Showing papers by "Marc A. Pfeffer published in 1991"

Progressive ventricular remodeling in rat with myocardial infarction.

Abstract: Ventricular dilatation may have important prognostic implications for the survival of patients with left ventricular (LV) dysfunction. To determine the manner and extent to which the left ventricle of the rat remodels and dilates after myocardial infarction, we obtained the passive pressure-volume relationships, chamber stiffness constants, and mass during both the early and late phases. In moderate and large infarcts as inflammation and edema developed, LV weight increased then progressively decreased as a thin scar formed, returning to normal values as a result of compensatory hypertrophy of the residual myocardium. LV dilatation occurred in all rats with infarcts but to different extents depending on infarct size and duration. In the early postinfarction phase, pressure-volume relationship was relatively unchanged in all infarct-size groups, except for significant rightward shift in low pressure range for rats with moderate and large infarcts and significant leftward shift in high pressure range for rats with small infarcts. During resolution of the inflammatory response, LV dilatation occurred in all infarct groups in relation to infarct size. As scar formation became complete, LV enlargement did not progress in rats with small infarcts but did so in rats with moderate and large infarcts. LV chamber stiffness remained within the range of normal values during the early phase in all rats with infarcts but decreased significantly during the late phase in rats with moderate and large infarcts in association with the extent of ventricular enlargement. Alterations in the volume-to-mass ratio (V/Vwt) were most marked in the late postinfarction phase, wherein both volume (increased) and mass (decreased, then increased) changed dramatically and V/Vwt progressively increased in rats with large infarcts.

Ventricular enlargement and remodeling following acute myocardial infarction: mechanisms and management.

Abstract: Severe myocardial ischemia, when sustained, leads to a predictable sequence of events, including myocardial necrosis, expansion of the infarct, and later its replacement by scar tissue. The nonischemic tissue sustains ventricular function, but it frequently adapts to the extra load placed on it by dilating. The enlargement and remodeling of the left ventricle may lead to ventricular failure and arrhythmias. Rational management to prevent these complications includes restoration of the patency of the occluded vessel and ventricular unloading. These two interventions may be useful both early and late in the course of infarction.

Selection Bias in the Use of Thrombolytic Therapy in Acute Myocardial Infarction

Abstract: Objective. —To determine whether clinical selection for thrombolytic therapy for acute myocardial infarction results in a skewed population for subsequent adverse cardiovascular events. Design. —A comparison of the clinical features of the patients in the Survival and Ventricular Enlargement Study who either had or had not received thrombolytic therapy was conducted in both univariate and multiple logistic regression analyses. Setting. —Hospitalized patients experiencing acute myocardial infarction from 112 broadly representative, private, academic, and government hospitals in the United States and Canada. Patients. —All patients in the Survival and Ventricular Enlargement Study had had a recent myocardial infarction ( Intervention. —Thrombolytic therapy was administered to 733 patients and was not given to 1498. Main Outcome Measures. —The comparisons with respect to use of thrombolytic therapy were formulated after the completion of enrollment and indicated that the majority of patients did not receive thrombolytic therapy. Results. —The 1498 (67.1%) patients who did not receive thrombolytic therapy were at higher risk (older age, lower functional capacity, greater likelihood of a history of prior myocardial infarction, angina, diabetes, and hypertension) for subsequent cardiovascular events and, as anticipated, were more likely to have concomitant gastrointestinal and neurological diseases. A multiple logistic regression analysis indicated that older age, prior myocardial infarction, impaired functional status, employment status, diabetes, and neurological diseases were predictors of use of thrombolytic therapy. Conclusion. —Although the Survival and Ventricular Enlargement Study population was selected for left ventricular dysfunction, the majority of patients who currently are judged clinically as unsuitable for thrombolytic therapy have a higher risk for adverse cardiovascular events. (JAMA. 1991;266:528-532)

Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events trial (CARE)

Abstract: Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., greater than 240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol less than 240 mg/dl (6.2 mmol/liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be greater than or equal to 5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.

Activation of neurohumoral systems following acute myocardial infarction

Abstract: studies have indicated that patients with an acute myocardial infarction have marked activation of all neurohumoral systems on admission to the hospital. This activation begins to subside within the first 72 hours so that by 7–10 days, all plasma neurohormones have returned to normal. The only documented exceptions were found to occur in patients with left ventricular dysfunction and overt heart failure, where both plasma renin activity and atrial natriuretic peptide were increased, and in patients with left ventricular dysfunction but no overt heart failure, where only atrial natriuretic peptide was increased. Although these studies suggest that neurohumoral activation rarely occurs at the time of hospital discharge, they were small and may have missed an important subgroup of patients with persistent neurohumoral activation. In the Survival and Ventricular Enlargement (SAVE) study, 522 patients had plasma neurohumoral levels measured at a mean of 12 days postinfarction. All SAVE patients had left ventricular dysfunction (left ventricular ejection fraction ≤40%), but no overt heart failure. In this group of patients, all neurohumoral levels (plasma renin activity, norepinephrine, arginine vasopressin, and atrial natriuretic peptide) were found to be increased compared with age-matched control subjects. These results indicate that, in fact, a sub-group of patients without overt heart failure has persistent neurohumoral activation at the time of hospital discharge postinfarction, and that this activation involves several neurohumoral systems. Since patients with persistent neurohumoral activation postinfarction are likely those most at risk of developing complications and the ones most likely to benefit from pharmacologic interventions blunting the effects of neurohumoral activation, measurement of predischarge neurohumoral levels may be useful.

Functional status versus utilities in survivors of myocardial infarction

Abstract: While much progress in assessing quality of life has been made since Karnofsky'sseminal effort,1 the plethora of instruments2 is an indication of the lack of a gold standard in the field. Types of measures include ordinal symptom and functional status scales, such as the Karnofsky scale,1'3 rating scales such as the 10 cm visual analogue scale,4 and utilities, such as the time trade-off,5 which gauge a person's strength of preference for their health state. Although comparisons have been made among functional status measures6-10 and among utility measures,11-14 utilities have rarely been directly compared with functional status measures.7'13'516 The purposes of this study were: 1) to assess the

Rationale, design and baseline characteristics of the survival and ventricular enlargement trial

Abstract: Heart failure, often associated with ventricular enlargement and recurrent myocardial infarction, is one of the major causes of postinfarction mortality. This observation suggests that measures used to prevent ventricular enlargement may improve postinfarction survival. The Survival and Ventricular Enlargement (SAVE) trial is a randomized, double-blind, placebo-controlled clinical trial with the purpose of evaluating the effect of angiotensin-converting enzyme (ACE) inhibition on postinfarction death and ventricular dilation. This multicenter trial had a sample size goal of 2,220 patients between 21 and 79 years of age who had recently sustained a myocardial infarction and who have an ejection fraction determined by radionuclide ventriculogram (RVG-EF) of ≤ 40%. In addition to conventional therapy, patients were randomly assigned to captopril or placebo therapy commencing within 3–16 days following their myocardial infarction. A second RVG-EF is performed on all surviving participants at the end of the average 3.5-year treatment and follow-up period. The study has 90% power to detect a 25% improvement in postinfarction mortality or prevention of ≥9 unit absolute reduction in radionuclide ejection fraction. Additional end points, design features, and the administrative organization of the trial are described.

Patency of the infarct-related coronary artery and ventricular geometry.

Abstract: The pathogenesis of acute myocardial infarction (AMI) involves a sudden thrombotic occlusion of a coronary artery. Spontaneous or pharmacologic thrombolysis may lead to myocardial salvage if patency is achieved within a narrow time window. However, patients in whom thrombolysis occurs late seem to demonstrate improved left ventricular (LV) function and prognosis, which may be independent of myocardial salvage. Preservation of normal LV geometry by reducing expansion of the infarcted segment is a likely mechanism for this benefit. Infarct expansion is most pronounced in patients with anterior wall AMI who have a persistently occluded infarct-related vessel. This process of expansion leads to early increases in LV volume and distortions of LV contour (abnormal LV geometry). Patients whose infarct segment is largest, patients who have manifested infarct expansion, and patients with a persistently occluded infarct-related artery are at highest risk for progressive LV dilation. Experimental data support the concept that reperfusion of occluded vessels that occurs too late for myocardial salvage will preserve LV geometry by limiting infarct expansion. Prospective clinical trials should address whether there is a late, “second time window” during which infarct expansion and distortions of LV geometry may be reduced by (1) therapy with thrombolytic agents applied late after infarction, (2) late mechanical reperfuston with percutaneous transluminal coronary angioplasty (PTCA) or related methods, and (3) load-reducing agents to decrease remodeling, such as angiotensin-converting enzyme inhibitors or nitroglycerin.

Ventricular enlargement following infarction is a modifiable process.

Abstract: The dilation and distortion of the left ventricle that may occur as a consequence of myocardial infarction are associated with a heightened risk for adverse cardiovascular events. Infarcts that are extensive, transmural, and involve the apex as well as persistently occluded, infarct-related coronary arteries are predisposing factors for ventricular enlargement. Infarct expansion is an early component of the overall process of volume enlargement, which later continues as a volume overload hypertrophy of the remaining myocardium. Therapy to limit myocardial necrosis has been associated with the preservation of a more normal ventricular architecture. The late phase of ventricular remodeling has also been shown to be amenable to therapy, as chronic administration of angkrtensin-converting enzyme (ACE) inhibitors has been associated with a reduction in the extent of ventricular dilation. There is currently a great deal of clinical investigative interest not only in whether ACE inhibition therapy following acute myocardial infarction will result in preservation of ventricular volume and topography, but, more importantly, whether it will lead to an improvement in clinical outcome.

Angiotensin converting enzyme inhibition therapy following myocardial infarction. Rationale for clinical trials.

Abstract: Progressive enlargement following myocardial infarction can be anticipated to adversely effect outcome since prognosis is intimately related to the degree of left ventricular dysfunction and resultant ventricular cavity size. Recent experimental and clinical data have indicated that chronic angiotensin converting enzyme inhibitor therapy can be effective in attenuating the ventricular enlargement which occurs following infarction. These observations have provided a rationale for ongoing large multicenter clinical trials designed to determine whether angiotensin converting enzyme inhibition will be of clinical benefit following infarction. This article reviews the rationale for studies of angiotensin converting enzyme inhibition in post-infarct patients and summarizes the ongoing international research effort to fully define the role of angiotensin converting enzyme inhibition following infarction.