Srinivasan, Manivannan

Background Structural and functional mitral valve abnormalities are commonly encountered in the general population. In order to determine which functional protein classes may be important to normal valve function we performed the first reported comprehensive proteomic profiling of structurally normal human mitral valves. Methods We harvested mitral valve leaflets from 5 patients who underwent orthotopic cardiac transplantation for cardiomyopathy. The morphologic appearance of mitral valves was normal with only mild functional mitral regurgitation on echocardiogram. High resolution 2D gel electrophoresis was performed to separate proteins. Gel spots were excised from 2 representative samples and protein identification was carried out using liquid chromatography tandem mass spectrometry. Results We identified 190 unique proteins with >99% probability and at least 2 unique peptides. The proteins were from various cellular locations, including cell surface, cytoskeleton, endoplasmic reticulum, extracellular matrix, mitochondrion, nucleus, cytoplasm, and plasma membrane. Functional clustering revealed that the identified proteins were involved in major molecular pathways including, energy along with fatty acid metabolism, calcium signaling acute phase response & oxidative stress, and anti‐apoptosis pathways. Conclusion Proteomic profiling of the normal human mitral valve demonstrates a pattern of expression suggesting multiple biological functions. Further quantification of protein levels and comparison with diseased mitral valves will provide new insights into the etiology and therapy of mitral valve disease in humans.

AbstractContext:Insulin resistance has been reported to be associated with development of atherogenic dyslipidemia. However, the confounding effects that obesity and low levels of cardiorespiratory fitness have on the relationship between insulin resistance and the development of atherogenic dyslipidemia remain to be adequately addressed.Objective:This study sought to examine the independent and combined effects of insulin sensitivity, body composition, and cardiorespiratory fitness on lipoprotein particle sizes and concentrations.Methods:Eight-four healthy, nondiabetic men (n = 43) and women (n = 41) were studied. The participants had a wide range of ages (18–30 and 65–80 yr), body composition (7.2–52.8% fat), and cardiorespiratory fitness (VO2 peak, 13.5–66.2 ml/kg·min). Body composition, cardiorespiratory fitness, insulin sensitivity, and lipoprotein particle profiles were assessed using dual-energy x-ray absorptiometry, cardiopulmonary exercise testing, a hyperinsulinemic-euglycemic clamp, and nuclear magnetic resonance spectroscopy, respectively.Results:Low levels of insulin sensitivity and cardiorespiratory fitness and higher levels of adiposity were associated with the accumulation of small, dense, low-density lipoprotein particles; small high-density lipoprotein particles; triglycerides; and very low-density lipoprotein particles. Multivariate forward-stepwise regression revealed that higher levels of adiposity, in particular truncal fat, were the strongest predictor of the lipoprotein particle size and concentration data, followed by insulin sensitivity.Conclusions:As expected, the accumulation of atherogenic lipoprotein particles (e.g. small, dense, low-density lipoprotein particles and small, high-density lipoprotein particles) was associated with low levels of insulin sensitivity, cardiorespiratory fitness, and higher levels of adiposity. However, multivariate forward-stepwise regression revealed that triglycerides, followed by truncal fat mass, were the strongest predictors of the lipoprotein particle size and concentration data.

A significant proportion of patients with ST-elevation myocardial infarction have persistent impairment of microvascular blood flow despite successful reperfusion of epicardial vessels. Microvascular dysfunction has been associated with larger infarct size, increased predisposition to ventricular arrhythmias, heart failure, cardiogenic shock, recurrent myocardial infarction, and death. It remains unclear whether this association is of direct mechanistic significance or whether the microcirculatory injury is an epiphenomenon and a manifestation of greater ischemic insult to the myocardium. Although several potential mechanisms have been proposed for the microvascular dysfunction, distal microembolization during mechanical reperfusion is likely to be an important contributor. Consequently, there has been increasing interest in the concept of adjunctive mechanical thrombectomy to improve outcomes in primary percutaneous coronary intervention. Until recently, randomized trials of thrombectomy and distal protection devices during primary percutaneous coronary intervention have provided conflicting results with no definitive evidence for efficacy. The recently published Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study has rekindled the interest in this area. This trial is the largest randomized study of a thrombectomy device published to date and demonstrates that adjunctive treatment with aspiration thrombectomy during primary percutaneous coronary intervention improves surrogate and clinical end points. The aim of the present report is to review the evidence to date on the role of mechanical thrombectomy and embolic protection in native coronary arteries during primary percutaneous coronary intervention.

Abstract Context: Levels of dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) are inversely associated with cardiovascular mortality in men but not women. Very little evidence is available on the impact of DHEA administration on lipoprotein profile in women. DHEAS levels are very low/undetectable in hypoadrenal women. Objective: The objective of the study was to determine the impact of DHEA replacement on lipoprotein profile in hypoadrenal women. Design and Setting: A double-blind, randomized, placebo-controlled, cross-over design study was conducted at the Mayo Clinic. Participants: Thirty-three hypoadrenal Caucasian women (mean ± sd; age 50.3 ± 15.2 yr, body mass index 26.6 ± 4.4 kg/m2) took part in the study. Intervention: Study participants were assigned to receive either a placebo or 50 mg/d of DHEA for 3 months each. Lipid levels and lipoprotein profile were analyzed using the Lipo Science Lipoprotein nuclear magnetic resonance system. Main Outcome Measures: Changes in various lipoprotein sizes and levels were measured. Results: The DHEA period had higher plasma DHEAS levels than during placebo (<0.3 ± 0.0 vs. 3.5 ± 1.3 nmol/liter, P < 0.001). DHEA replacement significantly reduced total cholesterol (20.0 vs. −22, P = 0.02) and high-density lipoprotein (HDL) levels (2.0 vs. −6.0, P = 0.006) and tends to reduce triglyceride and total low-density lipoprotein levels. Although, DHEA replacement had no effect on low-density lipoprotein particle size, it significantly reduced larger HDL particles and to modest extent small HDL particles. Conclusions: Our study findings showed that oral DHEA administration in hypoadrenal women results in an unfavorable lipoprotein profile. The results warrant long-term studies to determine the impact of DHEA replacement on cardiovascular risk.