Jacques Genest, Jr., MD FRCPC FACC

Jacques Genest was born (and raised) in Montréal, Québec. He trained at McGill University Medical School and did a residency in Internal Medicine at McGill and cardiology fellowship at Tufts University in Boston. He then did Postdoctoral studies in Boston in lipoprotein metabolism and molecular genetics.

For ten years, he directed the cardiovascular Genetics Laboratory at the Clinical Research Institute of Montréal. Since 2000, he has been Professor of Medicine and Head of Cardiology at McGill University, and he holds the McGill/Novartis Chair in Medicine at McGill.

His research involves clinical studies in cardiovascular risk factors, the genetics of premature coronary artery disease and in the translational biology of the formation of high density lipoproteins.

His funding comes from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. He sits on several advisory boards on clinical practice guidelines, pharmaceutical and biotechnology companies and is a reviewer for many scientific journals.

For the past 15 years, he has participated in the elaboration of Canadian Cholesterol Guidelines and has contributed the chapter on lipoprotein disorders and cardiovascular disease in the last 3 editions of Braunwald’s textbook of cardiology. Recently, his research has permitted further mechanistic insights on the genesis of HDL particles in man through the ABCA1 transporter.

2008 Ronnie Campbell Lecture
Statins at 21: A Brief Look Back and Long Look Forward

Sunday, March 16, 2008
6:00 PM

Download Dr. Genest’s complete slide set [12.3 MB PPT].
Download Dr. Genest’s featured preconference slides [464.15 KB PDF].

The Cholesterol molecule is the product of eons of evolutionary tinkering, likely arising within the Proterozoic period (2.5 billion years ago) and was probably well established in the Cambrian period (0.5 billion years ago). This remarkable degree of conservation attests to the importance of cholesterol in cellular functions. Found in mammals, fish, birds and insects, but not in plants (-not entirely true, however, some evolutionary tinkering took place), cholesterol is absorbed in the intestine. Most cells also possess the processing enzymes to make cholesterol from acetyl Coenzyme A. The major toxicity of cholesterol appears to be caused by the unregulated uptake of cholesterol-rich lipoproteins (those that contain apolipoprotein B) by macrophages. This may lead to cell death by apoptosis within the atherosclerotic plaque. Considering the fact that humans cannot break down the cholesterol molecule, cholesterol accumulates within the plaque unless removed by bulk transport in phagocytic cells or by HDL particles.

In 1987, the FDA allowed Merck to release lovastatin for the treatment of severe hypercholesterolemia. HMG CoA reductase inhibitors were first identified by a Japanese scientist, Dr. Arika Endo, following the discovery two decades earlier, at the Max Plank Institute in Germany of the enzymes that make cholesterol from simple molecules. Merck followed on Endo’s discovery to create lovastatin, followed by pravastatin by Bristol-Myers Squibb.

Statins inhibit the rate-limiting step of cholesterol biosynthesis and reduce serum levels of total cholesterol, LDL-C and, to a lesser extent, triglycerides. They were first used in patients with genetic lipoprotein disorders (familial hypercholesterolemia), for whom therapeutic options were scarce. Early trials of statin therapy showed a marked reduction of cardiac events (CHD death, non-fatal myocardial infarction and strokes) in secondary prevention and in high-risk individuals. More recently, clinical trials have shown that clinical benefit correlate with the magnitude of reduction of LDL-C triggering a paradigm shift in clinical practice along the lines that “Lower is better.” Some have challenged the widespread use of statins in several important sub-groups: the elderly, the young, the patient in primary prevention and in women in general. Others consider that the non-LDL effects of statins (pleiotropic effects) contribute to a significant reduction in cardiovascular risk, irrespective of lipid changes. The role of other medications to lower LDL-C (including intestinal cholesterol absorption inhibitors, squalene synthase inhibitors, apo B antisense mRNA) has been put into question in early clinical trials.

After reaching adulthood, the past 21 years have taught clinicians important lessons on the use of statins: First, they are generally safe and well tolerated; second, baseline cardiovascular risk is critical in determining the potential benefits of these compounds; third, the magnitude of reduction of LDL-C correlates with clinical benefit; fourth, some groups (low risk, pre-menopausal women in primary prevention) may not derive any benefits from statins. End-stage renal disease and severe heart failure are also unlikely to benefit from statins. Lastly, the judicious use of statins, following lifestyle changes with smoking cessation, diet, exercise, weight reduction and stress management has been shown to decrease mortality in high-risk patients.

Alcohol and Heart Disease: In Vino Veritas (Are you MADD?)

Wednesday, March 19, 2008
8:30 AM

Download Dr. Genest’s complete slide set [5.41 MB PPT].
Download Dr. Genest’s featured preconference slides [94.43 KB PDF].

The topic of alcohol takes on great importance at the ACC Lake Louise. Delegates and faculty alike have been known, on occasion, to partake in the imbibing of fermented beverages and distilled spirits to enhance the educational experience of the meeting. Common to these beverages is the presence of ethanol.

The word alcohol is derived from the Arabic الكحل (“al-kul”). Ethanol fermentation is the process by which sugars are converted into ethanol and carbon dioxide by yeasts (C6H12O6 → 2 C2H5OH + 2 CO2), under anaerobic conditions. The fermentation of barley (beer) and grapes (wine) were commonplace in the Middle East over 9,000 years ago. Sadly, anaerobic fermentation produces an ethanol content of 13-14% (vol/vol), after which the yeast passes on. Distillation of alcohol can be traced back to China, Central Asia and the Middle East. Muslim chemists were the first to produce purified distilled alcohol. The Renaissance allowed distillation to spread through Europe by the 12th century and reached its apogee by the 14th century. Benedictine Monks took full advantage of the science of distillation to create new spirits. Scots, having very little to do between battles invented whisky; many years after the Irish invented whiskey by the fermentation of grain mash. This invention is still in use today. The concentration of alcohol in a drink is specified in percent alcohol by volume (ABV); Degrees proof were formerly used in the UK where 100 degrees proof was 57.1% ABV (historically, the most dilute spirit which would sustain the combustion of gunpowder).

Ethanol affects the gamma-aminobutyric acid (GABA) receptors, to produce a depressant effect. It is only slightly toxic compared to other alcohols, with a lowest known lethal dose in humans of 1400 mg/kg. A blood alcohol concentration of 50 to 100 mg/dL (0.05-0.10g%, usually 0.08g%) may be considered legal drunkenness. In Canada the legal drinking age is 18 in the provinces of Alberta, Manitoba and Quebec only, and 19 elsewhere.

In moderation, alcohol consumption has significant health benefits. These include a lower risk of heart attack, lower risk of diabetes, lower risk of Alzheimer’s disease, reduced risk of stroke, and an increase in overall longevity. A recent meta-analysis of 34 studies (Di Castelnuevo A et al. Arch Intern Med 2006;166:2437-45) shows that the risk of mortality is lowest in men that drink 1-2 drinks/day and in women who drink 0.5-1.0 drink/day.

The organization Mothers Against Drunken Driving (MADD, www.madd.org) has led the fight in the US against drinking, especially in youth. Approximately 8-10 percent of the US population meets the diagnostic criteria for alcohol abuse or alcoholism. Some forms of cancer have been linked to excessive consumption of alcohol. The World Health Organization has classified alcohol as a Group 1 carcinogen. Its evaluation states, “There is sufficient evidence for the carcinogenicity of alcoholic beverages in humans [...]. Alcoholic beverages are carcinogenic to humans (Group 1).” Alcohol is also an addictive substance.

Alcohol addiction can lead to hepatic steatosis, alcoholic hepatitis and cirrhosis and hepatocellular carcinoma (drinking four cups of coffee per day reduces alcoholic cirrhosis risk by 80% among both men and women (Klatsky et al., Coffee, cirrhosis, and tranaminase enzymes. Archives of Internal Medicine, 2006, 166, 1190-1195). It can also lead to malnutrition because it can alter digestion and metabolism of most nutrients. Severe thiamine deficiency is common due to deficiency of folate, riboflavin, vitamin B6 and selenium. Muscle cramps, nausea, appetite loss, neuropathies and depression are some common symptoms. It can also lead to osteoporosis and bone fractures due to vitamin D deficiency. Alcohol stimulates insulin production, which may cause hypoglycemia.

Cheers!

Email to a colleague