Left Ventricular Systolic Dysfunction Precipitated by Verapamil in Cardiac Amyloidosis

Cardiac amyloidosis produces a restrictive cardiomyopathy with impaired diastolic function. We report a case in which low-dose verapamil resulted in marked worsening of congestive heart failure, as a result of a profound negative inotropic effect. Withdrawal of verapamil therapy demonstrated a return of systolic function to normal with improvement in heart failure. We postulate that patients with cardiac amyloidosis may be exceptionally sensitive to the negative inotropic effects of calcium-channel blockers either because of abnormal binding to amyloid fibrils or because their usual vasodilator effects are blunted. Cardiac amyloidosis produces a restrictive cardiomyopathy with impaired diastolic function. We report a case in which low-dose verapamil resulted in marked worsening of congestive heart failure, as a result of a profound negative inotropic effect. Withdrawal of verapamil therapy demonstrated a return of systolic function to normal with improvement in heart failure. We postulate that patients with cardiac amyloidosis may be exceptionally sensitive to the negative inotropic effects of calcium-channel blockers either because of abnormal binding to amyloid fibrils or because their usual vasodilator effects are blunted. Cardiac amyloidosis is characterized by a restrictive pathophysiologic state secondary to myocardial infiltration by amyloid fibrils. Heart failure is due predominantly to diastolic dysfunction, and it is only late in the course of the disease that the left ventricular (LV) ejection fraction falls.1Falk RH. Cardiac amyloidosis.Prog Cardiol. 1989; 2: 143-155Google Scholar Although calcium-channel blockers have been successfully used for the treatment of diastolic dysfunction in other conditions, these agents have occasionally been reported to precipitate or worsen heart failure in cardiac amyloidosis even in the presence of a normal ejection fraction.2Gertz MA Falk RH Skinner M Cohen AS Kyle RA. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents.Am J Cardiol. 1985; 55: 1645Abstract Full Text PDF PubMed Scopus (133) Google Scholar, 3Griffiths RE Hughes P Dowdle R Stephens MR. Cardiac amyloidosis with asymmetrical septal hypertrophy and deterioration after nifedipine.Thorax. 1982; 37: 711-712Crossref PubMed Scopus (47) Google Scholar, 4Bouhour JB Haddak M Lefevre M. Le risque des beta bloquers et des inhibiteurs calciques dans la cardiopathie amyloide.Presse Med. 1986; 15: 981Google Scholar Since patients with cardiac amyloidosis have a rapid, progressive, downhill course with a high mortality,5Cueto-Garcia L Reeder GS Kyle RA Wood DL Seward JB Naessens J et al.Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival.J Am Coll Cardiol. 1985; 6: 737-743Abstract Full Text PDF PubMed Scopus (226) Google Scholar it is not clear whether deterioration following a calcium-channel blocker truly represents a direct adverse effect of the drug or whether clinical deterioration is coincidental, resulting from the natural course of the disease. In this report, we describe a patient with amyloidosis of the heart in whom verapamil was responsible for severe congestive heart failure and disproportionately severe depression of LV function. A 60-year-old man with primary amyloidosis proved by biopsy specimen was evaluated for worsening heart failure. He had experienced exertional dyspnea for 18 months and had had recurrent episodes of atrial fibrillation, during which atypical chest pain occurred. There was no history of hypertension or myocardial infarction. Cardiac catheterization, performed a few months prior to hospital admission, revealed normal coronary arteries, normal LV ejection fraction, and elevated LV diastolic pressures compatible with diastolic dysfunction. Treatment with slow-release verapamil, 120 mg daily, was initiated and shortly afterwards, the patient noted worsening exertional dyspnea progressing to symptoms at rest, associated with peripheral edema. Increasing doses of diuretics and nitrates were prescribed with little benefit. At the time of hospital admission, he was in sinus rhythm and short of breath at rest. Supine blood pressure was 120/70 mm Hg, and there was evidence of biventricular failure and mitral regurgitation. Findings on the echocardiogram were typical of cardiac amyloidosis, showing increased wall thickness and mitral regurgitation. There was global LV hypokinesis with an ejection fraction of 33 percent calculated by computerized analysis of the two-dimensional echocardiogram (Fig 1, A). Verapamil therapy was discontinued and a repeat echocardiogram performed 3 days later showed a marked improvement in ejection fraction and a concomitant reduction in the severity of mitral regurgitation (Table 1 and Fig 1, B).Table 1Physical and Echocardiographic Findings With and Without Verapamil*HR = heart rate; BP = blood pressure; MR = mitral regurgitation; LVEF = left ventricular ejection fraction; NA = not assessed.HR, Beats/minBP, mm HgLVEF, %MRVerapamil (120 mg/d) 68120/7033+ + +No verapamil 87110/7056+No verapamil, peak exercise114140/8054NA* HR = heart rate; BP = blood pressure; MR = mitral regurgitation; LVEF = left ventricular ejection fraction; NA = not assessed. Open table in a new tab To determine functional capacity and the ventricular response to exercise, a stress echocardiogram was performed. The patient exercised for 6 min on a treadmill, using the Bruce protocol, and terminated exercise due to fatigue. A blunted heart rate and blood pressure response were noted (Table 1). The immediate postexercise echocardiogram showed preserved ejection fraction and no segmental wall motion abnormalities. Clinical improvement after discontinuation of verapamil therapy was maintained during the follow-up period but he died suddenly at home 6 months later. Worsening of clinical heart failure associated with verapamil has been reported previously in cardiac amyloidosis,2Gertz MA Falk RH Skinner M Cohen AS Kyle RA. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents.Am J Cardiol. 1985; 55: 1645Abstract Full Text PDF PubMed Scopus (133) Google Scholar, 3Griffiths RE Hughes P Dowdle R Stephens MR. Cardiac amyloidosis with asymmetrical septal hypertrophy and deterioration after nifedipine.Thorax. 1982; 37: 711-712Crossref PubMed Scopus (47) Google Scholar, 4Bouhour JB Haddak M Lefevre M. Le risque des beta bloquers et des inhibiteurs calciques dans la cardiopathie amyloide.Presse Med. 1986; 15: 981Google Scholar although documentation of the drugs effect on ventricular function was not described. In the present patient, withdrawal of a relatively small dose of verapamil was associated with rapid improvement, both in functional class and in signs of biventricular decompensation. Objective evidence of a marked improvement in the LV ejection fraction was documented by quantitative echocardiography. Calcium-channel blockers have beneficial effects in cardiac diseases associated with diastolic dysfunction.6Heywood JT. Calcium antagonists and left ventricular function.Am J Cardiol. 1991; 68: 52C-57CAbstract Full Text PDF PubMed Scopus (5) Google Scholar It is generally considered that, despite demonstration of in vitro negative inotropic properties, these drugs can be used safely in patients with mildly to moderately impaired systolic function. In the clinical setting, worsening of heart failure is presumably offset by their vasodilator effects and, possibly, by a resultant increase in baroreceptor-mediated sympathetic stimulation. We postulate that the abnormal autonomic regulation is a factor in the adverse response to verapamil in cardiac amyloidosis. Autonomic dysfunction and impaired vasomotor mechanisms are characteristic of this disease, resulting in a low systemic vascular resistance, ie, a disease-induced afterload reduction. Our patient had evidence of an abnormal autonomic response characterized by a blunted heart rate and blood pressure response to exercise. Under these circumstances, verapamil, which normally has its negative inotropic effect offset by vasodilation, is unable to cause further vasodilation and, consequently, the negative inotropic effect will be exposed. An additional factor that may enhance the direct negative inotropic effect of verapamil in cardiac amyloidosis is the potential for an increased binding of the drug to areas of high concentration of amyloid fibrils. Increased binding of various drugs to amyloid, including digoxin and nifedipine, has been reported previously.7Gertz MA Skinner M Connors LH Falk RH Cohen AS Kyle RA. Selective binding of nifedipine to amyloid fibrils.Am J Cardiol. 1985; 55: 1646Abstract Full Text PDF PubMed Scopus (44) Google Scholar It is possible that this also occurs with verapamil, although further study of the direct interaction of this drug with myocardial fibers in the presence of surrounding amyloid deposits is needed to verify this hypothesis. We thus confirm the previously described aggravation of symptoms in patients with cardiac amyloidosis treated with calcium-channel blockers, even in the presence of normal predrug ejection fraction. We have extended these clinical observations to show that this effect represents an exaggerated negative inotropic effect and we concluded that calcium-channel blockers have no role in the management of cardiac amyloidosis despite the severe diastolic dysfunction characteristic of this disease.