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4/29/2004

Failing Heart Can Be Revived, Researchers Report

Cheryl A. Thompson

Confronted with a shortage of hearts suitable for transplant, some clinicians are investigating whether a failing heart, if temporarily assisted by a mechanical pump and medications, can return to a functional level.

Transplant clinicians discussed the investigational therapy known as bridge to recovery at the annual meeting of the International Society for Heart and Lung Transplantation, held April 21-24 in San Francisco.

Pioneered at Harefield Hospital in the United Kingdom, bridge to recovery builds on two well-accepted uses for the left ventricular assist device (LVAD): temporary, as a bridge to heart transplantation; and long-term or permanent, as so-called destination therapy in patients with end-stage heart failure who do not qualify for transplantation.

An LVAD, once implanted alongside a patient's damaged heart, helps the weakened left ventricle pump blood and provides what is known as mechanical unloading.

Several brands of LVAD licensed in the United States have government-approved labeling for use in patients awaiting heart transplantation, and one is licensed for destination therapy. None is intended as a bridge to recovery, easing the workload until the heart grows strong enough to safely resume full-scale work.

For 10 bridge-to-recovery patients at Harefield, reported James Hardy of the cardiothoracic surgery department, their initially prolonged QTc interval decreased to an acceptable duration, around 403 milliseconds, in the two months to two years they had an LVAD and received a special combination of medications. The QTc interval, which is the length of time the ventricles take to electrically discharge and repolarize, then stayed about the same for at least the first 18 months after removal of the device.

Other indicators of the left ventricle's health also improved, he reported. Decreases in the internal diameter of the left ventricle at the end of systole and diastole were sustained for 18 months after device explantation, as was the increase, to an average of 67 percent, in the left ventricular ejection fraction.

The pharmacologic regimen, Hardy said, began with an angiotensin-converting-enzyme inhibitor, the angiotensin II-receptor antagonist losartan, spironolactone, and the nonselective beta-blocker carvedilol, which also blocks alpha-1-adrenergic receptors. Clenbuterol, an investigational beta2-agonist with anabolic steroid properties, was then administered to induce a mild hypertrophy of the cardiac muscle cells and improve organ function.

He said all of the patients had had the LVAD implanted because of dilated cardiomyopathy, a condition in which the heart's ventricles are larger than normal but incapable of pumping enough blood to meet the body's needs. The patients' hearts, at the time of LVAD explantation, were in sinus rhythm.

Nine of the 10 patients have no symptoms of heart failure and their "quality of life is excellent," said Magdi Yacoub, who leads the Harefield team and is regarded as the chief proponent of bridge to recovery.

The 10th patient consumed a massive amount of alcohol and needed a heart transplant, he said. An additional three bridge-to-recovery patients did not fare well without the LVAD and needed transplantation.

Yacoub described bridge to recovery as an example of cardiac regeneration. The combined actions of the LVAD and medications, he said, induce "maximal reverse modeling," with the left ventricle recovering from the electrical and physiologic changes that occurred with the original cardiac injury.

U.S. researchers at the meeting reported laboratory and clinical evidence supporting the Harefield group's idea that mechanical unloading enables the left ventricle to heal. Harefield researchers presented laboratory data suggesting that clenbuterol induces cardiac myocyte hypertrophy without the pathological growth found with the administration of isoproterenol or phenylephrine.

Not only does bridge to recovery potentially overcome problems with the availability of suitable donor hearts, Yacoub said, the strategy averts the complications that arise from the nonspecific suppression of the immune system to prevent organ rejection.