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.”

Moreover…

“…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.”

Moreover…

“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.

Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”

 

HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

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.”

Furthermore:

“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.

Low normal sodium a cardiovascular risk

Nutrition, Metabolism & Cardiovascular DiseasesSerum sodium levels are influenced by a number of factors linked to cardiovascular health including dysglycemia (blood glucose disorders), hypothyroid, adrenal dysregulation and others. Research just published in Nutrition, Metabolism & Cardiovascular Diseases identifies low serum sodium within the normal range as a risk predictor for cardiovascular disease and stroke. The authors state:

Hyponatremia, usually defined as serum sodium concentration <136 mEq/L, is one of the most common electrolyte abnormalities observed in hospitalised patients and in patients with chronic kidney disease (CKD), coronary heart disease (CHD) and heart failure (HF). Several clinical and epidemiological studies have shown hyponatremia to be associated with increased total mortality in these patients. More recently, attention has turned to the possibility that mild hyponatremia, may be associated with adverse outcomes in the general population…in the three population studies that have examined the relationship between hyponatremia and mortality in community based subjects, there is evidence that hyponatremia is associated with increased mortality and even a level of sodium concentration in the lower normal range (serum sodium 135-137 mEq/L), a level usually considered benign, is associated with increased mortality.”

Less is known about the association between serum sodium and potassium and the risk of cardiovascular disease and stroke in older men withoutmthese disorders. So the authors examined data for 3099 men aged 60-79 years without a history of cardiovascular disease for an average 11 years. During that time there were 528 major CVD events (fatal coronary heart disease [CHD] and non-fatal MI, stroke and CVD death) and 873 total deaths.

Mildly low sodium is not benign

 Although no association was seen between serum potassium and cardiovascular disease, low serum sodium within the normal range as well as high serum sodium is associated with increased risk of stroke and cardiovascular disease mortality:
“A U shaped relationship was seen between serum sodium concentration and major CVD events and mortality. Hyponatremia (<136 mEq/L) and low sodium within the normal range (136-138 mEq/L) showed significantly increased risk of major CVD events and total mortality compared to men within the upper normal range (139-143 mEq/L) after adjustment for a wide range of confounders and traditional risk factors [adjusted HRs 1.55 and 1.40 for major CVD events respectively and 1.30 and 1.30 respectively for total mortality]. Hyponatremia was associated with inflammation, NT-proBNP, low muscle mass and alkaline phosphatase; these factors contributed to the increased total mortality associated with hyponatremia but did not explain the increased risk of CVD events associated with hyponatremia or low normal sodium concentration. Hypernatremia (>145 mEq/L) was associated with significantly increased risk of CVD events and mortality due to CVD causes.”
In other words, both low normal and high sodium are a significant risk factor for cardiovascular disease and mortality.

Clinical Implications

Practitioner’s should bear in mind the authors’ conclusions and not dismiss low normal serum sodium:
“Hyponatremia and hypernatremia are both associated with increased risk of CVD incidence and mortality. Low sodium within the normal range is associated with significantly increased CVD events and total mortality in older men without major CVD or HF even in the absence of diuretic use and renal dysfunction. The data lends further evidence to the suggestion that the presence of mild hyponatremia is not benign. The findings may have important implications for the monitoring of sodium levels in clinical practice in older adults. The presence of mild hyponatremia in the absence of known causes such as renal dysfunction and diuretics may warrant further investigation in these men to assess CVD risk factors or possible underlying ill-health such as chronic inflammation. Further large studies are required to confirm and elucidate the nature of the association between low normal sodium and risk of incident CVD.”

Insulin resistance indicated by neutrophil-lymphocyte ratio

BMC Endocrine DisordersInsulin resistance (IR) is central to type 2 diabetes and a contributing cause to cardiovascular and neurodegenerative disorders, chronic kidney disease (CKD), a number of cancers and more. A study recently published in BMC Endocrine Disorders the ratio between neutrophils and lymphocytes (neutrophil-lymphocyte ratio, NLR) is a valuable and inexpensive predictive marker for insulin resistance. The authors note:

“Insulin resistance (IR) is a reduction in reaction or sensitivity to insulin and is considered to be the common cause of impaired glucose tolerance, diabetes, obesity, dyslipidemia, and hypertensive diseases….several studies have confirmed the relationship between systemic inflammation and insulin resistance, in which an altered immune system plays a decisive role in the pathogenesis of DM. The immune response to various physiological challenges is characterized by increased neutrophil and decreased lymphocyte counts, and NLR is often recognized as an inflammatory marker to assess the severity of the disease.”

Furthermore…

“Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR.”

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

So they investigated the neutrophil-lymphocyte ratio in 413 patients with T2DM, 310 of whom had a HOMA-IR value (fasting plasma glucose (mmol/L) multiplied by fasting serum insulin (mIU/L) divided by 22.5) of > 2.0, indicating insulin resistance. They were compared to a control group of 130 healthy subjects and found a strong association:

“The NLR values of the diabetic patients were significantly higher than those of the healthy control, and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0. Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR. Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95%) for every one unit increase in NLR.”

 Diabetes, cancer and cardiovascular diseases

In relation to their confirmation of NLR as a predictor for insulin resistance the authors observe…

“Many epidemiological studies have determined that DM is associated with chronic inflammation, which may contribute to the acceleration of diabetic microangiopathy and the development of macroangiopathy; IR is a characterized of T2DM, whereas the exact molecular action leading to IR is not yet understood, several studies have associated IR with inflammation, experimental studies have demonstrated a link between chronic inflammation and insulin resistance through mechanisms involving obesity and atherosclerosis. NLR has been recently defined as a novel potential inflammation marker in cancer and cardiovascular diseases. NLR can easily be calculated using the neutrophil-lymphocyte ratio in peripheral blood count. Calculating NLR is simpler and cheaper than measuring other inflammatory cytokines, such as IL-6, IL-1β, and TNF-α.”

Diabetes and chronic inflammation

These findings highlight the relationship between chronic inflammation, insulin resistance and type 2 diabetes.

“he pathological activation of innate immunity leads to inflammation of the islet cells, resulting in a decrease in pancreatic beta-cell mass and impaired insulin secretion. Patients with T2DM are in a state of low-degree chronic inflammation that induces hypersecretion of inflammatory factors, such as CRP, IL-6, TNF-α, and MCP-1, which results in a constantly elevated neutrophilic granulocyte count. One mechanism by which increased levels of neutrophils could mediate IR may be through augmented inflammation. The increase in NLR appears to underlie the elevated levels of pro-inflammation, as evident from the persistent neutrophil activation and enhanced release of neutrophil proteases with T2DM.”

 NLR tracks HgbA1c and triglycerides

Glycation of hemoglobin (HgbA1c) and triglycerides (TG) both go up as insulin resistance progresses along with the neutrophil-lymphocyte ratio.

“A logistic regression analysis of the following risk factors was conducted: NLR, TG and HbA1c. In our study, in conjunction with the rising of the level of HbAlc, the degree of IR increased significantly. HbA1c showed an association with early-phase insulin secretion assessed by insulinogenic index. Heianza et al. reported that elevated HbA1c levels of above 41 mmol/mol (>5.9%) were associated with a substantial reduction in insulin secretion and insulin sensitivity as well as an association with β-cell dysfunction in Japanese individuals without a history of treatment of diabetes. Increased accumulation of TG has been observed in human muscle tissue of obese and type 2 diabetic subjects, and associated with IR, which is in agreement with the present study. IR reduces the inhibition effect of lipolysis in adipose tissue, resulting in the increase of the free fatty acid (FFA) level in plasma.”

NLR is a superior biomarker

Although susceptible to modification by dehydration, elevated PSA or catecholamine release induced by exercise, the NLR is more sensitive than the neutrophil count alone or CRP levels.

“NLR represents a combination of two markers where neutrophils represent the active nonspecific inflammatory mediator initiating the first line of defense, whereas lymphocytes represent the regulatory or protective component of inflammation. NLR is superior to other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leukocyte counts) because of its better stability compared with the other parameters that can be altered by various physiological, pathological, and physical factors. Thus, as a simple clinical indicator of IR, NLR is more sensitive compared with the neutrophilic granulocyte count and CRP levels, which are widely used as markers of IR.”

Clinical bottom line

Practitioners should not fail to make use of this significant, inexpensive biomarker that is under our noses every day. The authors sum it up:

“…in the present study, NLR serves an important function in predicting the risk of IR. IR in diabetic patients is related to chronic inflammation, and NLR may be helpful in assessing the prognoses of these patients…We recommend that the NLR values of diabetic patients be calculated as NLR is a cheap, predictive, and prognostic marker for IR. High NLR values were independently related to IR.”

Stroke risk reduced by magnesium

StrokeStroke risk is reduced by higher plasma magnesium levels according to data from 32,826 women in the Nurses’ Health Study presented in a paper just published in the journal Stroke. The authors note:

Lower plasma magnesium levels may be associated with higher blood pressure and endothelial dysfunction, but sparse prospective data are available for stroke.”

So they compared plasma magnesium in stroke cases with controls matched for age, race/ethnicity, smoking status, date of blood draw, fasting status, menopausal status, and hormone use. Women with magnesium levels* that I see in lab reports had a signficantly increased risk for stroke:

“Conditional on matching factors, women in the lowest magnesium quintile had a relative risk of 1.34 for total ischemic stroke compared with women in the highest quintile. Additional adjustment for risk factors and confounders did not substantially alter the risk estimates for total ischemic stroke. Women with magnesium levels <0.82 mmol/L* had significantly greater risk of total ischemic stroke (multivariable relative risk, 1.57) and thrombotic stroke (multivariable relative risk, 1.66) compared with women with magnesium levels ≥0.82 mmol/L. No significant effect modification was observed by age, body mass index, hypertension, or diabetes mellitus.”

Magnesium is an anti-inflammatory agent

Clinical key  point: Cardiovascular and cerebrovascular disease have a well-known inflammatory component. Besides lowering blood pressure and promoting healthy endothelial function, magnesium is ‘nature’s anti-inflammatory mineral’ that supports parasympathetic nervous system function with a calming, anti-spasmodic effect.

* Plasma magnesium <0.82 mmol/L = 2.0 mg/dL.

The authors conclude:

Lower plasma magnesium levels may contribute to higher risk of ischemic stroke among women.”

Magnesium, inflammation and endothelial function

American Journal of Clinical NutritionRegarding additional mechanisms by which magnesium status is linked to stroke and cardiovascular disease, a study published in the American Journal of Clinical Nutrition provides evidence that magnesium is important for endothelial (blood vessel lining) health:

“We conducted a cross-sectional study of 657 women from the Nurses’ Health Study cohort who were aged 43-69 y and free of cardiovascular disease, cancer, and diabetes mellitus when blood was drawn in 1989 and 1990. Plasma concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2 (sTNF-R2), E-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Estimates from 2 semiquantitative food-frequency questionnaires, administered in 1986 and 1990, were averaged to assess dietary intakes.”

E-selectin recruits white blood cells to engage in the endothelial inflammatory process. The authors demonstrated a  role for magnesium significant for stroke:

“…magnesium intake was inversely associated with plasma concentrations of CRP, E-selectin, and sICAM-1. After further adjustment for physical activity, smoking status, alcohol use, postmenopausal hormone use, and body mass index, dietary magnesium intake remained inversely associated with CRP and E-selectin. Multivariate-adjusted geometric means for women in the highest quintile of dietary magnesium intake were 24% lower for CRP and 14% lower for E-selectin than those for women in the lowest quintile.”

Magnesium reduces CRP

Archives of Medical ResearchA recent study published in Archives of Medical Research also shows anti-inflammatory effect of magnesium in lowering CRP:

“It has been suggested that magnesium deficiency is associated with the triggering of acute phase response, which may contribute to type 2 diabetes and cardiovascular disease risk. We undertook this study to determine whether oral magnesium supplementation modifies serum levels of high-sensitivity C-reactive protein (hsCRP) in apparently healthy subjects with prediabetes and hypomagnesemia.”

The authors examined the effect of magnesium supplementation on 62 men and non-pregnant women aged 18–65 years who were newly diagnosed with prediabetes and hypomagnesemia (serum magnesium levels <0.74 mmol/L/1.8 mg/dL) for the effects of daily supplementation with magnesium in a double-blind placebo-controlled trial, leading to their conclusion…

Oral magnesium supplementation decreases hsCRP levels in apparently healthy subjects with prediabetes and hypomagnesemia.”

Walking in the evening improves cardiovascular markers better than walking in the morning

Preventive MedicineWalking is beneficial any time of day, but an interesting study published recently in the journal Preventive Medicine demonstrated significantly more improvement in some key cardiovascular lipid and inflammatory markers by walking in the evening versus in the morning. The authors set out to:

“…examine the influence of walking at different times of day on lipids and inflammatory markers in sedentary patients with coronary artery disease (CAD).”

They measured lipids and inflammatory markers data 330 patients evenly divided into a control group, morning or evening walking group who were asked to walk 30 min/day or more on at least 5 days/week either in the morning or evening before and after 12 weeks. Walking in the evening proved to have significant advantages:

“Compared with baseline, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were improved in all groups. Significances were shown in the changes of fibrinogen, high sensitivity C-reactive protein (hsCRP), white blood cell (WBC) count, TC, triglycerides, LDL-C, lipoprotein(a) between groups. The evening walking group had a larger decrease in fibrinogen, hsCRP, WBC count, and LDL-C than the other two groups.”

Note that all groups were rewarded with improvements in cholesterol levels, so better to walk anytime than not at all. These data, however, suggest their may be some additional benefit to walking in the evening when possible. Whether this is due to circadian effects on cortisol levels, more of a parasympathetic reaction, or other factors remains to be seen. The authors conclude:

“Our walking program successfully resulted in a favorable change in lipids and inflammatory markers. Patients in the evening walking group gained more benefits than those walking in the morning walking group.”

Exercise: moderation is best for the heart

heartExercise can benefit with surprisingly little effort and time as documented by recent studies, but like everything else there is a dose-response curve, meaning that the effect of exercise varies with the dose (intensity, duration). Now there is more evidence that exercising too intensively can do harm, particularly to the cardiovascular system. A study just published in the journal Heart associates too frequent intense physical activity (5 hours or more per week) at age 30 significantly increases the risk for atrial fibrillation. The authors sought to examine..

“…the influence of physical activity at different ages and of different types, on the risk of developing atrial fibrillation (AF) in a large cohort of Swedish men…We hypothesised that leisure-time exercise (considered as moderate-intensity to high-intensity activity) increases the risk of developing AF later in life, while walking/bicycling for transportation (low-intensity to moderate-intensity) decreases the risk.”

They collected data on physical activity 44,410 men aged 45–79 years without atrial fibrillation at baseline in 1997 that included the amount of time spent and type of activity throughout their lives. They were then followed-up in the Swedish National Inpatient Register for ascertainment of AF. The data revealed a surprising association:

“During a median follow-up of 12 years, 4568 cases of AF were diagnosed. We observed a RR [relative risk] of 1.19 of developing AF in men who at the age of 30 years had exercised for >5 h/week compared with <1 h/week. The risk was even higher (RR 1.49) among the men who exercised >5 h/week at age 30 and quit exercising later in life (<1 h/week at baseline). Walking/bicycling at baseline was inversely associated with risk of AF (RR 0.87 >1 h/day vs almost never) and the association was similar after excluding men with previous coronary heart disease or heart failure at baseline.”

The authors discuss important considerations based on age and intensity:

“This study, comprising 44 010 men followed for a median of 12 years, showed a complex association between physical activity and development of AF. High levels of leisure-time exercise (ie, exercising for more than 5 h a week), considered as moderate to high-intensity physical activity at the age of 30 years, was associated with an increased risk of AF later in life…The risk of AF was even greater (RR 1.49) among men who had exercised more than 5 h/week at the age of 30 years, and were inactive when they were older (mean age 60 years)…Our finding of an increased risk of AF with a high level of leisure-time exercise at a younger age is in agreement with the Physicians’ Health Study, a large prospective cohort study where subgroup analyses showed a 74% increased risk of AF associated with a high frequency of vigorous exercise (5–7 days/week) in men <50 years of age. Furthermore, previous case series and retrospective studies have found an increased risk of AF in young athletes and middle-aged men engaged in high-intensity exercise or endurance training.”

But the benefits of exercise for older age must be maintained, and…

“Our data did not show that leisure-time exercise in older age (mean age in the cohort at baseline is 60 years) increased the risk for AF. Furthermore, our data showed no increase in risk of AF with walking or bicycling at any age. In fact, walking or bicycling in older age was inversely associated with risk of AF, a finding that is consistent with the results found in the Cardiovascular Health Study.”

As for what would cause an increase in the risk for atrial fibrillation at higher exercise intensities:

“We think that a potential explanation for the different effects of exercise on the risk of AF depending on age could be because in older ages, the positive effects of physical activity on risk factors for AF dominate over the potential negative effects. Moreover, leisure-time exercise may be of lower intensity at an older age than at age 30 years.”

The authors summarize their findings:

“In conclusion, our results suggest that a high level of leisure-time exercise (moderate-intensity to high-intensity physical activity) in younger men is associated with an increased risk of AF later in life, and that the increase in risk becomes even higher for those who quit exercising later in life. On the other hand, walking/bicycling (low-intensity to moderate-intensity) at an older age seems to reduce the risk of AF, a finding that might be due to positive effects on several traditional cardiovascular risk factors.”

 

 

Cardiovascular mortality & exerciseAnother study published in the same issue of Heart presents evidence that while physical inactivity is certainly a risk factor, daily strenuous exercise increased the risk of dying from cardiovascular disease. Referring to current guidelines for exercise in secondary prevention of cardiovascular disease the authors state:

“While such recommendations are based on numerous clinical trials clearly showing that exercise-based cardiac rehabilitation improves prognosis in heart disease patients, only a few prospective studies have examined the potential benefit of physical activity in clinical practice under real-life conditions…In this study, we investigated the association of leisure time physical activity level with prognosis in a cohort of patients with coronary heart disease (CHD). We were especially interested in the dose–response relationship with different levels of physical activity and also took changes in physical activity level during long-term follow-up into account.”

So they analyzed data for 1038 subjects with stable CHD over 10 years of follow-up to assess the association of physical activity level with different outcomes of major cardiovascular events, cardiovascular mortality, all-cause mortality. Consonant with the study described above, a J-shaped pattern emerged:

“A decline in engagement in physical activity over follow-up was observed. For all outcomes, the highest hazards were consistently found in the least active patient group, with a roughly twofold risk for major cardiovascular events and a roughly fourfold risk for both cardiovascular and all-cause mortality in comparison to the reference group of moderately frequent active patients. Furthermore, when taking time-dependence of physical activity into account, our data indicated reverse J-shaped associations of physical activity level with cardiovascular mortality, with the most frequently active patients also having increased hazards (2.36, 95% CI 1.05 to 5.34).”

In other words, the least active group did the worst for cardiovascular and all-cause mortality, but the most active fared significantly more poorly than the moderately active group. The authors elaborate on their results:

“In this observational study in more than 1000 patients with manifest CHD, we investigated the prognostic implications of self-reported leisure time physical activity. As expected, we observed evidence for a poorer prognosis in physically inactive patients. Furthermore, our data indicated a reverse J-shaped association of physical activity, especially with cardiovascular mortality: both inactive and daily active patients had increased hazards of mortality compared to the reference group of patients who were active 2 to 4 times per week, but with the hazards being highest in the inactive patient group.”

Speculating on the reasons for the increased mortality in daily active group…

“A potential explanation of our finding of worse prognosis in the most frequently physically active group could be that vigorous exercise increases the risk of ventricular arrhythmias and sudden cardiac death during or after exertion, especially in adults with heart conditions.”

Clinical note: office assessment of heart rate variability is an invaluable tool in examining cardiac risk as well as a broad analysis of autonomic nervous system function.

The authors summarize their findings:

“To conclude, this study substantiated previous findings on the health benefits of physical activity in patients with manifest CHD: subjects who rarely or never engage in physical activity showed a substantially worse prognosis than those who were physically active for 2 to 4 times per week. Physical activity should thus be considered an integral part of a long-term secondary prevention strategy and further encouraged in inactive patients. In addition, consistent with the results of previous studies, despite differences in assessment of physical activity, we found that higher frequencies of physical activity did not confer additional benefit beyond that of physical activity of moderate frequency and duration, which suggests the existence of an upper limit for benefits. In some agreement with one previous study, our data even suggest that daily active subjects might have poorer prognosis compared to the moderately frequently active.”

 

In an editorial accompanying these two studies published in Heart E. Guasch and L. Mont state:

“Physical activity aggravating ischaemic heart disease seems counterintuitive, but it is supported by previous small studies. Using calcium score assessment or cardiac MRI, ultra-endurance runners have been suggested to have increased coronary artery disease. Correlating with exercise duration and intensity, endurance training induces an acute, reversible proinflammatory state, which might mediate atherosclerotic processes if prolonged enough. Patients with a pre-existing cardiovascular condition, such as those studied by Mons et al, develop a significant proinflammatory state at lower exercise doses. A crossover study in patients with ischaemic heart disease demonstrated that daily 60 min intense training promoted an inflammatory state and increased aortic wall stiffness, but opposite effects were found in a shorter, 30 min, daily intensive training regimen.”

 

 

BMJ Vol 348 Iss 7956It broadens our perspective to note in this context a research just published in BMJ showing that greater time spent in light physical activity significantly reduces disability independent of higher levels of activity. The authors set out to…

“…investigate whether objectively measured time spent in light intensity physical activity is related to incident disability and to disability progression.”

They used accelerometer monitoring to ascertain physical activity in 1680 community dwelling adults aged 49 years or older with knee osteoarthritis or risk factors for knee osteoarthritis and found that even an hour more per day of light physical activity can impart significant benefit.

“These prospective data from a large study of diverse community dwelling adults with or at high risk of knee osteoarthritis showed a significant and consistent relation between greater time spent in light intensity activity and a reduced risk of development or progression of disability. Our findings confirm that more moderate-vigorous activity time was related to less subsequent onset and progression of disability. Importantly, greater light activity time, independent of time spent in moderate-vigorous intensity activity, was significantly related to reduced risk and progression of disability. Our findings provide encouragement for adults who may not be candidates to increase the intensity of physical activity owing to health limitations. Greater daily physical activity time may reduce the risk of disability, even if the intensity of that additional activity is not increased.”

Here I think we can appreciate the virtue of ‘stand-up’ desks whose height is easily adjusted to permit working while standing.

 

heartClinical bottom line: Exercise and physical activity are crucial but as with everything else recommendations should be tailored for the individual. There is a dose-response relationship, especially with exercise, and at a certain more can be worse than better. The editorialists in Heart comment:

“Research aiming at providing a safety threshold that avoids ‘exercise overdose’ and permits maximisation of benefits is warranted. Drca et al and Mons et al identify >5 h/week and daily intense exercise as thresholds for increased AF incidence and cardiovascular events, respectively. These values should be considered solely as vague guidelines and might have little value in exercise counselling. In the clinical setting, an individualised mechanistic approach aiming to identify individuals at risk and detect the development of a deleterious substrate might better serve to titrate an optimal individualised dose of exercise…The beneficial effects of exercise are definitely not to be questioned; on the contrary, they should be reinforced. The studies reviewed here and future studies will serve to maximise benefits obtained by regular exercise while preventing undesirable effects—just like all other drugs and therapies.”