Yehuda Kamari

Circulating adiponectin concentrations in patients with congestive heart failure

Objectives: To determine concentrations of adiponectin and its predictive value on outcome in a cohort of patients with congestive heart failure (CHF). Methods: Serum and clinical data were obtained for outpatients with clinically controlled CHF (n  =  175). Serum concentrations of adiponectin, C reactive protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin (IL) -1β, IL-6, IL-8, IL-10, IL-12, tumour necrosis factor α and CD-40 ligand were determined. The association of adiponectin with the clinical severity of CHF was sought as well as the predictive value of this adipokine on mortality, CHF hospitalisations or the occurrence of each of these end points. Results: Concentrations of adiponectin were significantly increased in patients with CHF. Patients with higher New York Heart Association class had significantly higher serum concentrations of adiponectin. Adiponectin serum concentrations were lower in patients with diabetes and CHF as well as in patients with ischaemic cardiomyopathy. Serum adiponectin concentration was positively associated with age and NT-proBNP but was negatively correlated with C reactive protein concentrations. Serum adiponectin above the 75th centile was found to be an independent predictor of total mortality, CHF hospitalisations or a composite of these end points over a two-year prospective follow up. Conclusion: Adiponectin is increased in CHF patients and predicts mortality and morbidity.

Apolipoprotein A-V Deficiency Results in Marked Hypertriglyceridemia Attributable to Decreased Lipolysis of Triglyceride-Rich Lipoproteins and Removal of Their Remnants

Objective—ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV. Methods and Results—No significant difference in triglyceride production rate was found between apoa5−/− mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeled chylomicron remnants, the disappearance of 14C, 3H, and 125I was significantly slower in apoa5−/− mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in apoa5−/− mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in apoa5−/− mice. VLDL from apoa5−/− mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in apoa5−/− mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from apoa5−/− mice. Conclusions—These results support the hypothesis that the absence of apoAV slows lipolysis of TRL and the removal of their remnants by regulating their apoproteins content after secretion.

Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice

BACKGROUND & AIMS The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive. METHODS We employed IL-1α and IL-1β-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. RESULTS Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 fold-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, and TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ levels (p = 0.004). IL-1α mRNA levels were two-folds lower in IL-1β-deficient mice, and IL-1β transcripts were three-folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells was required for steatohepatitis development. CONCLUSIONS These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit the development of steatohepatitis should be explored.

Diuretic induced hyponatraemia in elderly hypertensive women.

Diuretics are recommended as first-line antihypertensive treatment in elderly patients. Although attention is usually paid to prevent hypokalaemia with diuretic therapy, risk of hyponatraemia is often ignored. We performed this study to characterise hypertensive patients at increased risk to develop hyponatraemia. We reviewed charts of hypertensive patients hospitalised in Chaim Sheba Medical Center for hyponatraemia from 1990 to 1997. Patients with other causes of hyponatraemia were excluded. The General Practice Maccabi database was used to estimate age and sex distribution of patients prescribed diuretics for hypertension. We identified 180 hypertensive patients (149 F, 31 M; mean age 76.4 ± 9.2 years) hospitalised because of hyponatraemia. Across all age groups, odds ratio (OR) to develop hyponatraemia was three times higher for women vs men (OR 3.10, 95% confidence interval (CI): 2.07–4.67). One hundred and sixty-two patients (90%) were older than 65 years. Patients of both sexes older than 65 years were 10 times (and if they were older than 75 years 16 times) more likely to develop hyponatraemia than those younger than 65 years (OR 9.87, 95%, CI: 5.93–16.64). Most patients (74.5%) used a thiazide-based diuretic; only 10% used a low dose (<25 mg/day). In 37% of patients diuretics were used for more than 1 year before hyponatraemia developed. Diuretic-induced hyponatraemia may be insidious and appear even after prolonged diuretics use. Elderly women seem to be at particularly high risk. In this population diuretic use should be associated with close monitoring of sodium and potassium levels.

Metabolic Syndrome: Comparison of the Two Commonly Used Animal Models

BACKGROUND The etiology of the metabolic syndrome (MS) includes both genetic and environmental factors. The two most commonly studied animal models of the MS are the high-sucrose diet given to spontaneously hypertensive rats (SHRs) and high-fructose diet given to Sprague Dawley rats (SDRs). This study compares between these two models. METHODS The two rat strains were examined; within each group, the rats were assigned to either the high-sugar diet (SDRs with fructose-enriched diet and SHRs with sucrose-enriched diet) or standard rat chow (control group). The rats were followed for 7 weeks. The main MS components (obesity, hypertension, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia) were measured. RESULTS At baseline systolic blood pressure (SBP), fasting blood levels of triglycerides and insulin, as well as glucose intolerance, were significantly higher among the SHRs compared to SDRs. Following fructose enrichment, SDRs became hyperinsulinemic, hypertriglyceridemic, hypercholesterolemic, hypertensive, and insulin resistant, whereas SHRs responded to sucrose supplementation by a significant elevation in blood pressure and mild worsening of insulin resistance. Endpoint results revealed superiority of sucrose--SHR model in terms of hypertension and superiority of fructose--SDR model in terms of hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia. Both models showed similar postintervention degree of glucose tolerance. CONCLUSIONS The fructose-fed SDR model represents a predominantly environmentally acquired MS, whereas the SHR model is less affected by dietary intervention and better displays the predominantly genetic spontaneous appearance of the syndrome. This fundamental difference should be taken into consideration when choosing an animal model to study the MS.

Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α.

OBJECTIVE Interleukin (IL)-1α and IL-1β are products of macrophages, endothelial cells and vascular smooth muscle cells; moreover, each of these cell types is affected by the pro-inflammatory properties of both IL-1s. Whereas several studies demonstrate the proatherogenic properties of IL-1β, the role of IL-1α in atherogenesis remains unclear. We assessed whether IL-1α and IL-1β from tissue resident vascular cells or emigrating bone marrow-derived cells promote the development of atherosclerosis in apoE-/- mice and determined the effect of selective macrophage IL-1α or IL-1β deficiency on degradation of LDL and cytokine production. METHODS We generated strains of double knock-out (KO) mice (apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-) and created chimeras consisting of apoE-/- mice reconstituted with bone marrow-derived cells from apoE-/-/IL-1+/+, apoE-/-/IL-1α-/- and apoE-/-/IL-1β-/-. RESULTS The areas of aortic sinus lesions were lower in either double KO mice compared to solely apoE-/- mice, despite higher non-HDL cholesterol levels. Importantly, selective deficiency of IL-1α or IL-1β in bone marrow-derived cells inhibited atherogenesis to the same extent as in double KO mice without affecting plasma lipids. Aortic sinus lesions in apoE-/- mice transplanted with IL-1β-/- or IL-1α-/- cells were 32% and 52% lower, respectively, than in IL-1+/+ transplanted mice. Ex vivo, isolated IL-1α-/- macrophages from atherosclerotic mice degraded LDL and secreted IL-6, TNFα and IL-12 similarly to IL-1+/+ macrophages; however, IL-1α deficient macrophages secreted reduced levels of IL-1β (-50%) and 2-3-fold higher levels of the anti-inflammatory cytokine IL-10. CONCLUSION We show for the first time that it is IL-1α from bone marrow-derived cells that accelerates atherogenesis in apoE-deficient mice rather than constitutive IL-1α in vascular cells, possibly by increasing the inflammatory cytokine profile of macrophages.

Triglycerides and HDL cholesterol: stars or second leads in diabetes?

Diabetes carries a high risk of atherosclerosis, and cardiovascular disease, especially coronary heart disease (CHD) and stroke, is by far the leading cause of death among patients with type 2 diabetes. Although statins reduce the risk of major vascular events by about one-fifth per millimole per liter reduction in LDL cholesterol, with similar proportional reductions in major coronary events, stroke, and the need for coronary revascularization, the residual risk remains high. In the Scandinavian Simvastatin Survival Study (4S) (1), although the relative risk reduction in diabetic patients was larger than in nondiabetic patients, simvastatin-treated diabetic patients were still at higher risk of death than the placebo-treated nondiabetic patients. Multifactorial intervention reduces the risk even further, but significant danger remains. Current guidelines call for an aggressive treatment strategy to reduce LDL cholesterol, blood pressure, and glucose levels in diabetic patients, but data concerning the management of high triglyceride (TG) levels and low HDL cholesterol levels remains inconclusive. This article reviews the data concerning diabetic dyslipidemia and its management. The cluster of lipid abnormalities associated with type 2 diabetes is defined by a high concentration of TG and small dense LDL and a low concentration of HDL cholesterol. Plasma LDL cholesterol levels are generally normal. Insulin resistance is believed to contribute to this atherogenic dyslipidemia by increasing the hepatic secretion of VLDL and other apolipoprotein (apo)B-containing lipoprotein particles, as a result of increased free fatty acid flux to the liver (2,3). This may also be the result of a diminished suppressive effect of insulin on apoB secretion, either at the level of the regulation of apoB degradation, or inhibition of microsomal TG transfer protein activity (4). Through the action of cholesterol ester transfer protein, TGs are transferred from VLDL to HDL, creating TG-rich HDL particles, which are hydrolyzed by hepatic …

Intolerance to Statins: Mechanisms and Management

Statins are considered very effective in reducing cardiovascular morbidity and mortality in high-risk patients. However, although adherence to statins improves morbidity and mortality (1), it remains suboptimal (2). One of the most important causes of nonadherence is the so-called statin intolerance, mainly because of muscle-related symptoms. These symptoms most often consist of myalgia unaccompanied by significant creatine kinase (CK) elevations. Less often, myositis (elevated CK >10 times the upper limit of normal) or rhabdomyolysis (CK level >10,000 IU/L or accompanied by significant elevation in creatinine level) develops. In randomized controlled trials, the incidence of statin myopathy is ~1.5–5.0% (3). However, this low incidence may be misleading for several reasons. First, in most studies patients with a history of statin intolerance were excluded. Other studies had a single-blinded statin run-in phase, and patients experiencing muscle-related symptoms or CK elevations during this phase were excluded. Patients who tend to be at risk for developing muscle-related symptoms, such as women, elderly patients, and patients with significant comorbidity, who comprise a large proportion of statin-treated patients in real-life settings, are underrepresented in randomized controlled trials. Some studies have defined muscle-related effects by elevated CK levels only, disregarding myalgia. Last but not least, patients enrolled in studies might be motivated and so minimize reporting of mild myalgias, thus leading to underestimation of the magnitude of the problem. Data concerning real-life incidence of statin-related myopathy are scarce. In the Prediction of Muscular Risk in Observational Conditions (PRIMO) study (4), 7,924 patients receiving high-dosage statin therapy in an outpatient setting in France were asked about muscle-related symptoms. Overall, muscular symptoms were reported by 10.5% of the patients. A weakness of this study is that it lacked a comparison/control group not treated with statins. In a study of adults aged ≥40 years who participated in National Health and …

Adiponectin: linking the metabolic syndrome to its cardiovascular consequences

Obesity and its related disorders, glucose intolerance, hypertension and hyperlipidemia, collectively named the metabolic syndrome, result in substantial cardiovascular morbidity and mortality. Recent data point to several underlying regulatory mechanisms through which obesity links these various outcomes. Adipose tissue is now understood to function not merely as a passive energy storage depot but as an active endocrine organ, producing a variety of bioactive substances termed adipocytokines. Adiponectin, an adipocytokine first described as the most abundant protein produced by adipocytes, appears to serve as a central regulatory protein in many of the physiologic pathways controlling lipid and carbohydrate metabolism, and to mediate various vascular processes. Adiponectin displays both anti-inflammatory and antiatherogenic properties. Unlike other adipocytokines, its levels are paradoxically decreased in obesity and insulin-resistance states including metabolic syndrome and diabetes, as well as hypertension and coronary artery disease. This review will detail the relationship of adiponectin to various features of obesity and insulin-resistance syndromes, as well as its relationship to the cardiovascular complications of these disorders.

Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice

OBJECTIVES Interleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1α and IL-1β are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1s effects in atherogenesis. METHODS AND RESULTS We generated apoE-/-/IL-1R1-/- double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20-47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1α and IL-1β upon stimulation with LPS was not altered in IL-1R1-/- compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules and IL-1α, in isolated human umbilical vein endothelial cells (HUVEC). CONCLUSIONS Vascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells.