Dennis M. Krikler

Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia.

The effect of amiodarone on survival was assessed in patients with hypertrophic cardiomyopathy and ventricular tachycardia in a drug trial with historical controls. During 1976 and 1977, 24 hour (seven) or 48 hour (79) electrocardiographic monitoring was performed in 86 consecutive patients; 24 had ventricular tachycardia and received conventional antiarrhythmic agents. Nineteen clinical, echocardiographic, and haemodynamic features were assessed. Seven patients died suddenly during follow up of three years; of these, five had continued to have ventricular tachycardia and two had no documented ventricular tachycardia. During 1978 and 1979, ventricular tachycardia was detected during 48 hour electrocardiographic monitoring in 21 of the next 82 consecutive patients with hypertrophic cardiomyopathy. They received amiodarone (150-400 mg/day, median 300); ventricular tachycardia was suppressed in all during repeat 48 hour electrocardiographic examination. Two patients died suddenly during a three year follow up, but neither belonged to the amiodarone treated group with ventricular tachycardia. The clinical and haemodynamic variables were similar in patients taking amiodarone and conventional agents. The fact that control of ventricular arrhythmia with amiodarone is significantly associated with improved survival suggests that amiodarone may prevent sudden death in patients with hypertrophic cardiomyopathy and ventricular tachycardia.

Nifedipine and propranolol: A beneficial drug interaction

The antianginal effects of two active drugs, nifedipine and propranolol, alone in combination, were compared with those of placebo in a double-blind clinical trial that included 16 patients with chronic stable angina triggered by exertion. A low dose and a high dose of the active drugs were used (nifedipine, 30 and 60 mg/day; propranolol, 240 and 280 mg/day). Precordial exercise mapping and continuous electrocardiographic recordings were used to assess objective response to therapy, and the patients were asked to keep a diary of episodes of chest pain and consumption of nitroglycerin tablets for subjective appraisal. Both frequency of chest pain and nitroglycerin consumption were significantly reduced by each of the active drugs when compared with placebo, and the combination of nifedipine and propranolol added significantly to the effectiveness. Reductions in area of ischemia and number of episodes of ST segment depression on 48-hour ambulatory electrocardiographic monitoring corroborated the efficacy of each active treatment with respect to placebo. Nearly 60 percent of all episodes of ST segment depression were painless and responded to the active treatment in the same manner as did the episodes associated with chest pain. Side effects were mild and all treatments were well tolerated. The objective methods used allowed for clear-cut differentiation of treatment effects with the various regimens. Although the two drugs alone were significantly more effective than placebo, their combination provided an even greater improvement (p less than 0.005), and therefore it appears to be a safe and effective form of treatment for chronic stable angina.

Frequency of risk factors for ischaemic heart-disease in a healthy British population. With particular reference to serum-lipoprotein levels.

Abstract The concentration of cholesterol and triglyceride in serum and in its lipoprotein classes has been measured in 276 carefully screened men and women aged 20-69 years, living in London, to ascertain the frequency of hyperlipidaemia and of abnormal lipoprotein patterns. The quantitative procedure of preparative ultracentrifugation was used. 4·3% of men and 4·8% of women aged 40-69 years had serum-cholesterol concentrations exceeding 300 mg. per 100 ml.; 14% and 3% of men and women had triglyceride levels greater than 2·0 mmol per litre. By these definitions, 17% of men and 8% of women had hyperlipidaemia. Physical signs suggesting hyperlipidaemia, such as xanthelasma, were rare. About one in twelve subjects had blood-pressures of 160/ 100 mm. Hg or more, and hyperuricaemia was also frequent. Even when cut-off points for I.H.D. lipid and other risk-factors were intentionally set high, their prevalence in this healthy working population was very substantial. Age and sex differences in lipid levels were noted, serum-triglyceride concentration being considerably higher in men. The abnormal lipoprotein patterns seen were raised levels of very-low-density (prebeta) lipoprotein (V.L.D.L.), of low-density (beta) lipoprotein, and of both lipoproteins. In a few subjects the cholesterol but not the triglyceride content of V.L.D.L. exceeded the 95th percentile. Triglyceride concentrations correlated positively with indices of obesity, and were slightly higher in women using oral contraceptives.

Side effects and possible contraindications of amiodarone use

With the increasing use of amiodarone, several unwanted effects have been recognized. We reviewed 140 patients treated with amiodarone over a 5-year period in an attempt to identify patients at risk, to assess the incidence of these effects and their possible relation to dose, and to determine their outcome. The most common effect was photosensitivity (57% of patients responding to a questionnaire), whereas asymptomatic corneal microdeposits were found in all patients undergoing ophthalmologic examination. In contrast, symptomatic eye changes (colored halos) and slate-gray skin pigmentation were rare. Of the metabolic alterations, the rise in hepatic enzymes correlated with dose and plasma drug and metabolite concentrations (r = 0.59, p less than 0.001; r = 0.62, p less than 0.001, respectively) but was not associated with clinical disease. This relation to dose was not evident in patients developing clinical thyroid abnormalities (two hypothyroidism, two hyperthyroidism), all of whom had normal thyroid function prior to therapy. Four of the five hypothyroid patients were over 70 years of age. No patients developed peripheral neuropathy, but tremor and sleeplessness were common complaints (30% and 28% of patients, respectively) that responded to a decrease in dose. One patient with an abnormal chest x-ray film prior to therapy developed pulmonary fibrosis. We suggest the restricted use of high doses of amiodarone for protracted periods. Patients at particular risk are the older age group (hypothyroidism) and those with abnormal lung function prior to therapy who may be predisposed to pulmonary alveolitis. Most of the observed unwanted effects resolve when amiodarone is decreased in dose or discontinued.

Sudden death in hypertrophic cardiomyopathy: associated accessory atrioventricular pathways.

Sudden death is a known but unpredictable complication of hypertrophic cardiomyopathy. We describe two patients who both had a strong family history of the disorder complicated by sudden death. Necropsy disclosed accessory bypass tracts, concealed in one and previously suspected in the other. One died from ventricular fibrillation and the other, who died outside hospital, had previously complained of palpitation. Arrhythmia complicating pre-excitation appears to be one of the factors responsible for sudden death in hypertrophic cardiomyopathy.

Serum Lipoprotein Abnormalities in Patients with Ischaemic Heart Disease: Comparisons with a Control Population

The frequency and nature of abnormalities of serum lipoproteins have been studied, using quantitative techniques, in 143 patients with ischaemic heart disease (I.H.D.). Rigorous selection criteria were used. The findings were related to the distribution of lipoprotein concentrations in a carefully screened control population. Hyperlipoproteinaemia occurred in 55% of patients and in 11 out of 15 patients aged less than 40 years. Raised triglyceride and cholesterol concentrations in very low density lipoprotein were the most frequent abnormalities followed by raised cholesterol content of low density lipoprotein. In young patients high density lipoprotein levels were subnormal. Hyperlipoproteinaemia of W.H.O. types IIa, IIb, III, IV, and V all seemed to be over-represented in I.H.D. I.H.D. patients with type IIa, IIb, and IV abnormalities were all significantly younger than I.H.D. patients with normal lipoprotein levels.

Arrhythmia in hypertrophic cardiomyopathy. II: Comparison of amiodarone and verapamil in treatment.

The antiarrhythmic effects of amiodarone and verapamil were compared in 19 patients with hypertrophic cardiomyopathy complicated by refractory arrhythmias. While verapamil did not reduce the incidence of arrhythmia, amiodarone abolished ventricular tachycardia in 10 of 13 patients and significantly reduced the number of ventricular extrasystoles. In addition, sinus rhythm was restored by amiodarone in three of five patients with longstanding atrial fibrillation.

VENTRICULAR ARRHYTHMIAS AND HYPOKALÆMIA

Two cases of life-threatening ventricular arrhythmia (torsade de pointes) due to chronic mild hypokalaemia, caused by hyperaldosteronism and familial periodic paralysis are described. Correction of the hypokalaemia, supplemented by mexiletine, controlled the arrhythmias.

A comparison of bepridil with amiodarone in the treatment of established atrial fibrillation.

Fourteen patients with established atrial fibrillation (longer than three months) that was refractory to treatment were studied to compare the clinical and electrophysiological effects of amiodarone and bepridil. All patients initially received bepridil for three weeks (200-600 mg/day), followed by amiodarone for two to three months (100-400 mg/day). Bepridil seemed to be slightly more effective than amiodarone in converting the fibrillation to sinus rhythm (nine of fourteen compared with four of ten). The ventricular response in atrial fibrillation was equally well controlled by bepridil and amiodarone, both at rest and during exercise. Bepridil was associated with the development of ventricular arrhythmias in eight of fourteen patients; two had torsade de pointes, which in one degenerated into fatal ventricular fibrillation. These arrhythmias seemed to be associated with bepridil induced prolongation of the QTc interval. No ventricular arrhythmias were seen during amiodarone treatment. Although bepridil seems to be an effective antiarrhythmic agent for the management of atrial fibrillation, its arrhythmogenic actions make it unsuitable for this purpose.

Right ventricular abnormalities in ventricular tachycardia of right ventricular origin: relation to electrophysiological abnormalities.

Patients with right ventricular tachycardia may have adverse electrophysiological abnormalities linked to disturbed right ventricular structure. Seventeen patients who presented with right ventricular tachycardia without coronary artery disease or gross abnormalities of left ventricular function were studied. Patients had the ventricular tachycardia characterised at electrophysiological study and most underwent radionuclide and contrast angiography. At echocardiography specific attention was paid to the right ventricular chamber size. Two groups were identified at echocardiographic study. In group 1, nine patients had normal left ventricular dimensions and relatively normal features at electrophysiological study. Mean right ventricular ejection fraction was 0.45 by krypton-81 measurement. Group 2 comprised eight patients who had dilatation of right ventricular inflow tract, outflow tract, and right ventricular body. This group had more severe features at presentation and at electrophysiological study. In this group all available echocardiographic measurements of right ventricular chamber size were greater than those of group 1 and outside the normal range. Four of the eight patients in group 2 showed regional right ventricular dyskinesia at echocardiography. Mean right ventricular ejection fraction (0.23) in group 2 was significantly lower than in group 1. One patient in group 2 subsequently died. In patients with right ventricular tachycardia, those with less favourable prognostic features at electrophysiological study may have distinct abnormalities of right ventricular structure that can be identified at echocardiographic study. Echocardiography may be of value in the recognition of potentially malignant clinical and electrophysiological features in this group.