Cardiovascular safety of drugs not intended for cardiovascular use: need for a new conceptual basis for assessment and approval

Recently, several drugs for non-cardiovascular diseases have ceased marketing because of cardiovascular risk, highlighting the importance of evaluating the cardiovascular safety of new drugs even if not intended for cardiovascular diseases. Assessing and ensuring acceptable cardiovascular safety of non-cardiovascular drugs is difficult; nonetheless, governmental regulatory agencies are likely to change the requirements for drug safety information. This article explores our recommendations for rethinking current regulatory policies, emphasizing the need for mandatory post-marketing surveillance registries and highlighting the exposures necessary to subserve the need for greater assessment of safety issue

Improving patient care: some unresolved issues in heart failure

Angiotensin-converting enzyme (ACE) inhibitors are considered as the cornerstone of the treatment of congestive heart failure with systolic dysfunction, proving beneficial in all grades of heart failure, from I to IV on the New York Heart Association scale. However, despite these positive results, a brief glance at the published mortality data or an hour spent in any heart failure clinic easily demonstrates that the problems of heart failure are far from being solved. Among the unresolved issues that will be addressed in this brief review are: the high incidence of deaths due to pump failure and sudden death in patients receiving ACE inhibitor therapy; methods of further improving exercise tolerance and quality of life, and, finally, current views regarding prevention of heart failure

Calcium antagonists or beta-blockers in chronic ischaemic left ventricular dysfunction?

Angina pectoris in patients with severe left ventricular dysfunction (LVD), with or without heart failure, is important clinically and socioeconomically. In the Studies of Left Ventricular Dysfunction (SOLVD), more than 36% of the patients had angina pectoris. Although angiotensin-converting enzyme (ACE) inhibitors improve survival and reduce the incidence of new, acute ischaemic events in these patients, they have no significant impact on the incidence of anginal attacks. Treatment of these patients must, therefore, primarily rely on nitrates, beta-blockers and calcium channel blockers. The beta-blockers, by lowering heart rate, improve the balance between myocardial oxygen supply and demand during exercise, and are among the most effective anti-anginal agents available. In addition, by reducing resting heart rate and by preventing excessive catecholamine stimulation of the myocardium, beta-blockers may slow the progression of ischaemic LVD. This may contribute to the improved survival observed when these agents are used following myocardial infarction. By reducing cardiac sympathetic stimulation, however, beta-blockers may depress right and left ventricular pump function. This depression is generally of no clinical consequence when the ejection fraction remains above 40%, but when the ejection fraction is below 35%, only 30% of patients without heart failure and 10% of those with heart failure seem to tolerate a full dose of beta-blocker. This limits their therapeutic use in angina in this setting. Moreover, beta-blockers do not act on the mechanisms underlying some anginal attacks, namely the vasoconstriction of large coronary vessels at the level of atherosclerotic plaques and the reflex vasoconstriction of small coronary arterioles.(ABSTRACT TRUNCATED AT 250 WORDS

Role of neurohormones in ventricular adaptation and failure

When the heart faces a hemodynamic challenge (pressure or volume overload, myocardial infarction, etc.), mechanical, neurohormonal, and metabolic changes occur and impact on the myocytes, the fibroblasts, and the microcirculation. These changes immediately modify the function of the heart but also trigger gene expression and protein synthesis, leading after days and months to a remodeled heart in which not only the geometry of the cavity is changed but the composition of the wall has also become markedly abnormal. The remodeling process is infinitely complex, because all factors involved interact in a complex way and because the genetic responses may vary between species and between individuals. Moreover, we still ignore the role (or even the existence) of many growth factors involved in the process. To illustrate this complexity, one can use 2 classic models: pressure-overload hypertrophy and acute myocardial infarction. In both situations, experimental models can be designed so that angiotensin II and aldosterone are elevated and in both types of models the use of an angiotensin-converting enzyme inhibitor favorably influences hypertrophy and survival. Interestingly, however, intense interstitial fibrosis leading to an increase in diastolic stiffness is present in the pressure overload models, whereas increased diastolic distensibility and cardiac dilation are observed in models of myocardial infarction. This clearly indicates that in addition to the renin-angiotensin system other factors interact in the remodeling process and modulate the effects of angiotensin-converting enzyme inhibition on ventricular remodeling

Diastolic dysfunction and myocardial energetics.

Myocardial relaxation is an energy-dependent process. Indeed, adenosine triphosphate (ATP) is required to pump free myoplasmic calcium back into the sarcoplasmic reticulum. It is also necessary to extrude the calcium ions which enter the cell during the plateau phase of the action potential. The calcium-sodium exchange mechanism does not seem to require energy in itself, but sodium exchanged for calcium eventually needs to be extruded via sodium/potassium ATPase and there is also an ATP-dependent calcium pump. Thus, when ATP production is limited, calcium may remain fixed to troponin for part or for the whole of diastole, resulting in a slower rate of isovolumic relaxation and reduced distensibility of the myocardium. Alterations in diastolic function caused by inadequate energy production occur in the high-demand type of myocardial ischaemia. There is also growing evidence that most forms of heart failure are accompanied by a state of energy depletion. Alterations in mitochondrial density and enzymatic activity are common in the failing myocardium and may partially explain the reduction in ATP production. Inadequate growth of the capillary network in hypertrophied myocardium, impaired subendocardial perfusion due to increased diastolic wall stress and/or coronary artery disease, probably also contribute to an imbalance between energy production and utilization. As relaxation is intrinsically a much slower process than activation and since changes in ATP concentration may also affect calcium efflux by allosteric effects, impaired relaxation and reduced diastolic distensibility are almost universal in chronic congestive heart failure. Optimal therapy of heart failure should, therefore, also aim at improving this phase of the cardiac cycle

High or low dose of angiotensin-converting enzyme inhibitor in patients with left ventricular dysfunction?

Although it is widely accepted that angiotensin-converting enzyme inhibitors have become a cornerstone in the treatment of congestive heart failure, controversy still exists regarding the optimal doses of these drugs to use, and important variations in the daily dose used are seen among different physicians and countries. Nevertheless, objective data indicate that the efficacy of these drugs increases with dose and that most patients with heart failure tolerate the relatively high doses that have been used in large mortality trials. Presently, therefore, and unless new contradictory data become available, every effort should be made to use high doses of angiotensin-converting enzyme inhibitor in heart failure patients

Angiotensin-converting enzyme inhibitors in the treatment of clinical heart failure.

During the last decade, angiotensin-converting enzyme inhibitors (ACE-I) have become cornerstones in the treatment of clinical congestive heart failure. There is convincing evidence that they improve survival and that, in this respect, they are superior to ordinary vasodilators. ACE-I administration also improves New York Heart Association functional class and the left-ventricular function, but their long-term effects on exercise tolerance and quality of life appear modest. During prolonged administration to patients with ischemic left-ventricular dysfunction, ACE-I also significantly reduce the incidence of new ischemic events (myocardial infarction, unstable angina)

Nisoldipine in severe ischaemic left ventricular dysfunction.

The use of calcium antagonists in patients with severe dysfunction is controversial because agents like verapamil, diltiazem and nifedipine have been shown to worsen or precipitate congestive heart failure. However, successive improvements in our understanding of the clinical pharmacology of these drugs, of their pharmacokinetics and of their action on several neuro-humoral regulatory mechanisms have led to a continuous improvement of the molecules available. Promising results have been obtained with nisoldipine in patients with ischaemic left ventricular dysfunction (improved exercise tolerance, improved diastolic filling probably related to a relative improvement of chronically ischaemic areas) and other studies are exploring the effects of the combination of nisoldipine with an ACE-inhibitor. Soon, these trials should tell us if there is a real clinical benefit in the use of this agent not only to improve symptoms but also to slow down progression of the ventricular dysfunction

Afterload is not an independent determinant of left ventricular pump fonction

Thèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 198