The Heart According to Piero Anversa

One important measure of a research paper is to have the report featured on the cover of the journal in which it is published. This should provide the first clue that the Cardiovascular Research Institute at New York Medical College has hit its stride. In the first three months of this year, all three of its published papers received this distinction.

With the seeming regularity of a monthly magazine, so much landmark data is offered to and accepted by elite journals in the field that Director Piero Anversa, M.D., and his team can barely find the time to do the grant applications and research papers that are essential to the task. Their scientific passion is heart failure, the number one cause of death and hospitalization in people over 65. Dr. Anversa accounts for his ingenuity and their industry this way:

“If you put together 3,000 cardiologists to get the definition of heart failure, you’ll get 3,000 opinions. Mine is simple: cell death. There is no heart failure without cell death, and that’s why I study cell death and cell growth, the two critical cellular events in the onset and progression of heart failure…When you lose more cells than you generate, you’re in serious trouble.”

If it sounds deceptively simple, that is his genius. Colleague John A. McClung, M.D. ’75, associate professor of medicine and a clinical cardiologist, is effusive when he talks about Anversa’s research—especially its focus on the link between diabetes and coronary heart disease, the single largest killer of males and females in America:

“For years there has been controversy about the cause of diabetic cardiomyopathy. Piero’s work is elegant stuff—the first clear exposition of cell death and high blood sugar—independent of heart attack, atherosclerosis and blood clots.” He is so impressed with the findings that he is designing a clinical trial to complement Anversa’s investigations. In their Vosburgh Pavilion laboratory, 15 scientists—many from Italy and mostly MDs—have established that high concentrations of glucose can induce a loss in number and hypertrophy (thickening) of myocytes (heart muscle cells), leading to the cardiomyopathy, diastolic dysfunction, loss of heart mass and cardiac insufficiency that accompany diabetes.

Dr. Anversa and the university began their fruitful association in 1972, when the Italian born and educated physician signed on as a visiting assistant professor of pathology. Some three decades later his reputation extends to the appointments he holds at Albert Einstein College of Medicine in the Bronx, and three institutions in Italy in addition to those at the College, where he is a professor in the departments of Pathology, Microbiology and Immunology, and Medicine. His work has been recognized with the Dean’s Distinguished Research Award for 1996, and an appointment as vice chairman of the Department of Medicine last year. Says William A. Frishman, M.D., the chairman who appointed him:

“Piero Anversa has made many of the seminal discoveries in cardiac pathology. His work, and that of his colleagues, have provided a better understanding of myocardial cell death, and the contribution of necrosis and apoptosis to cardiac pathology.

He was one of the first to observe that the heart is not a terminally differentiated organ and that it has the potential to reproduce itself—even in old age.”

Dr. Anversa is not only principal investigator on five National Institutes of Health grants totaling $1.9 million, but he also shares in an interdepartmental Physiology Program Project Grant that brings another $.3 million to the College annually. The nature of his research prompts him to use mostly human hearts, an expense he finds critical to studies that involve glycosylation, the addition of sugar. “Our animal model is a rat, but it does not get type 2 diabetes, which is the more common variety; it does get type 1 [juvenile diabetes], which is more serious…I plan to eventually submit a paper that shows our studies can be applied to both types of diabetes.” The human hearts are currently acquired from patients having biopsies or undergoing transplantation in Italy, but they presumably would be obtained more easily when heart transplant procedures—approved but not yet scheduled—commence at Westchester Medical Center.

Preceding the focus on diabetes, the laboratory’s most important papers dealt with myocyte death and regeneration, which appeared in Proceedings and the journal Circulation Research, Dr. Anversa says. (As is customary for established researchers, his name is placed last in both publications.) While this quest to heal the heart is decidedly basic research, Dr. Anversa designs the studies with a clinical effect in mind.

“Heart failure—despite the number of drugs on the market—still affects a tremendous number of people,” Dr. Anversa advises. “Each year they feel a little better and live a little longer, but they still die like crazy.

How Diabetes Leads to Heart Failure

The association between diabetes and coronary heart disease is so strong that it is often a cardiologist who takes care of a diabetic patient. This is why John A. McClung, M.D. ’75, associate professor of medicine at the College and chief of critical care cardiology at Westchester Medical Center, seldom misses early morning meetings at the Cardiovascular Research Institute led by Piero Anversa, M.D. His studies showing that high blood sugar kills heart muscle cells have motivated Dr. McClung into parallel research that he says has never been done in a human model.

In its quest to establish whether cardiac failure occurs at the cellular level, the Cardiovascular Research Institute has gained the clinical assistance of cardiologist John A. McClung, M.D. ’75. Here he is lending a hand with a system that measures the force developed by a single heart muscle cell. Dr. McClung is planning a trial with diabetic patients to clarify the role of diabetes in cardiac myopathy progressing to heart failure.

“Anversa is looking at a purely cellular event. We are looking at what the heart is doing as an organ,” he explains. “Over time, high blood sugar kills heart cells. The remaining ventricular muscle cells hypertrophy, causing the ventricle to lose its elasticity. These bigger cells require more blood flow, making the heart pump harder and harder to feed itself. The bigger cells also take up more space as the other heart cells are killed off…The diastolic dysfunction that results from cell death and cell hypertrophy is probably the first sign of heart failure in humans. In diabetics, unfortunately, it has not been shown to be reversible.”

In the trial Dr. McClung has designed, colleagues will look for signs of diastolic dysfunction in the hearts of diabetic patients by echocardiogram. Then, to establish whether the subject’s blood sugar is under control, they will use a simple hemoglobin AIC blood test to obtain a mean glucose reading for the previous two months. The researchers are betting that a high AIC level will correlate with poor ventricular diastolic function.

“We will treat these patients and get their sugar down, and half of them will also be treated with an AT1 receptor blocker [losartan]. After six months we will repeat their echocardiograms. If Piero is right, the echoes should be just as bad in those patients who did not receive the AT1 blockade, even though their sugar is under control, because heart cells have died. We are hoping that diastolic function will improve in patients who were treated with the AT1 blocker.

“We can keep a diabetic patient’s blood sugar stable,” Dr. McClung states, “but we probably cannot stop the damage without controlling the mechanism that Dr. Anversa has described.”

We need to develop new strategies to treat cardiac problems. For the last several years the approach has targeted the imbalance between cell growth and cell death. If we can prevent cell death and enhance cell growth, or find the proper balance between the two, the future lies in gene therapy—treating the overexpression of a gene product or the deletion of a gene.”

Meanwhile Dr. Anversa continues to explore diabetic cardiomyopathy and the loss of heart muscle cells, which he presented in abstract form at the American Heart Association annual meeting in November 1999. Subsequently published in Laboratory Investigation, the paper showed how sugar and apoptosis are dose- and duration-related, and it implicated angiotensin II in the triggering of cell death. Angiotensin, a family of peptides (amino acids), has the ability to narrow blood vessels (vasoconstriction), a dubious claim to fame since sound cardiac health hinges on unrestricted blood flow. In cardiac myocytes, he found, sugar increased the presence of angiotensinogen, the precursor of angiotensin II. In fact, sugar amplified the presence of renin and angiotensin.

“This suggests that it is angiotensin II binding to its receptor, AT1, that induces apoptosis. It is the consequence of a glycosylation process and how glucose contributes to the regulation of cell death and ultimately, to weaker hearts and cardiac myopathy,” states Dr. Anversa.

His bottom line is to establish that diabetes per se leads to cardiac myopathy and heart failure. Or, to put it “Jeopardy”-style, What are Piero Anversa and the Cardiovascular Research Institute well on their way to proving?