Mechanical Assist Plus Potent Medical Therapy Revives Failing Hearts

LONDON, Nov. 1 -- For a handful of carefully selected patients, a combination of mechanical and pharmacologic interventions has reversed severe heart failure and restored normal ventricular function, investigators here reported.

More than four years after the interventions, the mean left ventricular ejection fraction was 64% for patients who successfully completed the full course of medical and mechanical therapy, a greater than fivefold increase over baseline, according to results published in the Nov. 2 issue of the New England Journal of Medicine.

The 15 patients enrolled in the study all had received HeartMate left ventricular assist devices for treatment of stage D (New York Heart Association clinical stage IV) heart failure due to nonischemic cardomyopathy with no histologic evidence of active myocarditis.

Noting that unloading of the myocardium with a mechanical assist has been reported to result in myocardial recovery, the investigators used a potent drug cocktail to enhance this recovery process, reported Emma J. Birks, M.R.C.P., Ph.D., of the National Heart and Lung Institute at Imperial College here and Royal Brompton and Harefield Hospital in Harefield, England, and colleagues.

Patients were given a combination of combination of Zestril (lisinopril), Coreg (carvedilol), Aldactone (spironolactone) and Cozaar (losartan) to reverse remodeling after implantation of the HeartMate pump.

Weekly echocardiography was used to track the regression of left ventricular enlargement and once this regression was confirmed, patients were given clenbuterol, the b₂ adrenergic-receptor agonist that is popular with bodybuilders, to prevent myocardial atrophy.

Clenbuterol administration was associated with mild tremor in most patients, muscle cramps in four patients, and diaphoresis in one patient.

Eleven of 15 patients regained sufficient ventricular function to have the HeartMates explanted a mean of 320 days after implantation. One explanted patient died within 24 hours from intractable arrhythmias and a second died of lung cancer 27 months after the HeartMate was removed.

Among the findings:

• The mean LVEF with pump off for 15 minutes was 648% before explantation versus 126% before implantation (P=0.001)
• Before explantation the mean left ventricular end-diastolic volume was 55.98.3 mm versus 75.116.3 mm before implantation (P=0.002).
• Mean left ventricular end-systolic diameter was 39.66.5 mm versus 66.916.3 mm before implantation (P=0.002).
• The actuarial survival rate at one year after explantation was 90.9% and at four years it was 81.8%.
• Eight surviving patients continue at NYHA class I.
• One patient had a return of severe heart failure following an episode of heavy alcohol consumption at 21 months after explantation.

Hector Ventura, M.D., section head of the Ochsner Heart Failure and Cardiomyopathy Center at the Ochsner Health System in New Orleans, said the study was "very provocative" especially since the population studied rarely survives for more than two years after an LVAD is implanted.

The study "tantalizingly provided more than just a series of anecdotes regarding recovery from end-stage heart failure," wrote Dale G. Renlund M.D. and Abdallah G. Kfoury, M.D., of the Utah Tansplantation Affiliated Hospitals in an accompanying editorial.

Dr. Birks and colleagues did not explain the importance of individual agents used in to reverse remodeling, Dr. Renlund and Kfoury wrote.

Dr. Birks and colleagues acknowledged this limitation and concluded that those "issues as well as the question of which clinical characteristics are predictive of recovery, will need to be evaluated in future studies."

Drs. Renlund and Kfoury also questioned the use of clenbuterol, noting that the researchers failed to provide compelling evidence to support the necessity of using a selective b₂ agonist to minimize the adverse effects of chronic unloading.

Dr. Birks and colleagues agreed that the use of clenbuterol "should be interpreted with caution, because adverse effects of this agent on the myocardium and the skeletal muscle have also been reported in animal models."

Despite their concerns, Drs. Renlund and Kfoury agreed that the report from Dr. Birks and colleagues provided evidence that "active intervention may modify the natural history of heart failure.

The study was supported by Thoratec, maker of the HeartMate, the Royal Brompton and Harefield Charitable Trustees, the British Heart Foundation, and the Magdi Yacoub Institute. One of the co-authors, Magdi Yacoub, F.R.S., received an educational grant from Thoratec.