by a dramatic increase in leukocyte rolling and adhesion to endothelium and an increase in expression of vascular cell adhesion molecule-1…insulin signaling independent of NO is responsible for this effect.”

They state that IR promotes the necrotic core at the heart of vulnerable plaque:

Insulin resistance in macrophages, however, promotes formation of a necrotic core in atherosclerotic plaques by enhancing macrophage apoptosis. This is an important event in advanced atherosclerosis because exposure of the necrotic core to circulating blood in the event of plaque rupture can precipitate thrombosis, leading to unstable angina pectoris, transitory cerebral ischemia, stroke, or myocardial infarction.”

Regarding cardiomyocyte function…

“…it is likely that the changes in metabolic substrate inflexibility and increased mitochondrial production of oxidants caused by cardiomyocyte insulin resistance can contribute to development of heart failure in the metabolic syndrome.”

The authors conclude with important clinical points:

“Research on insulin receptor signaling using tissue–specific gene manipulation in mice as well as other methods has provided important insights into insulin action and revealed insulin effects in tissues that a decade or 2 ago were considered nonresponsive to insulin….insulin sensitizers would theoretically have better profiles of action if they improved insulin resistance in tissues regulating glucose and lipid metabolism, as well as in the endothelium and other vascular tissues where impaired insulin signaling is proatherosclerotic independent of metabolic effects. Second, insulin analogues should be carefully evaluated for deleterious effects on insulin signaling pathways which are not affected by insulin resistance, such as those pathways which promote dyslipidemia or increase vascular expression of endothelin-1.”

Insulin resistance promotes advanced plaque progression

A paper published in Cell Metabolism details additional mechanisms by which IR promotes atherosclerosis. The authors note that…

“…the pathophysiological processes involved in the initiation and progression of early lesions are quite different from those that cause the formation of clinically dangerous plaques,…advanced plaque progression is influenced primarily by processes that promote plaque necrosis and thinning of a collagenous “scar” overlying the lesion called the fibrous cap… and distinguishing the effects of insulin resistance and hyperglycemia on these processes is critically important.”

They echo other investigators who point out the crucial fact that insulin resistance does damage before glucose control is lost:

“There is ample clinical evidence that insulin resistance increases the risk for coronary artery disease (CAD) even in the absence of hyperglycemia. Insulin resistance syndromes can promote both atherogenesis and advanced plaque progression, and the mechanisms likely involve both systemic factors that promote these processes, particularly dyslipidemia but also hypertension and a proinflammatory state, as well as the effect of perturbed insulin signaling at the level of the intimal cells that participate in atherosclerosis, including endothelial cells, vascular smooth muscle cells, and macrophages.”

They highlight the critical clinical implication that insulin resistance also entails overstimulation of various tissues by insulin elevated in compensation for receptor resistance or by insulin-elevating medications:

“…“insulin resistance” can mean either defective insulin receptor signaling or, ironically, overstimulation of insulin receptor pathways caused by hyperinsulinemia.”

They also note the difference between ‘ordinary’ atherosclerosis and the lesions, vulnerable plaque, that actually cause heart attacks and ischemic strokes.

“Most importantly, the primary objective of this study was to address an entirely different question, namely, the effect of myeloid IR deficiency on advanced lesional macrophage apoptosis and plaque necrosis. Recall that most atherosclerotic lesions in humans do not cause acute coronary artery disease, because they undergo outward remodeling of the arterial wall, which preserves lumen patency, and do not undergo plaque rupture or erosion and thus do not trigger acute lumenal thrombosis. The small percentage of lesions that do cause acute vascular disease are distinguished by the presence of large areas of necrosis and thin fibrous caps, which promote plaque disruption, acute lumenal thrombosis, and tissue infarction. This concept is particularly important for the topic of this review, because advanced atherosclerotic lesions in diabetic subjects are characterized by large necrotic cores when compared with similarly sized lesions from nondiabetic individuals”

In their conclusion the authors state the role of insulin resistance over hyperglycemia:

“These studies have provided evidence that insulin resistance in macrophages and endothelial cells may play important roles in both atherogenesis and clinically relevant advanced plaque progression. Hyperglycemia, on the other hand, appears to primarily promote early stages of lesion formation…”

Insulin resistance inhibits nitric oxide synthase

An interesting paper published in the Italian journal Panminerva Medica further elucidates key mechanisms, including the damage by IR to nitric oxide regulation done by increasing asymmetric dimethylarginine, which inhibits nitric oxide synthase. The author includes this under the rubric ‘insulin resistance syndrome’.

“…the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration….Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome.”

Specifically in regard to cardiovascular disease…

“…in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension.”


“The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects.”


A paper published in Diabetes Metabolism Research and Reviews draws this point further.

“In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism.”

And a vicious cycle ensues…

“Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.”

In their conclusion the authors state:

“…endothelial dysfunction and insulin resistance commonly occur together and can be detected early in the pathogenesis of atherosclerosis. Insulin resistance can be inferred by the presence of a cluster of metabolic and cardiovascular abnormalities known collectively as the metabolic syndrome or by direct measurement of impaired insulin-stimulated glucose and lipid metabolism . Endothelial dysfunction can be documented by the demonstration of inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries. Lack of endothelial-derived NO may provide the link between insulin resistance and endothelial dysfunction.”

Plea to clinicians

Many resources are available for practitioners to apply a functional medicine model of objectively targeted treatment to resuscitate insulin receptor function and address lifestyle issues, especially diet, for the management of type 2 diabetes that minimizes the use of agents that lower glucose by increasing insulin, and therefore insulin resistance. It is my sincere wish that not only endocrinologists, but all clinicians, recall the mechanisms by which medications that promote insulin resistance increase cardiovascular disease, and act accordingly to protect their patients.

Insulin resistance is a huge topic, and there are numerous posts here pertaining to IR an conditions as diverse as Alzheimer’s disease and breast cancer that can be viewed by using the search box. They include the earlier post on the correlation of IR with blood vessel damage leading to heart attack and stroke.

Nitric oxide is essential for red blood cells to deliver oxygen

PNASThe tiny molecule nitric oxide is already known to be critical for blood vessel health and a multitude of functions throughout the body. Groundbreaking research published in PNAS (Proceedings of the National Academy of Sciences) reveals that nitric oxide is the third member of a three gas system (with oxygen and carbon dioxide) is carried by red blood cells and essential for oxygen delivery to tissues. The authors describe the critical role of hemoglobin βCys93, one of three amino acids found in the hemoglobin of all mammals and birds:

“…only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO [nitric oxide] bioactivity by Hb [hemoglobin] redefines the respiratory cycle as a triune system (NO/O2/CO2).”

In other words, the nitric oxide built into hemoglobin as βCys93 is required for RBC-mediated vasodilation. Without sufficient nitric oxide, vasodilation and thus oxygen delivery to tissues is impaired. Hypoxia in tissues is supposed to stimulate a vasodilatory reaction in blood vessel, but this fails to occur normally in RBCs that are deficient in nitric oxide:

“Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia.”

βCys93 nitric oxide in cardiovascular and fetal health

Too little oxygen gets to tissue under normal conditions, and it’s even worse with heart disease and fetal stress:

“In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia.”

The authors summarize the the huge importance of their study:

“These findings support a new view of the respiratory cycle wherein, remarkably, RBCs regulate blood flow and (βCys93NO)-Hb is necessary for adequate tissue oxygenation and normal cardiovascular function.”

Transforms understanding of the respiratory cycle

Three-gas systemAn excellent review of this research in Medical News Today states:

“In their study they show that hemoglobin – the protein in red blood cells that picks up oxygen from the lungs – also needs to carry nitric oxide to enable blood vessels to open and supply the oxygen to tissues.”

Quoting lead author cardiologist Jonathan Stamler, professor of medicine at Case Western Reserve University School of Medicine…

“Prof. Stamler says “blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system.”

He and his colleagues say their findings will transform our understanding of the respiratory cycle and could save lives.”


“Prof. Stamler explains how the mice had red blood cells “that by all traditional measures are completely normal in carrying oxygen and releasing it and then in picking up carbon dioxide, yet these animals cannot oxygenate their tissues. Lacking nitric oxide in red cells, oxygen deficiency could not induce vasodilation, which is essential for sustaining life as we know it.”

The study shows that when the mechanism that releases nitric oxide from the amino acid binding site in the hemoglobin is working, the blood vessels dilate and allow oxygen-rich red blood cells to flow into the tissue.

The findings also provide evidence that blood flow is not just under the control of blood vessels – red blood cells are also involved. This has not been appreciated before, with some scientists hypothesizing instead that the lack of blood flow that causes heart attacks and strokes is nothing to do with red blood cells – it is all about what happens in blood vessels. The authors suggest this view needs to be revised, as Prof. Stamler explains:

“Within the tissues, the tiny vessels and the red blood cells together make up the critical entity controlling blood flow. Red blood cell dysfunction is likely a hidden contributor to diseases of the heart, lung and blood such as heart attack, heart failure, stroke and ischemic injury to kidneys.”

Implications for blood transfusion

There are dire consequences when transfused blood is not replete with nitric oxide:

“Recent evidence shows blood transfusions lacking nitric oxide are linked to higher risk of heart attacks, disease and death.

Prof. Stamler says the effects being reported in these cases are similar to what they observed in the mice – the common factor is lack of nitric oxide.

“It’s not enough to increase to oxygen content of blood by transfusion; if the nitric oxide mechanism is shot, oxygen cannot make it to its destination. We know that blood in a blood bank is deficient in nitric oxide, so infusing that blood may cause plugging of blood vessels in tissues, making things worse,” he notes, and concludes:

“Essentially, blood flow cannot autoregulate (increase) without nitric oxide. In terms of developing future therapies, the goal must be restoring red blood cell function, complete with nitric oxide delivery capability. As for the nation’s blood supply, the blood should be replenished with nitric oxide.”

Clinical Note

Recently for the first time practitioners can directly test nitric oxide sufficiency and replete NO resources when deficient (see Neogenis Medical Practitioner Resources). The clinical importance of nitric oxide regulation can hardly be overstated. This approximately 3 minute video explains the unique properties of their product for NO levels and production.

Oxidized LDL promotes atherosclerosis

Science SignalingOxidized LDL, low density lipoprotein that has been that has been subject to oxidation as participates in a vascular infllammatory process, is a direct risk factor for heart attacks and ischemic strokes and a more accurate predictor than ‘ordinary’ undamaged LDL. Research recently published in Science Signaling elucidates one of the mechanisms by which oxidized LDL promotes atherosclerosis.

Oxidized LDL promotes foam cell generation

Foam cells are the macrophages (white blood cells) filled with fat that accumulate in the build-up of atherosclerotic plaque.

“One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have previously shown that the binding of oxidized low-density lipoprotein (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation.”

The authors demonstrated that blocking the ion transporter Na+/K+-ATPase, a key link in this signaling chain, protects against diet-induced atherosclerosis:

“We identified the plasma membrane ion transporter Na+/K+-ATPase as a key component in the macrophage oxLDL-CD36 signaling axis. Using peritoneal macrophages isolated from Atp1a1 heterozygous or Cd36-null mice, we demonstrated that CD36 recruited an Na+/K+-ATPase–Lyn complex for Lyn activation in response to oxLDL. Macrophages deficient in the α1 Na+/K+-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibit migration of these macrophages. Furthermore, Apoe-null mice, which are a model of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1 Na+/K+-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the α1 Na+/K+-ATPase subunit. These findings identify Na+/K+-ATPase as a potential target for preventing or treating atherosclerosis.”

Clinical Note

Case management of cardiovascular risk entails the measurement of oxidized LDL as a key predictive biomarker, and interval changes are important to objectively gauge the effectiveness of lifestyle and other interventions.

Atrial fibrillation risk increased by non-steroidal antiinflammatory drugs

BMJAtrial fibrillation, the most common heart rhythm disorder, is a troublesome, uncomfortable condition that significantly increases the risk for heart attack and stroke. While it is becoming better recognized that none of the non-steroidal anti-inflammatory drugs (NSAIDs) other than aspirin are safe in cardiovascular terms, it is often overlooked that NSAIDs increased the risk for atrial fibrillation specifically. Consider a study published in BMJ (British Medical Journal) in which the authors state…

“Any confirmed association between use of NSAIDs and atrial fibrillation would have major clinical and public health implications. Older people are of special concern because the prevalence of use of NSAIDs and the incidence of atrial fibrillation increase with age. To address the limitations of the existing literature, we conducted a large population based case-control study examining whether and to what extent use of NSAIDs increases the risk of atrial fibrillation or flutter.”

They examined data on 32,602 patients with atrial fibrillation compared to 325,918 age matched and sex matched controls for exposure to NSAID use before or at the time of admission for their arrhythmia. They also distinguished between recent and long term use and found significantly increased risk:

“2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 for non-selective NSAIDs and 1.50 for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 for non-selective NSAIDs and 1.27 for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 for non-selective NSAIDs and 1.71 for COX 2 inhibitors. Results for individual NSAIDs were similar.”

That’s a 46% and 71% increase for non-selective NSAIDs and COX 2 inhibitors respectively in new users, and it didn’t appear to matter which NSAID was used. The authors conclude:

Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.”


Archives of Internal Medicine Vol 170 No. 16Evidence that  antiinflammatory medications increase the risk for atrial fibrillation was also presented in a paper published in JAMA Internal Medicine. Having noted the previously described association between the use of corticosteroids (steroidal anti-inflammatory drugs [SAIDs]) and the risk of atrial fibrillation (AF) they examined data for 1035 patients with incident chronic AF and 525 with paroxysmal AF and found:

“We confirmed the previously reported association between current use of SAIDs and chronic AF (rate ratio [RR], 2.49. However, we also found that the current use of NSAIDs was associated with an increased risk of chronic AF. Such risk was further increased among long-term users with a treatment duration of longer than 1 year. The increased risk of chronic AF was not explained by the occurrence of heart failure. The use of NSAIDs was not associated with paroxysmal AF.”

They posit that inflammation may be a common cause for atrial fibrillation and the use of NSAIDs:

Underlying inflammatory conditions could favor the onset or maintenance of AF. Atrial fibrosis is the most frequent pathoanatomical change found in AF. Patchy fibrosis in close proximity with normal atrial fibers may account for conduction inhomogeneities, and it has been argued that fibrosis precedes the onset of AF. Atrial fibrosis is currently the main structural target for the proposed use of drugs inhibiting the renin-angiotensin system in AF and may be caused by inflammation, as seen in cardiac sarcoidosis and autoimmune disorders. Inflammation, possibly also through the production of thromboxane A2 and prostaglandin F2α, has recently been shown to cause inflammatory tachycardia. It is possible, and we would like to propose, that conditions presenting systemic inflammation, such as autoimmune and rheumatic disorders, represent an independent risk factor for atrial fibrosis and subsequently for an increased risk of onset or persistence of AF. Consequently, the use of anti-inflammatory drugs may be a proxy for an underlying inflammatory substrate favoring AF.”


Heart RhythmThe authors of the JAMA paper concentrate on inflammation as a shared cause for atrial fibrillation and the prescription of NSAIDs, but it’s important to reflect on the fact that NSAIDs increase intestinal barrier permeability which contributes to the loss of immune tolerance and autoimmunity. The resultant autoimmune inflammation can target the conductive system of the heart and produce arrhythmias as described in a paper published in the journal Heart Rhythm:

“…accumulating evidence suggests that a number of vascular and cardiac conditions are autoimmune mediated. Recent studies indicate that autoantibodies play an important role in the development of cardiac arrhythmias, including atrial fibrillation, modulation of autonomic influences on heart rate and rhythm, conduction system abnormalities, and ventricular arrhythmias. This article will review the current evidence for the role of autoantibodies in the development of cardiac arrhythmias.”


Heart Rhythm Vol 10 No. 11And a recent paper in the same journal identified autoantibodies to β-adrenergic receptors (β2ARs) as culprits for inducing atrial arrhythmias:

“Taking into account only the sustained arrhythmias, there were 6 episodes in 20 events in the postimmune studies compared with 0 episodes in 20 events in the preimmune studies. Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of β2AR in transfected cells in vitro compared to the preimmune sera…Enhanced autoantibody activation of β2AR in the rabbit atrium leads to atrial arrhythmias mainly in the form of sustained atrial tachycardia.”


Medicine & Science in Sports & ExerciseClinicians should bear in mind that athletes are especially vulnerable because exercise induces small intestinal micro-injury. The authors of a study published in the journal Medicine & Science in Sports & Exercise state:

Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals.”

They examined the effects of 400 mg of ibuprofen taken twice before cycling, cycling without ibuprofen, 400 mg of ibuprofen taken twice while at rest, and 4) rest without any ibuprofen. They used plasma intestinal fatty acid binding protein (I-FABP) levels and urinary excretion of orally ingested multisugar test probes to assess small intestinal injury and GI permeability respectively:

“Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen. In line, small intestinal permeability increased, especially after cycling with ibuprofen, reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly.”

This study reveals a link between ibuprofen taken during exercise and atrial fibrillation due to autoimmune inflammation promoted by damage to the intestinal barrier. The authors conclude:

“This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged.”


International Journal of Sports MedicineSadly, the wonder drug aspirin does not get a free pass in this context. The authors of a study published in the International Journal of Sports Medicine provide evidence that aspirin also increases gut permeability:

“The primary purpose of this study was to determine the aspirin dose that increases gastrointestinal (GI) permeability. A pilot study was also conducted to determine whether the menstrual cycle affects GI permeability. Both portions of the study involved 4 experimental conditions. For the aspirin portion, 8 subjects ingested 0 mg, 325 mg, 650 mg, or 975 mg of aspirin the night before and the morning of an experiment. For the menstrual cycle pilot study, 5 female subjects with regular menstrual cycles were tested for GI permeability on the same day each week for 4 weeks. GI permeability was assessed by the urinary excretion of ingested probes. Sucrose (5 g) was used to determine gastroduodenal permeability. Lactulose (5 g) and rhamnose (2 g) were used to assess small intestinal permeability via the lactulose-to-rhamnose urinary excretion ratio (L/R).”

Interestingly, menstruation did not increase gut permeability in their study subjects, but aspirin certainly did:

“The data indicated that the menstrual cycle had no effect on GI permeability. In contrast, gastroduodenal permeability was significantly increased following a dose of 650 mg aspirin and small intestinal permeability (L/R) was significantly increased following a dose of 975 mg aspirin. These results suggest healthy individuals should be cautious even with acute aspirin use as it may result in GI barrier dysfunction.”


Clinical note: practitioners must bear in mind the potential for all non-steroidal anti-inflammatory drugs to cause atrial fibrillation by aggravating or triggering latent autoimmune inflammation due to gut barrier compromise.

Aspirin Cardiovascular/Gastrointestinal Risk Calculator

Alimentary Pharmacology & TherapeuticsAspirin has been shown to be worthy of consideration for secondary, and in some cases primary, prevention of heart attacks and strokes but carries known risks for gastrointestinal side effects. If you’re not certain whether to recommend low-dose aspirin to a patient, the aspirin cardiovascular/gastrointestinal risk calculator can help with the clinical decision. A paper recently published in the journal Alimentary Pharmacology and Therapeutics describes the development and use of this practical tool. The investigators state:

Assessment of both GI and CV risks vs. the benefits of low-dose aspirin for individual patients can be difficult in clinical practice.”

Therefore they determined to…

“…develop a tool to estimate CV and GI risks to facilitate the clinical decision-making process…We constructed risk-ratio estimations and determined the incidence of CV events and upper GI complications according to the presence of different risk factors. For upper GI complications we assumed a baseline incidence of 1 case/1000-persons-year, a twofold increased risk with low-dose aspirin, and estimated a 60% GI risk reduction with proton pump inhibitors (PPI) co-therapy and a 60% risk reduction with H. pylori eradication in patients with a history of peptic ulcer.”

The full text of their paper is available at Medscape Family Medicine. A summary of their results states:

“In patients with low CV risk the number of GI complications induced by low-dose aspirin may be greater than the number of CV events prevented. In patients with high CV risk, low-dose aspirin is recommended, but the number of GI complications induced may still overcome the CV events saved. The use of PPI reduces the number of complication events induced by low-dose aspirin, but the number of CV events saved may still be offset by the number of GI complications induced in patients at very high GI risk.”

The authors conclude:

“…the use of algorithms to integrate the stratification of individual CV risk with that of upper GI risk is an important clinical situation to consider in patients with suspected coronary artery disease. A proper quantification of GI risk should identify patients who may benefit more from the avoidance of LDA therapy, or from the addition of appropriate therapeutic modifications to avoid complications and obtain the maximal benefit of LDA. For this reason, the use of the aspirin CV/GI risk calculator should guide physicians in choosing appropriate treatment for primary CV prevention.”

Erectile Dysfunction is a risk factor for cardiovascular disease and mortality

PLoS MedicineMore evidence that erectile dysfunction is a risk factor for cardiovascular disease is presented in a study just published in PLoS Medicine (Public Library of Science). This should come as no surprise considering that health of vascular  endothelium is one of the elements necessary to ensure blood delivery to the ‘periphery’. The authors added to literature on this topic by examining the degree of erectile dysfunction in relation to cardiovascular risk:

Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes.”

To do so they examined hospitalisation and death data for 95,038 men 45 years and older, analyzing the relationship of reported severity of erectile dysfunction to all-cause mortality and hospitalisation for cardiovascular disease. Men with and without previous CVD were, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and treatment for hypertension and/or high cholesterol. The data describe a strong association:

“There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60), heart failure (8.00), peripheral vascular disease (1.92), “other” CVD (1.26), all CVD combined (1.35), and all-cause mortality (1.93). For men with previous CVD, corresponding RRs (95% CI) were 1.70, 4.40, 2.46, 1.40, 1.64, and 2.37, respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66), atrioventricular and left bundle branch block (6.62), and (peripheral) atherosclerosis (2.47), with no significant difference in risk for conditions such as primary hypertension (0.61) and intracerebral haemorrhage (0.78).”

Clinicians’ notes: (1) Phosphodiesterase type 5 inhibitors (Viagra®, etc.) do not remediate the underlying causes. (2) Don’t forget to check ADMA (asymmetric dimethyl arginine levels for endothelial nitric oxide capacity. As authors conclude, erectile dysfunction is an alert to examine all the risk factors for CVD:

These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment…The findings of this study highlight the need to consider erectile dysfunction in relation to the risk of a wide range of CVDs that extends beyond ischaemic heart disease and stroke and includes conditions such as heart failure and conduction disorders. They also provide evidence that CVD risk is elevated across a spectrum of severity of erectile dysfunction and that men with mild or moderate erectile dysfunction should be considered at increased risk, in addition to those with severe disease.”

Insulin resistance correlates with blood vessel damage leading to heart attack and stroke

PLOS ONEThere is a wealth of evidence showing the relationship between insulin resistance (diminished ability of cells to take up and metabolize glucose in response to insulin) and cardiovascular disease. Carotid intima–media thickness (thickening of the lining of the carotid artery) is a particularly strong risk factor indicator heart attack and stroke. A study just published in PLOS ONE (Public Library of Science) shows a strong association of insulin resistance with the blood vessel damage resulting in increased carotid intima–media thickness. The authors observe:

Insulin resistance (IR) is considered an important risk factor for both atherosclerotic cardiovascular disease, and type 2 diabetes, and a key determinant of cardiovascular risk factors, including visceral obesity, atherogenic dyslipidemia, and hypertension, clustering within the metabolic syndrome. Accumulating evidence suggests an association between hyperinsulinemia and/or IR and cardiovascular diseases.”

Furthermore, insulin resistance appears to carry more weight than hyperinsulinemia:

“Importantly, it has been shown that IR…rather than hyperinsulinemia, was independently associated with early vascular atherosclerosis.”

But insulin resistance is notoriously difficult to measure:

“…methods to directly measure IR are complex, time-consuming, expensive, and unsuitable for large scale epidemiological studies. Therefore, surrogate indexes of insulin sensitivity have been developed using fasting insulin and/or glucose levels alone or in combination with insulin and glucose levels during an oral glucose tolerance test (OGTT) as well as with other metabolic variables. Since IR occurs in multiple tissues, these indexes reflects predominantly either hepatic or muscle IR.”

So it had not yet been made clear if these IR indexes are specifically associated with vascular atherosclerosis. They decided to investigate using carotid artery intima–media thickness because:

Intima–media thickness (IMT) of common carotid artery is a well-recognized index of vascular damage, and is widely utilized as a surrogate marker for cardiovascular disease.”


“The aim of this study was to examine the relationship between different indexes of insulin resistance and common carotid IMT in a cohort of nondiabetic Caucasian individuals.”

They performed a 75 gram oral glucose tolerance test on 847 non-diabetic subjects and computed a variety of indexes of insulin. IMT was measured by ultrasound method. There was an outstanding feature in their data:

The Stumvoll ISIOGTT index was correlated with IMT more strongly than the other indexes of IR. The IR indexes correlated significantly with all cardiovascular risk factors examined. The Stumvoll ISIOGTT index was correlated with waist circumference and high sensitivity C-reactive protein more strongly than the other indexes of IR. The area under the ROC curve (AUC), used to evaluate the accuracy of the IR indexes in identifying individuals with vascular damage defined as IMT >0.9 mm, for the Stumvoll ISIOGTT index was significantly higher as compared with the AUCs of Matsuda, OGIS, HOMA and Liver IR indexes. In a logistic regression model adjusted for age and gender, subjects in the lowest tertile of the Stumvoll ISIOGTT index had the highest risk of having vascular damage as compared to the corresponding tertiles of the other surrogate indexes.”

In other words, the Stumvoll ISIOGTT index as a metric for insulin resistance outperformed the others in correlating with blood vessel damage manifested by carotid intima-media thickening. Practitioners, and all other readers, should bear in mind that this cardiovascular damage happens before diabetes. The authors reiterate the significance of insulin resistance in these matters:

 “IR is also a key feature of a spectrum of metabolic abnormalities such as obesity and glucose intolerance, and is associated with multiple cardiovascular risk factors (visceral adiposity, hypertension, atherogenic dyslipidemia), a clinical constellation that has been referred to as metabolic syndrome. IR is a predictor of atherosclerotic cardiovascular disease, and this association has vast social implications, and calls for intensive investigation of the causes of the disease, to optimize its treatment and to possibly prevent its onset.”

I think it can be fairly said that managing insulin resistance is a crucial core element of cardiovascular disease treatment and prevention.The authors conclude:

“In conclusion, in the present study we demonstrated that, among the different validated surrogates indexes of IR, the Stumvoll ISIOGTT index correlates better with vascular damage, as assessed by IMT of common carotid artery, in a large cohort of non-diabetic individuals. Thus, the Stumvoll ISIOGTT index might be a significant indicator of vascular damage with an important clinical significance.”

High blood pressure: when is medication needed for hypertension?

High blood pressure management is fundamental for the prevention and treatment of heart attacks, strokes and kidney disease. What should be the target blood pressure for medication? Overmedication is common and can damage function with adverse effects on quality of life. The authors of an intervention review published recently in the highly respected Cochrane Library examine all the relevant randomized controls trials and come to the conclusion that medicating mild hypertension (systolic blood pressure (BP) 140-159 mmHg and/or diastolic BP 90-99 mmHg) confers no benefit. They begin by stating:

“Individuals with mildly elevated blood pressures, but no previous cardiovascular events, make up the majority of those considered for and receiving antihypertensive therapy. The decision to treat this population has important consequences for both the patients (e.g. adverse drug effects, lifetime of drug therapy, cost of treatment, etc.) and any third party payer (e.g. high cost of drugs, physician services, laboratory tests, etc.).”

They examined evidence comparing the health outcomes between treated and untreated individuals with mildly high blood pressure in order to…

“…quantify the effects of antihypertensive drug therapy on mortality and morbidity in adults with mild hypertension (systolic blood pressure (BP) 140-159 mmHg and/or diastolic BP 90-99 mmHg) and without cardiovascular disease.”

So they searched an extensive collection of databases for random controlled trials (RCTs) lasting at least a year. These included MEDLINE extending from 1948 to 2011, EMBASE from 1980 to 2011, and others. The also searched the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness (DARE) for reviews and meta-analyses of high blood pressure drug treatment compared to placebo or no treatment. They used death, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), and withdrawals due to adverse effects as their primary outcomes. What did the data show?

“Treatment for 4 to 5 years with antihypertensive drugs as compared to placebo did not reduce total mortality. In 7,080 participants treatment with antihypertensive drugs as compared to placebo did not reduce coronary heart disease, stroke, or total cardiovascular events. Withdrawals due to adverse effects were increased by drug therapy, ARR 9%.”

While it is well established that appropriate medication for moderate-severe hypertension reduces heart attacks, strokes and kidney disease, this study and other evidence suggests that medication confers no benefit for mild high blood pressure. Lifestyle and other interventions are likely preferable. The authors conclude:

Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs. Available data from the limited number of available trials and participants showed no difference between treated and untreated individuals in heart attack, stroke, and death. Treatment caused 9% of patients to discontinue treatment due to adverse effects. More RCTs are needed in this prevalent population to know whether the benefits of treatment exceed the harms.”

It is not at all unusual for patients to come to my practice having been unnecessarily medicated for blood pressure lower than 140-159 mmHg and/or diastolic BP 90-99 mmHg. In addition to the obvious cautions, clinicians must remember that as the circulatory system becomes less elastic with age it can require a little more pressure to perfuse the brain and the rest of the body with blood and oxygen. The full text of this important review is available here. For a thorough review of blood pressure guidelines, including special considerations for diabetes and kidney disease, see the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment ofHigh Blood Pressure.

Dried apples and plums lower cardiovascular disease risk in postmenopausal women

Dried apples? A clinical trial just published in the Journal of the Academy of Nutrition and Dietetics offers evidence that consuming a modest amount of dried apples and plums (prunes) can lower cardiovascular disease risk by improving lipids and reducing inflammation. The authors state…

“Evidence suggests that consumption of apple or its bioactive components modulate lipid metabolism and reduce the production of proinflammatory molecules. However, there is a paucity of such research in human beings…Hence, we conducted a 1-year clinical trial to evaluate the effect of dried apple vs dried plum consumption in reducing cardiovascular disease risk factors in postmenopausal women.”

They randomly assigned 160 qualified postmenopausal women to one of two groups: dried apple (75 g/day) or dried plum (comparative control). While documenting physical activity and diet the collected fasting blood samples at baseline, 3, 6, and 12 months to measure various cardiovascular disease risk markers. The data showed that both dried apples and dried plums were helpful in their own way:

“…women who consumed dried apple lost 1.5 kg body weight by the end of the study, albeit not significantly different from the dried plum group. In terms of cholesterol, serum total cholesterol levels were significantly lower in the dried apple group compared with the dried plum group only at 6 months…women who consumed dried apple had significantly lower serum levels of total cholesterol and low-density lipoprotein cholesterol by 9% and 16%, respectively, at 3 months compared with baseline. These serum values were further decreased to 13% and 24%, respectively, after 6 months but stayed constant thereafter. The within-group analysis also reported that daily apple consumption profoundly improved atherogenic risk ratios, whereas there were no significant changes in lipid profile or atherogenic risk ratios as a result of dried plum consumption. Both dried fruits were able to lower serum levels of lipid hydroperoxide and C-reactive protein. However, serum C-reactive protein levels were significantly lower in the dried plum group compared with the dried apple group at 3 months.”

So both were successful in reducing cardiovascular disease risk factors including ‘bad’ cholesterol and markers of inflammation. The authors conclude.

“There were no significant differences between the dried apple and dried plum groups in altering serum levels of atherogenic cholesterols except total cholesterol at 6 months. However, when within treatment group comparisons are made, consumption of 75 g dried apple (about two medium-sized apples) can significantly lower atherogenic cholesterol levels as early as 3 months. Furthermore, consumption of dried apple and dried plum are beneficial to human health in terms of anti-inflammatory and antioxidative properties.”

Magnesium reduces death from cardiovascular disease

Additional evidence that magnesium is important in reducing mortality from cardiovascular disease is offered in a study recently published in the journal Atherosclerosis. The authors’ intent was to…

“…investigate the relationship between dietary magnesium intake and mortality from cardiovascular disease in a population-based sample of Asian adults.”

They examined 58,615 healthy Japanese aged 40–79 years for dietary magnesium intake by a validated food frequency questionnaire administered over two years with a median 14.7-year follow-up. During that time they documented 2690 deaths from cardiovascular disease (1227 deaths from strokes and 557 deaths from coronary heart disease). What did the data reveal for the importance of magnesium?

Dietary magnesium intake was inversely associated with mortality from hemorrhagic stroke in men and with mortality from total and ischemic strokes, coronary heart disease, heart failure and total cardiovascular disease in women. The multivariable hazard ratio (95% CI) for the highest vs. the lowest quintiles of magnesium intake after adjustment for cardiovascular risk factor and sodium intake was 0.49 (0.26–0.95), P for trend=0.074 for hemorrhagic stroke in men, 0.68 (0.48–0.96), P for trend=0.010 for total stroke, 0.47 (0.29–0.77), P for trend<0.001 for ischemic stroke, 0.50 (0.30–0.84), P for trend=0.005 for coronary heart disease, 0.50 (0.28–0.87), P for trend=0.002 for heart failure and 0.64 (0.51–0.80), P for trend<0.001 for total cardiovascular disease in women.”

In other words, the overall risk for stroke and heart disease was reduced by approximately half. Bear in mind that calcium opposes magnesium; this is the likely mechanism by which calcium supplementation can promote cardiovascular inflammation. The authors state:

“In conclusion, dietary magnesium intake was associated with reduced mortality from cardiovascular disease in Japanese, especially for women.”

You may wish to read earlier posts on magnesium, calcium and cardiovascular disease by entering these terms as search items above.