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.

Fracture healing requires intact nitric oxide production

BoneFracture healing gone awry can result in delayed or nonunion with significant morbidity. Useful research just published in the journal Bone shows that reduced nitric oxide production impairs fracture healing. The authors note:

“Between 5% and 10% of all fractures fail to heal adequately resulting in nonunion of the fracture fragments. This can significantly decrease a patient’s quality of life and create associated psychosocial and socio-economic problems.”

Nitric oxide synthase and fracture healing

Nitric oxide is known to be crucial for respiration, cardiovascular health, immune health and numerous other functions, and known to be involved in fracture healing. The authors take this a step further:

“Nitric oxide (NO) and nitric oxide synthases (NOS) have been found to be involved in fracture healing, but until now it is not known if disturbances in these mechanisms play a role in nonunion and delayed union development. In this study, we explored the role of endothelial and inducible NOS deficiency in a delayed union model in mice.”

They used femur osteotomy with periosteal damage for their model of fracture to observe the healing response in both normal (‘wild’) and NOS knockout (Nos2−/− and Nos3−/−) mice ‘engineered’ to not produce nitric oxide synthase and generate nitric oxide. Fracture healing completely stalled in the latter:

“With μCT [micro-computed tomography], delayed union was observed in wild type animals, whereas in both Nos2−/− and Nos3−/− mice nonunion development was evident. Both knock-out strains also showed a significantly increased influx of MPO [myeloperoxidase] when compared with wild type mice. Concentrations of amino acids and expression of enzymes related to the arginine-NO metabolism were aberrant in NOS deficient mice when compared to contralateral control femurs and wild type samples.”

Clinical note

Testing and for nitric oxide sufficiency and replenishment in the context of impaired NOS function is now very practical (see Neogenis Medical in Useful Links) and should be standard of care in fracture management, especially when there is a history of hypertension or other cardiovascular disorders. The authors conclude:

“In the present study we show for the first time that the absence of nitric oxide synthases results in a disturbed arginine-NO metabolism and inadequate fracture healing with the transition of delayed union into a nonunion in mice after a femur osteotomy. Based on these data we suggest that the arginine-NO metabolism may play a role in the prevention of delayed unions and nonunions.”

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.

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.”

Therapeutic resources for inflammatory bowel disease

Autoimmune disease in general and inflammatory bowel disease in particular arise from a constellation of causes that should be investigated and addressed on an individual basis. Nonetheless, methods that calm the inflammatory cascade (without harmful side-effects) are important practical tools. As forthcoming posts will describe in greater detail, nitric oxide production is a critical step in the production of damaging inflammation. A paper published in the European Journal of Clinical Investigation highlights this fact:

Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn’s disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO…”

And of interest for clinical case managment…

“The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis.”

A study published in the British Journal of Pharmacology examines the ability of the natural flavonoid quercitrin (related to quercitin) to inhibit production of iNOS (‘inducible nitric oxide synthase, the ‘bad’ nitric oxide producing enzyme). The authors state:

Quercitrin, 3-rhamnosylquercetin, is a bioflavonoid with antioxidant properties, which exerts anti-inflammatory activity in experimental colitis. In the present study, different in vivo experiments were performed in order to evaluate the mechanisms of action involved in this effect, with special attention to its effects on proinflammatory mediators, including nitric oxide (NO).”

They examined the effects of quercitrin on inflammation of the intestinal mucosa (‘lining’) induced by DSS (dextran sodium sulfate) both preventatively and, in another cohort, on already established colitis. The results were significant:

“Oral treatment of quercitrin…ameliorated the evolution of the inflammatory process induced when administered in a preventative dosing protocol…on established colitis, it facilitated the recovery of the inflamed mucosa…The beneficial effects exerted by quercitrin were evidenced both histologically and biochemically, and were associated with an improvement in the colonic oxidative status…”

Regarding the role of NO and inflammatory bowel disease…

“…a reduction of colonic NO synthase activity was observed, probably related to a decreased expression in the inducible form of the enzyme [iNOS] via downregulation in the colonic activity of the nuclear factor-κB.”

The authors discuss their findings in summary:

“During the last decade, it has become increasingly clear that NO overproduction by iNOS is deleterious to intestinal function…thus contributing significantly to gastrointestinal immunopathology…the results obtained in the present study reveal that colonic inflammation is associated with a higher colonic NOS activity, mainly attributed to an increase in iNOS expression…the effect showed by quercitrin is most probably related to an inhibition of the expression of this enzyme, which is upregulated as a consequence of the colonic inflammatory process…The antioxidant and/or scavenging properties ascribed to this flavonoid could also contribute to its intestinal anti-inflammatory effect…”

A study published in the European Journal of Immunology sheds more light on the use of quercitin for inflammatory bowel disease. Examining the relationship between quercitrin and quercitin, the authors find…

“…that the in vivo effects of quercitrin…can be mediated by the release of quercetin generated after glycoside’s cleavage by the intestinal microbiota. This is supported by the fact that quercetin, but not quercitrin, is able to down-regulate the inflammatory response of bone marrow-derived macrophages in vitro.”

They also describe evidence for the effect of quercitin on iNOS and the the NF-κB pathway:

“Moreover, we have demonstrated that quercetin inhibits cytokine and inducible nitric oxide synthase expression through inhibition of the NF-κB pathway…(both in vitro and in vivo). As a conclusion, our report suggests that quercitrin releases quercetin in order to perform its anti-inflammatory effect…”

A paper published in the journal Digestive Diseases examines the ability of quercitin to help repair the gut barrier in inflammatory bowel disease. Regarding the intestinal epithelial barrier (‘lining’) the authors state:

In inflammatory bowel disease (IBD), epithelial barrier function is impaired contributing to diarrhea by a leak flux mechanism and perpetuating inflammation by an increased luminal antigen uptake. This barrier of the intestinal epithelium is composed of the apical enterocyte membrane and the epithelial tight junction (TJ) and can be affected by TJ alterations, induction of epithelial apoptoses and appearance of gross lesions like erosions or ulcers as well as by accelerated transcytotic antigen uptake.”

They note that in addition to therapies that oppose Th1 cytokine activity in Crohn’s disease  and Th2 cytokine activity in ulcerative colitis, other agents have been shown to improve barrier function:

“…zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown. Finally, food components can strengthen the epithelial barrier as for example the flavonoid quercetin which has been shown to upregulate claudin-4 within the epithelial TJ.”

Curcumin (extracted from the yellow spice turmeric) should also be considered in the functional management of inflammatory bowel disease. The authors of a study published in the journal Inflammatory Bowel Diseases observe:

“Neutrophils (PMN) are the first cells recruited at the site of inflammation. They play a key role in the innate immune response by recognizing, ingesting, and eliminating pathogens and participate in the orientation of the adaptive immune responses. However, in inflammatory bowel disease (IBD) transepithelial neutrophil migration leads to an impaired epithelial barrier function, perpetuation of inflammation, and tissue destruction via oxidative and proteolytic damage. Curcumin (diferulolylmethane) displays a protective role in mouse models of IBD and in human ulcerative colitis, a phenomenon consistently accompanied by a reduced mucosal neutrophil infiltration.”

They investigated the phenomenon of neutrophil modulation by curcumin in vitro and in vivo. Their accumulated data demonstrated that…

“Curcumin attenuated lipopolysaccharide (LPS)-stimulated expression and secretion of macrophage inflammatory protein (MIP)-2, interleukin (IL)-1β, keratinocyte chemoattractant (KC), and MIP-1α in colonic epithelial cells (CECs) and in macrophages. Curcumin significantly inhibited PMN chemotaxis against MIP-2, KC, or against conditioned media from LPS-treated macrophages or CEC, a well as the IL-8-mediated chemotaxis of human neutrophils. At nontoxic concentrations, curcumin inhibited random neutrophil migration, suggesting a direct effect on neutrophil chemokinesis.”

In other words, curcumin was shown to significantly attenuate proinflammatory cytokine expression and white blood cell ‘attack movements’. Thus the authors conclude:

“Our results indicate that curcumin interferes with colonic inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil chemotaxis and chemokinesis.”

A double-blind, placebo-controlled trial of curcumin for the treatment of ulcerative colitis was reported in the journal Clinical Gastroenterology and Hepatology. The authors state:

“Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC).”

They divided a cohort of 89 patients with quiescent UC into a treatment group of 45 who added 1 gram of curcumin taken two times per day to their usual therapy. The other 44 got a placebo.  After 6 months the relapse percentages were 4.65% for those who received curcumin and 20.51% for the placebo group.

“Furthermore, curcumin improved both CAI [clinical activity index] and EI [endoscopic index], thus suppressing the morbidity associated with UC.”

The authors conclude:

Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.”

It’s also worth noting a paper published in the journal Current Pharmaceutical Design examines the multiple anti-inflammatory effects of curcumin. The authors first state:

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life… it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines.”

They note that earlier research has demonstrated that curcumin inhibits inflammation through action on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB, a key factor in the production of proinflammatory cytokines), and has a strong anti-oxidant effect.

“Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles…”

And in an early successful human IBD study..

“…patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD.”

While it’s difficult to predict ahead of time which patients will have the best response to agents such as curcumin and quercitin, since they are so safe and wholesome we can welcome the authors’ conclusion:

The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivaled safety profile suggest that it has bright prospects in the treatment of IBD.”

Champagne helps open up blood vessels for heart protection

British Journal of NutritionIn time for New Year’s eve, an interesting study was recently published in the British Journal of Nutrition that investigated the effects of champagne on blood vessel function. “In order to assess whether acute and moderate Champagne wine consumption is capable of modulating vascular function, we performed a randomised, placebo-controlled, cross-over intervention trial.” The authors stated in their findings that “consumption of Champagne wine, but not a control matched for alcohol, carbohydrate and fruit-derived acid content, induced an acute change in endothelium-independent vasodilatation at 4 and 8 h post-consumption.” (Vasodilation = blood vessel opening.) They also observed “a significant decrease in plasma levels of oxidising species,” and conclude: “Our data suggest that a daily moderate consumption of Champagne wine may improve vascular performance…” Best wishes for the new year!