Irit Hochberg

Interindividual Heterogeneity in the Hypoxic Regulation of VEGF Significance for the Development of the Coronary Artery Collateral Circulation

BACKGROUND The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF). METHODS AND RESULTS We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9+/-0.2 versus 3.2+/-0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals. CONCLUSIONS This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.

Haptoglobin Phenotype Is an Independent Risk Factor for Cardiovascular Disease in Individuals With Diabetes: The Strong Heart Study

OBJECTIVES The goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM). BACKGROUND Cardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications. METHODS We sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years. RESULTS In multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype. CONCLUSIONS This study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient.

Haptoglobin phenotype and vascular complications in patients with diabetes.

To the Editor: Vascular complications cause serious morbidity in patients with diabetes mellitus. Two such complications are diabetic nephropathy and restenosis after percutaneous transluminal coro...

Haptoglobin phenotype and diabetic nephropathy

Aims/hypothesis. To determine if the haptoglobin 2 allele is associated with an increased risk for the development of diabetic nephropathy. Methods. This study included 110 consecutive normotensive subjects with Type I (insulin-dependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes mellitus seen in two outpatient clinics in Israel. Diabetes duration was greater than 10 years for Type I diabetes and more than 5 years for Type II diabetic subjects. Microalbuminuria was defined as urinary protein excretion of 30 to 300 mg/24 h, and macroalbuminuria was defined as urinary protein excretion of greater than 300 mg/24 h. Serum was taken from subjects for haptoglobin typing by gel electrophoresis. Results. Of the participating subjects 54 had Type I and 56 had Type II diabetes. None (0/18) of the subjects homozygous for the haptoglobin 1 allele (1–1) showed any sign of diabetic nephropathy, as compared with 34 % (19/55) of subjects homozygous for the haptoglobin 2 allele (2–2) and 27 % (10/37) of heterozygous subjects (2–1) (p < 0.04). Of the subjects 29 showed macroalbuminuria. The risk of developing macroalbuminuria was found to be greater in subjects with two haptoglobin 2 alleles (22 %) (12/55) as compared with one haptoglobin 2 allele (8 %) (3/37) or no haptoglobin 2 alleles (0 %) (0/18) (p < 0.03). Conclusion/interpretation. By showing a graded risk relation to the number of haptoglobin 2 alleles in Type I and Type II diabetic subjects, these studies further support our hypothesis that the haptoglobin phenotype is a major susceptibility gene for the development of diabetic nephropathy. [Diabetologia (2001) 44: 602–604]

Dilated cardiomyopathy: an unusual complication of clozapine therapy

Background A 42-year-old obese man presented with acute pulmonary edema. He had a history of chronic residual schizophrenia for which he had been taking clozapine for 7 years, but had no known prior cardiac disease. Echocardiography demonstrated severe biventricular systolic and diastolic dysfunction with severe left ventricular enlargement. Cardiac catheterization showed no coronary artery disease.Investigations Physical examination, chest radiography, electrocardiography, transthoracic echocardiography, laboratory testing, viral serology, cardiac catheterization, coronary angiography and abdominal and renal ultrasonography.Diagnosis Clozapine-induced dilated cardiomyopathy.Management Intravenous nesiritide, furosemide and morphine followed by oral heart-failure therapy comprising ramipril, metoprolol succinate, spironolactone, and furosemide. Clozapine therapy was withdrawn.

Patterns of alveolar fluid clearance in heart failure

Alveolar fluid clearance (AFC) is important in keeping the airspaces free of edema. This process is accomplished via passive and active transport of Na(+) across the alveolo-capillary barrier mostly by apical Na(+) channels and basolateral Na,K-ATPases, respectively. Patterns of alveolar fluid clearance were found to be decreased in acutely elevated left atrial pressures, possibly due to the inhibition of alveolar epithelial active sodium transport. On the other hand, chronic elevation of pulmonary capillary pressure, such as seen in experimental and clinical congestive heart failure, increases alveolar fluid clearance most likely secondary to upregulation of active sodium transport.

Interaction Between the Haptoglobin Genotype and Vitamin E on Cardiovascular Disease in Diabetes

Purpose of ReviewDespite compelling evidence regarding the importance of oxidant stress in the development of vascular complications and observational studies suggesting that vitamin E may be protective from these complications, multiple clinical trials have failed to show benefit from vitamin E supplementation in the prevention of vascular complications in diabetes. One possible explanation for this failure of vitamin E may have been inappropriate patient selection. This review seeks to provide the clinical evidence and mechanistic basis for why a subset of individuals defined by their haptoglobin (Hp) genotype may derive cardiovascular protection by vitamin E supplementation.Recent FindingsClinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes.SummaryVitamin E may provide benefit in reducing CVD in Hp2-2 individuals with diabetes. However, in order for this pharmacogenomic algorithm to be accepted as a standard of care and used clinically, an additional large prospective study will need to be performed.