Faculty Bibliography

Chronic angina pectoris affects millions of patients every year. During the past 2 decades, advances in medical therapy have led to substantial reductions in the symptoms of angina. Nonetheless, many patients continue to experience persistent angina that causes debilitating symptoms and lifestyle changes. Moreover, many current therapeutic agents cause side effects that can induce substantial morbidity on their own. In major clinical trials, the drug ranolazine has been shown to bring symptomatic relief to large numbers of patients who have chronic angina. Herein, we review the physiology of the sodium channel; the pharmacology of ranolazine; clinical trials that support use of the drug; recent evidence about ranolazine's therapeutic effect on diastolic heart failure, glycemic control, and atrial fibrillation and other arrhythmias; officially approved clinical indications; and avenues of future study

Hypertension commonly clusters with other cardiovascular risk factors, giving rise to the concept that hypertension is a multifaceted disease that potentially shares common pathogenic pathways with other risk factors. The renin-angiotensin-aldosterone system has a central role in the shared mechanisms of hypertension and cardiovascular disease, primarily through angiotensin II. Increased levels of angiotensin II disrupt the balance of vasoactive substances and growth factors that regulate endothelial structure and function, and inhibition of the renin-angiotensin-aldosterone system with an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker helps restore this equilibrium. Some pathogenic mechanisms may also be favorably affected by calcium channel blockade. While the relative contribution of pleiotropic effects to clinical benefit is difficult to quantify, based on recent data it is reasonable to consider using newer antihypertensive agents in selected high-risk patients to realize the benefits that may derive from interfering with pathogenic mechanisms of disease

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque

A consensus panel was formed to review the rapidly emerging literature on the vascular-specific inflammatory marker lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and to update recommendations for the appropriate use of this novel biomarker in clinical practice. The recommendations of the panel build on guidelines of the Adult Treatment Panel III (ATP III) and the American Heart Association/Centers for Disease Control (AHA/CDC) for cardiovascular risk assessment. Consistent with the ATP III guideline recommendations for the use of inflammatory markers, Lp-PLA(2) is recommended as an adjunct to traditional risk assessment in patients at moderate and high 10-year risk. A simplified framework for traditional Framingham risk factor assessment is proposed. As a highly specific biomarker for vascular inflammation, elevated Lp-PLA(2) levels should prompt consideration of increasing the cardiovascular risk category from moderate to high or high to very high risk, respectively. Because intensification of lifestyle changes and low-density lipoprotein (LDL) cholesterol lowering is beneficial in high-risk patients, regardless of baseline LDL cholesterol levels, consideration should be given to lowering the LDL cholesterol target by 30 mg/dL (1 mg/dL = 0.02586 mmol/L) in patients with high levels of Lp-PLA(2). Lp-PLA(2) is recommended as a diagnostic test for vascular inflammation to better identify patients at high or very high risk who will benefit from intensification of lipid-modifying therapies. However, at this time Lp-PLA(2) cannot be recommended as a target of therapy

Fibrates are a class of lipid-lowering medication primarily used as second-line agents behind statins. Acting via the peroxisome proliferators-activated receptor-alpha, their main lipoprotein effects are to lower serum triglyceride levels and to raise high-density lipoprotein-cholesterol, with modest effects on low-density lipoprotein-cholesterol. However, many clinical trials indicate that fibrates may have benefits beyond simply altering one's lipid profile. Several angiographic studies show retardation in the progression of atherosclerotic lesions in coronary vessels. Although clinical trials have failed to show a reduction in mortality with fibrates, several post hoc analyses indicate that there may be a mortality benefit in patients with features of the metabolic syndrome. Given that fibrates are often used as second-line agents, it is essential they are safe to be given in combination with other agents, particularly statins and ezetimibe. Although the side-effect profile of fibrates includes gastrointestinal symptoms, increased liver function tests, a reversible rise in creatinine and myositis, in general, fibrates seem to be safe to use in combination with other lipid lowering medications. Thus far, fibrates have not shown a mortality benefit in randomized clinical trials; as a result, they cannot be considered first-line medication for the primary or secondary prevention of coronary artery disease

During the past 25 years, the role of traditional 'risk factors' in the genesis of atherosclerotic vascular disease has been convincingly validated. The impact of elevated low-density lipoprotein cholesterol, hypertension, type II diabetes, and metabolic syndrome are now well accepted. However, until recently, there was guilt by association without a clear understanding of the manner in which the crime was committed. It is now acknowledged that the presence of multiple risk factors can increase the likelihood of an ischemic event. This has become a great concern, given the very high prevalence of patients who fall into this category. In light of this information, the mandate for appropriate guideline-driven therapy has become even stronger, and we must consider the use of multiple medications to effectively neutralize this risk