Michel Accad

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. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.

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. The ACAT1-deficient lesions have reduced macrophage immunostaining and more free cholesterol than control lesions. Our findings suggest that selective inhibition of ACAT1 in lesion macrophages in the setting of hyperlipidemia can lead to the accumulation of free cholesterol in the artery wall, and that this promotes, rather than inhibits, lesion development.

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. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.

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. A clearer picture of the functions of ACAT enzymes in cellular cholesterol metabolism and physiologic processes is now emerging. These insights may have relevance for the development of ACAT inhibitors for treating hypercholesterolemia or atherosclerosis in humans.

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. Methods and Results—Ten patients referred for diagnostic evaluation underwent left heart catheterization and coronary angiography from the radial artery. At baseline and then during EECP, central aortic pressure, intracoronary pressure, and intracoronary Doppler flow velocity were measured using a coronary catheter, a sensor-tipped high-fidelity pressure guidewire, and a Doppler flow guidewire, respectively. Similar to changes in aortic pressure, EECP resulted in a dramatic increase in diastolic (71±10 mm Hg at baseline to 137±21 mm Hg during EECP; +93%;P <0.0001) and mean intracoronary pressures (88±9 to 102±16 mm Hg; +16%;P =0.006) with a decrease in systolic pressure (116±20 to 99±26 mm Hg; −15%;P =0.002). The intracoronary Doppler measure of average peak velocity increased from 11±5 cm/s at baseline to 23±5 cm/s during EECP (+109%;P =0.001). The TIMI frame count, a quantitative angiographic measure of coronary flow, showed a 28% increase in coronary flow during EECP compared with baseline (P =0.001). Conclusions—EECP unequivocally and significantly increases diastolic and mean pressures and reduces systolic pressure in the central aorta and the coronary artery. Coronary artery flow, determined by both Doppler and angiographic techniques, is increased during EECP. The combined effects of systolic unloading and increased coronary perfusion pressure provide evidence that EECP may serve as a potential mechanical assist device.

Cholesterol homeostasis: A role for oxysterols

Abstract Recent experiments have identified LXR α , a nuclear hormone receptor that binds oxysterols, as a key regulator of hepatic cholesterol homeostasis.

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. Next, I point to the equivocal use of the terms “alive” or “living” as being at the root of conceptual errors about brain death. I appeal to the Thomistic definition of life and to the hylomorphic concept of “virtual presence” to clarify this confusion. Finally, I show how the Thomistic definition of life supports the traditional criterion for the determination of death. Lay summary By the mid-1960s, medical technology became available that could keep “alive” the bodies of patients who had sustained complete and irreversible brain injury. The concept of “brain death” emerged to describe such states. Physicians, philosophers, and ethicists then proposed that the state of brain death is equivalent to the state of death traditionally identified by the absence of spontaneous pulse and respiration. This article challenges the major philosophical arguments that have been advanced to draw this equivalence.

Risk-Factor Medicine: An Industry out of Control?

epidemiologic considerations [25] . Despite their questionable place in nosology, these 2 conditions have gained International Classification of Disease (ICD) codes and generate huge medical expenditures [26] . Moreover, after years of public awareness campaigns, hypertension and hypercholesterolemia have become household names that, when applied to some persons, provoke detrimental psychosomatic or economic consequences, or both – the so-called ‘labeling effectt [27, 28] . Minor risk factors have achieved disease rating, too. Hypertriglyceridemia, for example, attracts a great deal of interest because of findings from new epidemiologic studies [29] . Those studies, however, required the scrutiny of hundreds of thousands of patients to detect minimal excesses of risk. Likewise, obesity is a trivial independent contributor to cardiovascular disease [30, 31] and, in some cases, might even protect against certain cardiac complications [32, 33] . Yet, reshaping the population at large is at the forefront of public health efforts these days [34–36] . New risk factors emerge regularly in the clinical literature [37–40] . Most of these are said to be ‘pro-inflammatory’, ‘pro-atherogenic’, or ‘pro-thrombotic’, but their excess or deficiency does not yet diagnose any specific disease. Nevertheless, compounds such as C-reactive protein, homocysteine, and lipoprotein(a) have garnered sufficient favor to be part of a clinical work-up and the basis for treating millions of people [41, 42] . In 1961, the Framingham investigators introduced the term ‘risk factor’, thereby ushering in the era of risk modification to prevent cardiovascular disease [1] . Initially, the strategy focused on treating individuals who were likely to develop symptoms or die prematurely [2–5] . Over time, however, and with impetus from eminent epidemiologists [6–9] , the approach shifted to managing the entire population. Although controversial from the very beginning [10–12] , this expansion of risk factor modification ultimately earned endorsement from the American Heart Association [13] , the Institute of Medicine [14] , the US Department of Health and Human Services [15] , and the World Health Organization [16] . Nowadays, risk factor reversal is an established surrogate for quality of care [17] and a basic ingredient of most pay-forperformance plans [18, 19] . But has the process grown out of control? Ponder the following: Risk factor refers to ‘a single characteristic statistically associated with, although not necessarily causally related to, an increased risk of morbidity or mortality’ [20] . Accordingly, the term has relevance primarily in epidemiologic contexts and is subject to the complexities, constraints, and controversies of population studies [21–23] . Notwithstanding these liabilities, cardiovascular risk factors now commonly acquire the status of fully fledged diseases [24] . Prime examples are hypertension and hypercholesterolemia, both of which are defined by arbitrary cut-off numbers determined – and repeatedly revised – solely on the basis of Received: June 16, 2010 Accepted after revision: July 2, 2010 Published online: October 5, 2010

Does evidence based medicine adversely affect clinical judgment

For practical and theoretical reasons, says Michel Accad, evidence based medicine is flawed and leads to standardised rather than excellent individualised care, but Darrel Francis argues that it protects patients from seemingly rational actions that cause more harm than good

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. I further show that the previous Instruction, Donum vitae, implicitly points to an ontological or spiritual consideration at play during gestation. This consideration is likely related to the procreative function identified in Dignitas personae. Finally, I place these two textual arguments in the context of the debate concerning HET and conclude that metaphysical questions must be clarified in order for the immorality of HET to be understood from a suitable anthropological perspective and gain more widespread acceptance.