Clustering Of Coronary Risk Factors Research Articles

Patients with CD36 Deficiency Are Associated with Enhanced Atherosclerotic Cardiovascular Diseases

The clustering of dyslipidemia, impaired glucose tolerance and hypertension increases the morbidity and mortality from cardiovascular events. A class B scavenger receptor, CD36, is a receptor for oxidized LDL and a transporter of long-chain fatty acids. Because of the impaired uptake of oxidized LDL in CD36-deficient macrophages and from the results of CD36 knockout mice, CD36 deficiency (CD36-D) was supposed to be associated with reduced risks for coronary artery disease (CAD); however, CD36-D patients are often accompanied by a clustering of coronary risk factors. The current study aimed to investigate the morbidity and severity of cardiovascular diseases in CD36-D patients. By screening for CD36 antigen on platelets and monocytes using FACS or the absent myocardial accumulation of 123I-BMIPP by scintigraphy, 40 patients with type I CD36-D were collected, the morbidity of CAD and their features of atherosclerotic cardiovascular diseases were observed. Screening for CD36-D in both CAD patients (n = 319) and healthy subjects (n = 1,239) were underwent. The morbidity of CAD was significantly higher in CD36-D patients than in the general population; 50% of patients (20 out of 40) had CAD identified by BMIPP scintigraphy and 37.5% (3 out of 8) by FACS screening, respectively. Three representative CD36-D cases demonstrated severe CAD and atherosclerosis. The frequency of CD36-D was three times higher in CAD patients than in healthy subjects (0.9% vs 0.3%, p < 0.0001). The morbidity of CAD is significantly higher in CD36-D patients suffering from severe atherosclerosis, implying that the status of CD36-D might be atherogenic.

The superiority of waist-to-height ratio as an anthropometric index to evaluate clustering of coronary risk factors among non-obese men and women

Backgrounds. Overtly obesity is relatively rare among the Japanese despite the high prevalence of metabolic disorders, which suggests the need to develop simple and effective methods for assessing metabolic risks among the non-obese individuals as part of public health education. Methods. We compared body mass index (BMI), waist circumference, and waist-to-height ratio (W/Ht) as indices for evaluation of clustering of coronary risk factors (hypertension, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and low HDL cholesterol) in 4,668 men and 1,853 women with BMI < 25 kg/m 2. Results. The sum of coronary risk factors correlated positively with all anthropometric indices, with the closest correlation found for W/Ht. Multiple regression analysis showed that height was a negative independent predictor of the sum of coronary risk factors, while age and waist circumference were positive independent predictors. Among the various proposed anthropometric indices for the evaluation of metabolic risk, the sensitivities for identification of clustering of ≥2 and ≥3 coronary risk factors were highest for a waist-to-height ratio ≥0.5 in both genders. Conclusions. Waist-to-height ratio is more sensitive than BMI or waist circumference alone to evaluate clustering of coronary risk factors among non-obese men and women.

Sterol regulatory element-binding protein (SREBP)-1: gene regulatory target for insulin resistance?

The combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome. Alterations in transcription factors result in complex dysregulation of gene expression, which might be the key to understanding insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are peroxisome proliferator-activated receptors and sterol regulatory element-binding proteins (SREBPs), which also appear to be novel drug targets. The authors have recently shown that SREBPs are substrates of mitogen-activated protein kinases, and propose that SREBP-1 might play a role in the development of cellular features belonging to lipotoxicity and, possibly, syndrome X.

SREBP‐1: Gene Regulatory Key to Syndrome X?

Combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome or syndrome X. Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. Major signaling pathways coupling transcription factors to extracellular stimuli are the MAP kinase cascades. We have recently shown that SREBPs appear to be substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly syndrome X. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression.

The role of PPARγ in high-fat diet-induced obesity and insulin resistance

It has been well demonstrated that insulin resistance plays an important role in the clustering of coronary risk factors through the progression of atherosclerosis in animal models of insulin resistance. In humans, a high-fat diet is the major cause of obesity and insulin resistance. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in high-fat diet induced-obesity and insulin resistance by gene targeting and case-control study using the common PPARγ2 polymorphism in human subjects. Homozygous PPARγ-deficient embryos died at 10.5–11.5 dpc due to placental dysfunction. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet and the phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARγ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARγ. A Pro12Ala polymorphism has been detected in the human PPARγ2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARγ, this polymorphism may be associated with decreased insulin resistance and decreased risk of Type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARγ2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against Type 2 diabetes. These results revealed that both in mice and humans, PPARγ is a thrifty gene mediating Type 2 diabetes.

Beta-blockers and diabetes: the bad guys come good.

Type 2 diabetes is becoming very common and is closely linked to physical inactivity and obesity. It is associated with clustering of coronary risk factors and 60-80% of cases have hypertension. The first therapeutic action is appropriate adjustment of life style. Anti-hypertensive therapies such as diuretics, ACE inhibitors and calcium antagonists have been effective in reducing cardiovascular events in type 2 diabetes, though calcium antagonists may be less effective than older therapies and ACE-inhibitors in reducing the risk of heart attacks and heart failure (but possibly more effective in stroke reduction). Beta-blockers (BBs) have a poor image as a potential therapy due to apparent adverse effects on surrogate end-points such as insulin-resistance. However large, controlled trials have shown BBs to be highly effective in reducing the risk of cardiovascular events and death in post myocardial infarction patients with diabetes. The UKPDS study in type 2 diabetics with hypertension showed first-line beta-blockade to be at least as effective as ACE-inhibition in preventing all primary macrovascular and microvascular end-points. The active ingredient appears to be beta-1 blockade, acting not only to lower blood pressure but also to prevent sudden death and cardiovascular damage stemming from chronic beta-1 stimulation associated with raised noradrenaline activity. By contrast, in the LIFE study atenolol was less effective than the angiotensin receptor antagonist losartan in reducing cardiovascular events and all-cause mortality in mainly elderly hypertensives with diabetes. Thus the best beta-blocker results in reducing hard cardiovascular end-points occur in hypertension studies (including the UKPDS study) involving younger/middle aged (say less than 60-65 years) patients, with relatively high sympathetic activity, relatively compliant/elastic arteries (narrow pulse-pressure) and normally functioning beta-1 receptors. In elderly hypertensive patients beta-blockers may be given as second-line therapy on the back of a low-dose diuretic (but possibly as first line agent in elderly hypertensives with prior myocardial infarction). Thus inappropriate attention to surrogate end-points can lead to faulty prescribing habits. Beta-blockers, currently severely underprescribed, should be considered as a first line therapeutic option for all diabetics with ischaemic heart disease or younger/middle aged diabetics with hypertension (but co-prescribed with low dose diuretic therapy in the elderly). The active ingredient for cardiovascular protection appears to be beta-1 blockade; optimal efficacy in lowering blood pressure and safety e.g. reducing risk of bronchoconstriction, is achieved by choosing an agent with high beta-1 selectivity.

Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.

Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. This study examined the effects of insulin resistance on coronary risk factors in IRS-1 deficient mice, a nonobese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1 deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1 deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis to be involved in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors which may accelerate the progression of atherosclerosis in subjects with insulin resistance.

Clustering of coronary risk factors with increasing blood pressure at rest and during exercise.

The metabolic cardiovascular syndrome is the label given to the clustering of unfavourable levels of a number of coronary risk factors in subjects with high resting blood pressures. We found recently that exercise blood pressure had a strong independent prognostic value. To search for possible similar associations between exercise blood pressure levels and coronary risk factors by studying conventional and recently acknowledged coronary risk factors. The study population comprised 1999 healthy men aged 40-59 years. Age-adjusted coronary risk factor levels and their relation to resting and exercise blood pressures were studied. Resting blood pressure was measured after subjects had rested supine for 5 min. The exercise blood pressure used was the systolic blood pressure measured with the subject sitting on a bicycle ergometer at the end of a work load of 600 kpm/min (100 W) for 6 min. Besides corroborating the relation between the metabolic syndrome and resting blood pressure levels, we observed similar or even stronger associations between levels of various coronary risk factors and exercise blood pressure. We found rather strong, direct associations between exercise blood pressure and total cholesterol level, fasting triglyceride level and body mass index whereas inverse relations were found for glucose tolerance, physical fitness, pulmonary functioning and the ability to increase heart rate during exercise. Virtually all these associations had a level of statistical significance of P<0.001. High exercise blood pressure levels are strongly associated with unfavourable levels of a number of important coronary risk factors. A similar metabolic syndrome to that observed in subjects with high resting blood pressures therefore appears to be present in subjects with high exercise blood pressure responses. These associations may considerably amplify the independent risk of high blood pressure responses to moderate exercise.

Intra‐abdominal fat in obese children

We investigated the distribution of abdominal fat accumulation in obese children to know whether a clustering of coronary risk factors was demonstrated in visceral fat obesity as reported in adults. The relative indicator of intra-abdominal fat accumulation was obtained from computed tomography scans at the umbilicus level in 36 obese subjects (24 males, 12 females). There was no visceral fat obesity in this study by reported criteria. All metabolic variables except triglyceride did not correlate significantly with intra-abdominal fat accumulation. We conclude that visceral fat obesity is a rare status and has no close relationship to coronary risk factors in childhood.

The beta 1 hyperselectivity in beta-blocker treatment.

Coronary heart disease (CHD) is the most common cause of death in Western industrialized countries. CHD is more common in individuals with clustering of coronary risk factors, e.g., hypertension and blood lipid abnormalities. There is a good rationale for the use of beta-blockers for prevention of myocardial infarction (MI) in high-risk groups, as beta-blockade decreases myocardial oxygen consumption and, by decreasing turbulent blood flow patterns, reduces endothelial shear forces, thus making plaque rupture (and the ensuing thrombotic events) less likely. Clinical trial data have shown beta-blockade to be effective in the prevention of cardiovascular end points. In both younger and older hypertensive patients there is a significant reduction in the incidence of stroke and in younger hypertensive patients there is about a 15% reduction in MI. Left ventricular hypertrophy (particularly by ECG) is significantly diminished. In secondary prevention of MI there is about 15% reduction after early and 25-30% reduction after late intervention with beta-blockers given post-MI. In both stable and unstable angina, beta-blockade appears to be beneficial not only in improvement of symptoms but also in prevention of hard cardiovascular end points. There are also promising data suggesting that beta-blockade is useful in endothelial protection and atheroma prevention, and benefits patients with hypertrophic cardiomyopathy and heart failure. beta-Blockers have evolved from early nonselective agents, e.g., propranolol, to modern highly beta 1-selective agents, e.g., bisoprolol. beta 1-Blockade is the essential element that leads to the above cardiovascular benefits in addition to improving the quality of life (similar to angiotensin-converting enzyme inhibitors).

Hidden Heart Hazards

E i 0 new predictor of heart disease risk and could force them to reexamine dietary prescriptions for improving heart health. By some estimates, up to 25 percent of trim people in the United States inherit or acquire an inefficient response to insulin, the pancreas-secreted hormone that directs cells to take up glucose. These people are not diabetic, but their lethargic response to insulin means the pancreas must churn out more of the hormone to keep blood sugar levels normal. Most diabetes specialists believe people with insulin resistance face a risk of developing Type II, or non-insulindependent, diabetes when the pancreas exhausts its ability to crank out enough hormone to meet the body's needs. Not everyone with insulin resistance develops Type II diabetes, which generally strikes after age 40. Yet even in those who escape it, some researchers now believe that a long-standing elevation of insulin in the blood silently damages the cardiovascular system by an unknown process that results in the buildup of fatty deposits on artery walls. That theory has sobering implications for outwardly healthy people with insulin resistance as well as for the 10 million Type 11 diabetics in the United States, most of whom are insulin resistant. Resistance to insulin-stimulated glucose uptake is involved in the development of coronary artery contends Gerald M. Reaven of Stanford University School of Medicine. Although this concept may seem outlandish at first blush, the notion is consistent with available experimental data. Reaven's 20 years of research on insulin resistance led him in 1988 to coin the term X, describing seemingly healthy people who have insulin resistance and display a cluster of coronary risk factors, including high blood pressure, elevated triglycerides (a form of lipid, or fat, in the bloodstream) and decreased high-density lipoproteins, or HDLs the beneficial transport molecules that carry cholesterol from the bloodstream to the liver for excretion (SN: 9/9/89, p.171). Insulin resistance may explain why Type 11 diabetics are two to four times as likely as nondiabetics to develop heart disease, running a coronary risk comparable to that of insulin-dependent, Type I diabetics without kidney disease. But Reaven's theory of syndrome X goes well beyond diabetics in stating that trim, outwardly healthy people with a defective insulin response also face a greaterthan-average risk of heart disease a notion many diabetes specialists view with cautious skepticism. It's an interesting idea, but [syndrome X] is not proven by the data, comments diabetes researcher Daniel W Foster of the University of Texas Southwestern Medical Center in Dallas. Adds cholesterol researcher Scott M. Grundy, also at Southwestern Medical Center: Syndrome X might be syndrome zero. Nonetheless, the notion is attracting considerable attention as new scientific reports from around the world support the link between insulin resistance and coronary artery disease.

Familial aggregation of coronary heart disease and its relation to known genetic risk factors

The question of how much of the familial aggregation of coronary heart disease is explained by familial clustering of coronary risk factors was approached by a case-control study involving 145 white male survivors of myocardial infarction, 145 age-matched white male blood donors, and the first-degree relatives of both groups. Certain risk factors such as serum cholesterol, triglyceride, and fasting blood glucose levels, blood pressure, and smoking history were determined in patients and control subjects. Relatives were interviewed. If the person was deceased, a copy of the death certificate was obtained. With the exception of high blood pressure, risk factors were significantly more frequent in patients than in control subjects. Among first-degree relatives of survivors of myocardial infarction, 16% had had a myocardial infarction, compared with 8.9% of relatives of control subjects. The frequency of coronary heart disease among first-degree relatives of patients and control subjects was 20.5 and 14.7%, respectively. To find out whether this higher frequency among relatives of patients was fully explained by the existence of known genetic risk factors among survivors of myocardial infarction, 2 approaches were taken. First, statistical analysis that eliminated the role of the various known genetic risk factors (by data stratification according to confounding risk variables and subsequent calculation of a pooled relative risk estimate according to the Mantel-Haenzel method) still indicated an approximately 2-fold (2.14) relative risk for myocardial infarction among families of survivors of myocardial infarction (and a risk of 1.71 for coronary heart disease). Similarly, another approach (Cox's life table regression analysis) confirmed that the classic risk factors could not predict familial occurrence. These results indicate that the familial aggregation of coronary heart disease is not entirely explained by the familial clustering of currently known coronary risk factors. Such familial aggregation could be caused by yet undefined genetic factors, by environmental factors common to family members, or by interaction of genetic factors with environmental agents.