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Verapamil and norverapamil plasma concentrations during long-term therapy in patients with hypertrophic obstructive cardiomyopathy.

Plasma concentrations of verapamil and norverapamil were measured with a gas chromatographic method in 31 patients with hypertrophic obstructive cardiomyopathy during long-term maintenance therapy (6 months-5 years) with verapamil. In 20 patients on a maintenance dosage of 480 mg/day, verapamil concentrations approximately 12 hr after the last regular dose were 91 ± 76 ng/ml (mean ± SD) and levels 1 hr after an oral test dose of 160 mg were 355 ± 253 ng/ml. The values before and after the test dose were highly correlated, r = 0.7272 (p < 0.001). The concentration of norverapamil before the test dose in these 20 patients (160 ± 121 ng/ml) showed a strong positive correlation with the corresponding verapamil concentrations. Verapamil and norverapamil did not accumulate in plasma during long-term treatment with 480 mg daily. A 25-fold difference between patients on this dosage was found for verapamil plasma concentrations before the test dose and a 13-fold difference after it. This large interpatient variation may be mainly due to differences in the first-pass metabolism of verapamil. We recommend that verapamil plasma concentrations be measured to guide therapy with this drug.

10-year results and survival of patients with hypertrophic cardiomyopathy treated with calcium antagonists

Hypertrophic cardiomyopathy is characterized by progredient myocardial hypertrophy causing ventricular systolic and diastolic dysfunction. Long-term results of beta-blocker therapy have been disappointing. Neither the impaired ventricular filling or the prognosis are improved. In contrast, calcium antagonists mainly influence diastolic ventricular dynamics, but also have beneficial effects on systolic function. The results of long-term therapy with calcium antagonists, including patients treated for more than 10 years, are presented here. A total of 84 consecutive patients (mean age 43 years; 20 female and 64 male) with confirmed hypertrophic cardiomyopathy were treated with high doses of calcium antagonists (mean doses of 515 mg verapamil or 158 mg gallopamil per day). In the course of therapy with a mean duration of 52 months, heart size--assessed by X-ray technique--and Sokolow-index in the ECG decreased significantly (heart volume: from 947 to 885 ml/1.73 m2 body surface; Sokolow-index: from 5.0 to 4.5 mV). The echocardiogram showed a significant decrease in left atrial diameter, whereas wall thickness only tended to decrease. Hemodynamic control investigations confirmed an improvement in systolic as well as in diastolic ventricular function (mean follow-up period was 31 months). According to these findings the condition and stress tolerance improved in 84% of the patients. Therapy with calcium antagonists also improved prognosis: without treatment or following treatment with beta-blocking agents, annual mortality is approximately 3.5%, whereas in the described patient population mortality dropped to less than 2%. Thus, a calcium antagonist is the medication of first choice for patients with hypertrophic cardiomyopathy.

Effect of propranolol and disopyramide on left ventricular function at rest and during exercise in hypertrophic cardiomyopathy.

In 19 patients with hypertrophic cardiomyopathy (15 males, 4 females, mean age 49.2 ± 10.8 years) left ventricular function was studied with radionuclide ventriculography at rest and during exercise i

Verapamil Treatment of Hypertrophic Cardiomyopathy

The natural course of hypertrophic cardiomyopathy is usually characterized by variable degrees of progression [10, 11, 18]. Long-term therapy with beta-blocking agents has proved to be disappointing [3, 11]. Surgical intervention led to initial improvement in many patients, but complaints may reappear with time [17]. These therapeutic strategies thus seem unable to influence either the progression or the long-term prognosis of the disease.

Is technetium-99 m-pyrophosphate scintigraphy valuable in the diagnosis of cardiac amyloidosis?

Amyloidosis is a systemic disease frequently involving the myocardium and leading to functional disturbances of the heart. Amyloidosis can mimic other cardiac diseases. A conclusive clinical diagnosis of cardiac involvement can only be made by a combination of different diagnostic methods. In 7 patients with myocardial amyloidosis we used a combined first-pass and static scintigraphy with technetium-99 m-pyrophosphate. There was only insignificant myocardial uptake of the tracer. The first-pass studies however revealed reduced systolic function in 4/7 patients and impaired diastolic function in 6/7 patients. Therefore, although cardiac amyloid could not be demonstrated in the static scintigraphy due to amyloid fibril amount and composition, myocardial functional abnormalities were seen in the first-pass study.

Effects of nifedipine and propranolol combined therapy in patients with hypertrophic cardiomyopathy

Fifteen (14 male and one female) patients with hypertrophic cardiomyopathy, ranging from 22 to 67 (mean: 45.5) years of age were treated with oral nifedipine and propranolol for 6 to 24 (mean:18) months. Twelve of the patients had been pretreated with a mean oral dose of 560 mg verapamil for 60 up to 93 (mean: 78.5) months, showing slight subjective and objective improvement. Treatment with nifedipine-propranolol was terminated in five cases due to deterioration or side effects after 6 and 12 months, respectively. During combined therapy, two patients reported subjective improvement, but in five cases there was no change and eight patients reported deterioration. The mean Sokolow-index showed no change. The radiologically determined heart volume increased in 11/15 patients and significantly in the mean of all patients from 887 +/- 239 to 947 +/- 246 ml/m2. In addition, echocardiographic measurements showed a significant increase in left atrial diameter from 40.0 +/- 9 to 42.1 +/- 9 mm, whereas ventricular wall thickness remained unchanged. Thus, high dose verapamil therapy seems superior to nifedipine-propranolol therapy in most patients with hypertrophic cardiomyopathy.

Radionuclide ventriculography: acute and chronic response to verapamil in patients with hypertrophic cardiomyopathy

Eleven patients with hypertrophic cardiomyopathy were investigated by repeated radionuclide ventriculography. Nine of them were studied for the first time while under long-term treatment for 14 to 84 months. In all eleven patients radionuclide ventriculography was performed after a withdraw of verapamil for at least 14 days or before the onset of therapy respectively (control period). A third investigation was carried out 60 to 90 min after acute administration of 90 mg oral verapamil. A last radionuclide ventriculography was performed following 2 weeks of therapy with 480 mg oral verapamil. After acute administration heart rate significantly increased from 69 +/- 10 to 80 +/- 15/min. EDV was in the normal range. Left ventricular global ejection parameters showed no significant changes except for minimal decrease in ejection time from 309 +/- 29 to 278 +/- 50 ms after acute verapamil administration. The sectorial ejection fraction improved in apical sectors in relation to the basal one, while the global EF remained constant. The ventricular global peak filling rate increased significantly from 283 +/- 61 to 325 +/- 64%/EDV/s after acute administration of verapamil and the sectorial peak filling rate increased in apical sectors compared to basal sectors following acute administration as well as long-term therapy. After withdrawal of verapamil, six out of 11 patients showed a homogeneous left ventricular delay of contraction by means of the Fourier phases which were normalized under short- and long-term verapamil treatment. In conclusion, verapamil caused a marked improvement of the left ventricular contraction delay without significant changes in global systolic function.

Calcium antagonist treatment in mild forms of cardiomyopathy

Twenty-one patients with a mild form of cardiomyopathy (with normal ejection fraction but histologically-confirmed hypertrophy of myocardial cells and/or elevated diastolic pulmonary artery pressure during exercise) received 120 mg verapamil t.i.d. or no therapy at all for a period of 2 months in an open randomized cross-over study. Out of the 21 patients, 14 improved clinically, one patients condition deteriorated and six remained unchanged (p less than 0.05). The mean diastolic pulmonary artery pressure during exercise decreased (25.3 +/- 7.6 to 20.1 +/- 6.6 mm Hg, n = 21, p less than 0.05). At rest, the decrease was only significant in the subgroup with pressures above 12 mm Hg (15.4 +/- 2.7 to 11.1 +/- 4.1 mm Hg, n = 9, p less than 0.05). All other hemodynamic data displayed no significant change. The benefits of verapamil therapy may be attributed to an improvement in diastolic ventricular function. The disturbance in diastolic relaxation might be of greater importance than the disturbance in systolic function in patients with mild forms of cardiomyopathy.

Myocardial biopsy in patients with hypertrophic cardiomyopathy: Correlations between morphologic and clinical parameters and development of myocardial hypertrophy under medical therapy

Left ventricular biopsies from 38 patients with hypertrophic cardiomyopathy (HOCM 28, HNCM 10) were investigated to evaluate possible correlations between morphological and clinical parameters. No correlation was found between the degree of myocardial hypertrophy (muscle cell diameter), nuclear size of the myocytes, fibrous tissue content and various clinical data such as pressure gradient, left ventricular end-diastolic pressure, Sokolow index and heart volume. In 11 patients with HOCM, a second biopsy was performed after medical therapy (verapamil, n = 9; propranolol, n = 2) over 33 +/- 12 months. Increasing myocardial hypertrophy (cell diameter 16.2 +/- 4.4 mu vs. 20.3 +/- 4.2 mu) was observed in all 11 patients. The interstitial fibrous tissue content increased from 5.7 +/- 6.3 to 12.7 +/- 6.8%. The volume fraction of myofibrils decreased (48.8 +/- 2.7 vs. 43.6 +/- 5.3%). The morphological changes were observed regardless of the clinical outcome which was improved in four, unchanged in five and worsened in two cases. The underlying hypertrophic process in HCM seems to be slowly progressive in most patients and cannot be influenced by medical treatment.

Verapamil Plasma Concentrations and Indices of Heart Size in Hypertrophic Obstructive Cardiomyopathy - Evidence for the Existence of a Therapeutic Range

1. The question of a relationship between plasma verapamil concentration and pharmacological response in hypertrophic obstructive cardiomyopathy (HOCM) patients was investigated using Sokolow-Lyon index (SLI) and heart volume (HV) measurements. 2. Twenty-six patients were treated with maintenance doses of verapamil (usually 3×160 mg Isoptin daily) and plasma level measurements were done using a gas/chromatographic method specific for verapamil. Considerable interpatient variation in plasma verapamil concentration was present attributable to variability in hepatic first-pass extraction and systemic clearance. 3. Approximately 50% of patients showed 10% decrease in SLI and 40% a 10% decrease in HV. Concentrations of verapamil were usually higher in these patients and in the case of SLI a good correlation was observed between the change in ECG and plasma verapamil level r = 0.6245, P<0.01. 4. In HOCM patients plasma concentrations of verapamil in the range 100 to 400ng/ml (pre-dose concentration 100ng/ml) will produce clinically important changes in HV and SLI in most patients and these concentrations are suggested as a provisional therapeutic range. 5. In order to ensure that plasma verapamil concentrations in HOCM patients are in the therapeutic range it is necessary to measure plasma verapamil levels.