Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs.

Heart failure (HF) is a major cause of mortality and morbidity worldwide, yet with limited therapeutic options. Cardiac bridging integrator 1 (cBIN1), a cardiomyocyte transverse-tubule (t-tubule) scaffolding protein which organizes the calcium handling machinery, is transcriptionally reduced in HF and can be recovered for functional rescue in mice. Here we report that in human patients with HF with reduced ejection fraction (HFrEF), left ventricular cBIN1 levels linearly correlate with organ-level ventricular remodeling such as diastolic diameter.

Of wholes and parts: A Thomistic refutation of "Brain Death".

I propose a refutation of the two major arguments that support the concept of "brain death" as an ontological equivalent to death of the human organism. I begin with a critique of the notion that a body part, such as the brain, could act as "integrator" of a whole body. I then proceed with a rebuttal of the argument that destruction of a body part essential for rational operations-such as the brain-necessarily entails that the remaining whole is indisposed to accrue a rational soul.

Heterologous embryo transfer: Magisterial answers and metaphysical questions.

The debate regarding the morality of heterologous embryo transfer (HET) as a solution for the fate of cryopreserved embryos remains active. This paper endeavors to show that the magisterial instructions on bioethical issues can only lead to the conclusion that HET is always morally illicit. I begin by showing that the text of Dignitas personae recognizes HET as a procedure accomplishing a procreative function, and I indicate that it is through gestation that this procreative function occurs.

Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation.

Background: Enhanced external counterpulsation (EECP) is a noninvasive, pneumatic technique that provides beneficial effects for patients with chronic, symptomatic angina pectoris. However, the physiological effects of EECP have not been studied directly. We examined intracoronary and left ventricular hemodynamics in the cardiac catheterization laboratory during EECP.

Management After Myocardial Infarction.

Individuals who survive an acute myocardial infarction (MI) have up to a ninefold greater risk of cardiovascular morbidity and mortality compared with the general population. The modification of traditional coronary risk factors, including hypertension, hyperlipidemia, tobacco use, and diabetes mellitus, constitutes one of the cornerstones of management after acute MI. Therapies aimed at reversing the pathophysiologic disorders that lead to endothelial dysfunction, thrombosis, and atherosclerotic plaque instability may improve the prognosis for patients after acute MI.

Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages.

During atherogenesis, circulating macrophages migrate into the subendothelial space, internalize cholesterol-rich lipoproteins, and become foam cells by progressively accumulating cholesterol esters. The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis. We show here, however, that hypercholesterolemic LDL receptor-deficient (LDLR(-/-)) mice reconstituted with ACAT1-deficient macrophages unexpectedly develop larger atherosclerotic lesions than control LDLR(-/-) mice.

Mammalian acyl-CoA:cholesterol acyltransferases.

Cholesterol, the chief sterol found in vertebrates, exists both as a free sterol and as a component of cholesterol esters, which are synthesized by acyl-CoA:cholesterol acyltransferase (ACAT) enzymes. Considerable knowledge concerning cholesterol ester metabolism has accumulated during the past century. However, rapid advances have occurred in the past 7 years since the cloning of an ACAT gene, including the discovery that two ACATs function in mammalian biology.

Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice.

The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol.

Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1.

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation.