It is gratifying to learn that the Survival And Ventricular Enlargement (SAVE) study continues as a highly cited publication. A major part of the attractiveness and impact of this clinical trial stems from its firm and, at the time, novel conceptual foundation. The treatment of patients with heart failure was directed at improving pump function or hemodynamics. SAVE enrolled patients with recent myocardial infarction and asymptomatic left ventricular dysfunction to test the concept that long-term therapy with an angiotensin converting enzyme inhibitor (captopril) would, by attenuating left ventricular enlargement, result in improved clinical outcome. As such, it was the first major test of the ventricular remodeling hypothesis. The late Dr. Janice Pfeffer generated the underlying study hypothesis in her animal studies and has been affectionately termed, "The Mother of SAVE."

Retracing her career path serves to underscore the importance of the integration of basic investigators in Departments of Medicine. Janice Sikorski Pfeffer had a passion for the educational process. As an undergraduate at Rockford College, she thrived in chemistry and mathematics. However, a turning point occurred during a turtle heart experiment as part of a physiology course. She and her laboratory partner, Marc Pfeffer, became so caught up in integrative physiologic mechanisms that they together went on to obtain their Ph.D. degrees in Physiology and Biophysics from the University of Oklahoma. There the lab partners married, and continued their careers under the mentorship of Dr. Edward Frohlich. Janice Pfeffer’s Ph.D. thesis "Longitudinal Changes in Cardiac Function and Geometry During the Natural Development of Left Ventricular Hypertrophy in the Spontaneously Hypertensive Rat" became the underpinnings for the remodeling concept tested in SAVE.

She continued her studies as a post-doctoral fellow in Dr. Eugene Braunwald’s laboratory at the then Peter Bent Brigham Hospital, Harvard Medical School, as Marc pursued internship and medical residency training. The Braunwald laboratories were at the forefront of establishing the principle of infarct size limitation. Dr. Janice Pfeffer utilized the infarct model not for myocardial salvage, but rather to determine the relationship between the extent of infarction and left ventricular size and function. She demonstrated that progressive ventricular enlargement occurs following an infarction, continuing long after the histologic resolution of the infarcted region. Employing her prior experience in hypertension, she then developed and tested the hypothesis that this insidious process of ventricular enlargement was amenable to pharmacologic therapy. Her pivotal study, "Influence of Chronic Captopril Therapy on the Infarcted Left Ventricle of the Rat" (by JM Pfeffer, MA Pfeffer, E Braunwald, Circ. Res. 57: 84-95, 1985), definitively demonstrated that the process of ventricular enlargement, termed "ventricular remodeling," could be attenuated. These favorable alterations in ventricular remodeling in the animal model were associated with improved cardiac performance and prolonged survival. These animal studies introduced the concept of ventricular remodeling as a potential therapeutic target. Small mechanistic clinical studies then confirmed that ventricular remodeling occurs in selected patients following infarction and that the use of an ACE inhibitor could similarly attenuate this process.

The SAVE study did indeed demonstrate that a mortality benefit could be achieved in relatively asymptomatic patients with myocardial infarctions with this new use of captopril therapy, and a robust echocardiographic sub-study confirmed the remodeling hypothesis.

Use of ACE inhibitors in MI has become well studied with consistent favorable results.

Beyond the concrete benefits from the utilization of an ACE inhibitor to prevent morbidity and mortality in myocardial infarction survivors, Dr. Janice Pfeffer introduced ventricular remodeling as a therapeutic target for new product development as well as advancing our understanding of pathophysiology. Her accomplishments also underscore the importance of a basic science career fostered within a clinical department of medicine.