Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk S2

The goals of the …

/pdf/2013-acc-aha-guideline-on-the-treatment-of-blood-cholesterol-pvngcav7fq.pdf

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

0.63; 95% confidence interval [CI], 0.50-0.79;P,.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P = .002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95;P = .02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.520.85; P = .001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P = .006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.

https://jamanetwork.com/journals/jama/articlepdf/187569/JOC80151.pdf

Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels: Results of AFCAPS/TexCAPS

We studied physical fitness and risk of all-cause and cause-specific mortality in 10 224 men and 3120 women who were given a preventive medical examination. Physical fitness was measured by a maximal treadmill exercise test. Average follow-up was slightly more than 8 years, for a total of 110 482 person-years of observation. There were 240 deaths in men and 43 deaths in women. Age-adjusted all-cause mortality rates declined across physical fitness quintiles from 64.0 per 10 000 person-years in the least-fit men to 18.6 per 10 000 person-years in the most-fit men (slope, —4.5). Corresponding values for women were 39.5 per 10 000 person-years to 8.5 per 10 000 person-years (slope, —5.5). These trends remained after statistical adjustment for age, smoking habit, cholesterol level, systolic blood pressure, fasting blood glucose level, parental history of coronary heart disease, and follow-up interval. Lower mortality rates in higher fitness categories also were seen for cardiovascular disease and cancer of combined sites. Attributable risk estimates for all-cause mortality indicated that low physical fitness was an important risk factor in both men and women. Higher levels of physical fitness appear to delay all-cause mortality primarily due to lowered rates of cardiovascular disease and cancer. ( JAMA . 1989;262:2395-2401)

Physical Fitness and All-Cause Mortality: A Prospective Study of Healthy Men and Women

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v 8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.

The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in Incidence of Coronary Heart Disease, and II. The Relationship of Reduction in Incidence of Coronary Heart Disease to Cholesterol Lowering

Drug Abuse in the United States

Organophosphorus-induced delayed polyneuropathy (OPIDP) is initiated by the phosphorylation of a protein neurotoxic esterase (NTE) in the nervous system. A second step, the “aging” of the phosphoryl-enzyme complex, is required to produce the toxic effect. The experimental evidence for this molecular target and the importance of the aging process are reviewed. The catalytic activity of NTE has been used to develop an in vitro screening test that may distinguish the organophosphorus compounds (OPs) that cause neuropathy from those that do not, thereby providing a means for prevention of OPIDP. Moreover, a biochemical screening test, the determination of NTE activity in blood lymphocytes, may predict the development of OPIDP after acute or chronic exposure to OPs, and requires evaluation by carefully designed studies of occupational exposure to OPs.

Organophosphate polyneuropathy: Pathogenesis and prevention

https://www.annemergmed.com/article/S0196-0644(03)00109-4/pdf

Unexpected “gas” casualties in Moscow: A medical toxicology perspective

The safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men wh...

Charles E. Becker

Papers

The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in Incidence of Coronary Heart Disease, and II. The Relationship of Reduction in Incidence of Coronary Heart Disease to Cholesterol Lowering

Drug Abuse in the United States

Organophosphate polyneuropathy: Pathogenesis and prevention

Unexpected “gas” casualties in Moscow: A medical toxicology perspective

Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers