Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations.

BACKGROUND: Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. METHODS AND RESULTS: We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). CONCLUSIONS: These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.

Prior coronary artery bypass surgery and risk of death among patients with ischemic left ventricular dysfunction.

BACKGROUND: Patients with ischemic LV dysfunction are at high risk of sudden death. However, no benefit from prophylactic defibrillator therapy was observed in a group of patients with LV dysfunction undergoing CABG (CABG Patch trial). Thus, the effect of CABG on future risk of sudden death in patients with LV dysfunction is of considerable interest. METHODS AND RESULTS: Mortality and modes of death in 5410 patients with ischemic LV dysfunction who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) trials were evaluated. Outcomes of patients with (n=1870, 35%) versus without (n=3540) history of prior CABG were compared, and stratification by baseline ejection fraction (EF) values (<0.25, 0.25 to 0.30, and >0.30) was performed. Prior CABG was associated with a 25% (95% CI, 15% to 36%) reduction in risk of death and a 46% (95% CI, 30% to 58%) reduction in risk of sudden death independent of EF and severity of heart failure symptoms. As baseline EF declined, absolute reduction in risk of sudden death with prior CABG increased (P<0.01). No alteration in risk of death from progressive heart failure was observed with prior CABG. When these results were applied to a group of patients with LV dysfunction who had not undergone prior surgery (Coronary Artery Surgery Study Registry) predicted annual rates of death (8.2%) and sudden death (2.4%) were similar to those observed in the CABG Patch trial (7.9% and 2.3%, respectively). CONCLUSIONS: In patients with ischemic LV dysfunction, prior CABG is associated with a significant independent reduction in mortality. These results appear to account for the lack of benefit from defibrillator therapy in the CABG Patch trial.

Similarity of idiopathic aldosteronism and essential hypertension. A statistical comparison.

There is clinical, biochemical, and pathological evidence that idiopathic aldosteronism is part of a continuum which includes low-renin and normal-renin essential hypertension. In a retrospective statistical study, 89 patients with essential hypertension have been compared with 22 cases of idiopathic aldosteronism and 34 cases of aldosterone-secreting adrenal adenomas. Measurements of serum sodium, potassium, bicarbonate, and plasma angiotensin II concentrations and estimates of exchangeable sodium and potassium were obtained for individual patients. By using various combinations of these biochemical variables, a statistic, the Mahalanobis distance, was described for each of the three populations, essential hypertension, idiopathic aldosteronism, and adrenal adenomas. For each combination of variables, the distribution of the idiopathic aldosteronism group resembled that of the essential hypertension group more closely than that of the aldosterone-secreting adrenal adenoma group. Thus, the use of this statistical technique provides further evidence of the similarity of essential hypertension and idiopathic aldosteronism.

Exchangeable sodium in DOC-salt and post-DOC-salt hypertension in rats.

Eighteen male Sprague-Dawley rats were fed a sodium-free diet and given NaCl (154 mmol/l) labelled with 22Na (37 Bq/l [1 microCi/l]) to drink. Following equilibration, each had a unilateral nephrectomy; 10 days later the animals started a series of 10 injections of deoxycorticosterone (12.5 mg twice-weekly for 5 weeks). Thereafter the animals were split into two groups, one to continue with DOC injections and diet as previously (DOC-salt), the other to stop DOC injections and continue a sodium-free diet and labelled saline of lower concentration (89 mmol/l) (post-DOC). During the period of DOC injections to both groups, blood pressure and exchangeable sodium rose significantly and were significantly correlated. In the post-DOC group, hypertension persisted and was not significantly different from that in the DOC-salt group. However, in the post-DOC-salt group, exchangeable sodium fell to levels similar to those found in uninephrectomized control animals of similar age which had never been given DOC or a high salt intake and had never been hypertensive. Thus an expanded sodium space does not contribute to maintenance of hypertension in the post-DOC-salt model.

Inverse relation of exchangeable sodium and blood pressure in hypertensive patients with renal artery stenosis.

Measurements of exchangeable sodium, arterial pressure and plasma concentrations of active renin, angiotensin II, aldosterone, sodium and potassium were made in 35 hypertensive patients with renal artery stenosis, 30 having unilateral renal arterial lesions. Plasma urea was below 7 mmol/l in 24 of the patients with unilateral lesions. In these and in the whole group of 35 patients there were significant inverse correlations between exchangeable sodium and diastolic blood pressure and between plasma sodium concentration and diastolic pressure. Six patients had hyponatraemia with a plasma sodium concentration less than 135 mmol/l. All were sodium-deplete with secondary hyperaldosteronism, three also having malignant-phase hypertension. Twelve of the patients with unilateral renal artery stenosis underwent bilateral ureteric catheterization. Sodium excretion was greater from the contralateral kidney than from the affected kidney and the rate of sodium excretion from the former, but not from the latter, was significantly related to arterial pressure. The relation of diastolic blood pressure and exchangeable sodium is the opposite of the positive correlation found in essential hypertension and Conn's syndrome. In renal artery stenosis the inverse correlation could result from a natriuretic effect of increased arterial pressure occurring mainly in the contralateral kidney.

Altered cardiac hemodynamic and electrical state in normal sinus rhythm after chronic dual-chamber pacing for relief of left ventricular outflow obstruction in hypertrophic cardiomyopathy.

Dual-chamber (DDD) pacing relieves left ventricular (LV) outflow tract obstruction in patients with hypertrophic cardiomyopathy. The reduction in LV outflow gradient persists in some patients after cessation of pacing. Twelve-lead and signal-averaged electrocardiograms were obtained before and after 12 weeks of DDD pacing in 18 patients with obstructive hypertrophic cardiomyopathy to determine whether the altered hemodynamic state after chronic pacing is accompanied by electrical changes. Hemodynamic studies were performed at baseline and at follow-up. Signal-averaged electro-cardiograms were obtained using a Corazonix Predictor and bidirectional filters at 25 Hz to a noise level of less than 0.5 microV. At follow-up, LV outflow tract gradients were reduced significantly during DDD pacing and with cessation of pacing in sinus rhythm by 56 +/- 10 and 47 +/- 10 mm Hg, respectively (p less than 0.001). There was no simple relation between changes in LV outflow tract gradient and in the electrocardiogram. For example, amplitude of the R wave in V5,6 was reduced by greater than or equal to 0.5 mv in 4 patients, unchanged in 12 and increased in 2. Similarly, the S wave in leads V1,2 was reduced in 7 patients, unchanged in 7 and increased in 4. The T wave became more negative (greater than or equal to 0.1 mv) in leads II, III, aVF and V5,6 in 13 patients and more positive in leads I and aVL in 12.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin converting enzyme inhibitors and moderate hypertension.

Recently there has been extensive development of orally active angiotensin converting enzyme (ACE) inhibitors in addition to those already marketed, for example, captopril, enalapril, lisinopril and ramipril. It was initially thought that ACE inhibitors were likely to be most useful as antihypertensive agents in conditions in which circulating renin and angiotensin II were elevated. However, it is now clear that they can also lower arterial pressure when plasma renin is not high. In addition, they have beneficial effects in cardiac failure. Thus, captopril, enalapril, lisinopril and ramipril can be used in the treatment of mild to moderate hypertension either alone or in conjunction with diuretics or calcium antagonists. Broadly speaking, efficacy appears to be similar to that of beta-blockers or diuretics. Unfortunately, however, there are no long term studies comparing one ACE inhibitor with another or with other classes of antihypertensive agents. Furthermore, there are no prognostic studies which show that use of ACE inhibitors reduces morbidity or mortality in hypertension. Many new ACE inhibitors are undergoing clinical assessment, including alacepril, cilazapril, fosenopril, perindopril, quinapril and ramipril. The drugs vary, in that some exist in the active form whereas others are prodrugs which are converted to the active agent following absorption. In addition they each possess one of several ligands, for example, carboxyl, phosphinyl or sulfhydryl groups, and so vary in their affinity for ACE. Although many of these agents are renally excreted, a small number are metabolised via the liver (e.g. quinapril and spirapril) and this may prove advantageous in the presence of renal impairment. In common with captopril and enalapril, the new ACE inhibitors inhibit the renin-angiotensin system and initial results suggest that they are effective in lowering blood pressure in essential hypertension. Furthermore, they reduce systemic vascular resistance in the absence of a reflex tachycardia. There are a number of adverse effects which are attributable to the pharmacological mechanism of the ACE inhibitors as a group; these include hypotension, particularly in patients with high renin levels, prior diuretic use, renal impairment or in the elderly. Additional adverse effects may relate to chemical structure. The high incidence of adverse effects noted in early studies related to excess dosage and to the presence of a sulfhydryl group, which the more recently developed ACE inhibitors lack. The adverse effects most commonly reported with established and new ACE inhibitors include headache and fatigue, cough, skin rashes, hypotension and diarrhoea. As a group, ACE inhibitors have an acceptable but not negligible adverse effect burden.(ABSTRACT TRUNCATED AT 400 WORDS)

beta-blockers in heart failure: recently completed and ongoing clinical trials.

beta-Blockers have emerged as an important therapy in patients with symptomatic left ventricular systolic dysfunction. Early studies demonstrated that beta-blocker therapy improved left ventricular function, reduced neurohumoral activity and reduced heart failure symptoms in these patients. While none of these small studies demonstrated a significant benefit in terms of overall survival, several meta-analyses suggested that beta-blocker therapy could, in fact, reduce mortality in patients with left ventricular systolic dysfunction and mild to moderate heart failure symptoms (New York Heart Association class II or III). Three large, recently completed, trials have confirmed the benefit of beta-blockade in these patients. This report reviews some of the initial clinical studies of beta-blockade in heart failure, examines the findings of the three large multicentre trials and other relevant research. Finally, ongoing trials designed to assess the relative efficacy of different beta-blockers and evaluate the utility of beta-blockade in specific subsets of patients with heart failure are discussed.

The effect of chronic prazosin therapy on the response of the renin-angiotensin system in patients with essential hypertension.

Changes in plasma active and inactive renin and angiotensin II in response to tilt and intravenous frusemide were assessed in ten patients with essential hypertension, before treatment and again during chronic therapy with the alpha 1-adrenoceptor antagonist prazosin. During prazosin treatment blood pressure in the patients fell from mean levels 172/108 mmHg to 149/88 mmHg (P less than 0.05). Both before and during prazosin, tilt and frusemide each led to significant elevation of plasma active renin (P less than 0.001) and angiotensin II (P less than 0.05). Inactive renin tended to fall with tilt, and fell significantly following frusemide (P less than 0.05). Active renin (P less than 0.05) and angiotensin II (P less than 0.01) were lower 15 hours after dosing during chronic prazosin therapy than before treatment, but changes after tilt and frusemide were not attenuated during treatment. Chronic prazosin administration does not appear substantially to affect changes in active renin or angiotensin II in response to two standard stimuli, and may be useful in controlling hypertensive patients pending investigation of their renin-angiotensin system.

Computed tomography in the localization of aldosterone-secreting adrenal adenomas.

Computed tomography (CT) has been shown to detect both adrenal glands in 88.5% of upper abdominal examinations and can visualize at least one gland in 96.5% of patients. However, in examinations carried out specifically to visualize the adrenals, the glands were located in 98% of cases. This technique was used in 18 patients with primary aldosteronism to localize aldosterone-secreting adrenal tumours and to distinguish these from non-adenomas (bilateral adrenal hyperplasia). The results were compared with quadric analysis, a statistical technique used to predict the likely surgical outcome. In seven patients the CT results were verified by operation (six adenomas, one adrenal hypertrophy). However, in one further patient a large adenoma (20 mm in diameter) which had not been predicted by CT scanning was found at operation. In the remaining ten patients who have been medically treated, results concordant with quadric analysis were obtained in eight cases. We would suggest that CT scanning should be the initial investigation for the pre-operative localization of adenomas but further comparative studies are required.

Staphylococcal septicaemia complicated by probable cloxacillin neurotoxicity and by jaundice induced by fusidic acid.

Two weeks following a renal arteriogram a 56-year-old man with severe hypertension developed a staphylococcal septicaemia. After six weeks treatment with intravenous fusidic acid and cloxacillin he became icteric, confused and disorientated. The fusidic acid was stopped and the serum bilirubin fell to normal. His confusion persisted and serum cloxacillin levels were found to be grossly elevated. The patient's mental state returned to normal following withdrawal of cloxacillin. We attribute his jaundice to treatment with fusidic acid and his acute confusional state to cloxacillin neurotoxicity.

The 'third drug' trial: a comparative study of anti-hypertensive agents added to treatment when blood pressure is uncontrolled by a beta-blocker plus thiazide diuretic.

Hydralazine, labetalol, methyldopa, minoxidil, prazosin and placebo were compared when added to atenolol 100 mg and bendrofluazide 5 mg daily in hypertensive patients inadequately controlled by the beta-blocker/diuretic combination. Atenolol was withdrawn in those allocated to labetalol and minoxidil was given only to men. The order of acceptability was: placebo, hydralazine, prazosin, methyldopa, minoxidil, labetalol. All the active agents were more effective than placebo. Minoxidil was more effective than the other active drugs, which had similar potency to one another. Hydralazine was the most generally suitable third drug, with prazosin a close second. Minoxidil was effective in the milder hypertensives, but in the present regimen caused fluid retention in those with more severe hypertension. Labetalol probably should be introduced at lower dose (150 mg daily) even as replacement for full doses of a previously administered beta-blocker.

Suppression of incessant ventricular tachycardia in hypertrophic cardiomyopathy associated with improvement of severe left ventricular dysfunction.

A 32-year-old black man presented with a history of palpitations since childhood and two syncopal episodes. He was found to have incessant ventricular tachycardia, impaired left ventricular contraction (ejection fraction 9%), and nonobstructive hypertrophic cardiomyopathy. Procainamide abolished the arrhythmia and the ejection fraction rose to 22% in sinus rhythm. Later treatment was switched to amiodarone, which suppressed the ventricular tachycardia but necessitated pacemaker implantation. He has remained well during the subsequent 2 years. Left ventricular ejection fraction has increased to 47% measured in paced rhythm. The improvement in left ventricular function has been attributed to suppression of the incessant ventricular tachycardia.

Hypertrophic cardiomyopathy: evaluation and treatment of patients at high risk for sudden death.

Hypertrophic cardiomyopathy (HCM) is a heritable disease characterized by LV hypertrophy with markedly variable clinical, morphological, and genetic manifestations. It is the most common cause of sudden death in otherwise healthy young individuals. HCM patients often have disabling symptoms and are prone to arrhythmias. Frequently, there is associated LV systolic and diastolic dysfunction, LV outflow obstruction, and myocardial ischemia. Over the past decade, progress has been made in identifying patients who are at high risk for sudden death, in elucidating potential mechanisms of sudden death, and in defining therapeutic algorithms that may improve prognosis. It has also been possible to determine the genetic defect in some of the patients and to correlate clinical findings with the molecular defects. An exciting development has been the use of dual chamber pacemaker as an alternative to cardiac surgery to improve symptoms and relieve LV outflow obstruction.

Newer beta blockers and the treatment of hypertension.

Beta-adrenoceptor blocking agents are established as one of the principal classes of antihypertensive agents. Despite progressive refinements over the years, they still possess some unwanted effects, which limit their considerable value. In recent years a wide range of variations upon the beta-blocker theme has been developed. The full clinical advantages of the newer agents remain to be defined.

Radiofrequency catheter atrioventricular node ablation in patients with permanent cardiac pacing systems.

Following successful RF ablation of the atrioventricular node (AVN), temporary pacing is necessary prior to insertion of a permanent pacemaker. The risks and inconvenience of temporary pacing could be avoided if a permanent pacemaker is already in place. This study reports the feasibility of RF ablation of the AVN in 27 patients (age 55 +/- 17 years, 15 males) with hypertrophic cardiomyopathy and pacemakers. Indications for AVN ablation were drug refractory atrial fibrillation in 24 patients, and rapid AVN conduction preventing septal pre-excitation by DDD pacemaker, inserted for relief of left ventricular outflow obstruction, in three cases. Sixteen patients had DDD devices and 11 patients had VVI devices. During RF ablation, each pacemaker was programmed to VVI at 50 beats/min. The ablation catheter was manipulated with fluoroscopic control to avoid close contact with or disturbance of the pacing leads. In 16 patients, RF ablation was performed immediately following pacemaker implantation but in the remaining patients, the AVN was ablated 6-32 months after pacemaker implantation. The power applied was 25-50 watts for a duration of 15-60 seconds. AV block was achieved in all cases but required 34 +/- 36 applications for 16.5 +/- 17.8 min/case. RF ablation consistently caused reversion to magnet rate in one patient and temporarily inhibited appropriate pacemaker discharge in another. However, no other pacemaker or lead malfunction was detected so that temporary pacing was not required in any case. At 6 +/- 3 months follow-up, all pacemakers were functioning normally without alteration in pacing parameters from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of patients with hypertrophic cardiomyopathy at high risk for sudden death.

Patients with hypertrophic cardiomyopathy are at increased risk for sudden death. Recent studies have improved our ability to risk-stratify such patients and have elucidated several potential mechanisms of sudden death and syncope. Certain noninvasive tests, such as signal-averaged electrocardiography and measurements of cardiac autonomic function and QT/QT dispersion, are often abnormal in hypertrophic cardiomyopathy, but are not useful for risk stratification. Myocardial ischemia determined by exercise thallium scintigraphy, however, identifies young patients with hypertrophic cardiomyopathy who are at high risk for cardiac arrest and syncope. Nonsustained ventricular tachycardia on ambulatory Holter monitoring in the absence of symptoms of impaired consciousness is associated with a benign prognosis and is not predictive of sudden death. Conversely, ventricular tachycardia induced at electrophysiologic study identifies adult patients with hypertrophic cardiomyopathy who subsequently experience sudden death. Finally, characterization of the natural history of the genetic defects will increasingly become an integral part of risk evaluation in hypertrophic cardiomyopathy.

Exchangeable sodium in rats with Goldblatt two-kidney one-clip hypertension.

1. Exchangeable sodium (NaE) was measured serially in rats given a sodium-free diet to eat with sodium chloride solution (85 mmol/l) containing 22Na to drink. 2. After 15 days, nine rats had a left renal artery clip applied; nine had a sham operation. 3. There was no significant difference in NaE between the two groups during the 6 week period after clipping, at the end of which blood pressure was 189 +/- 8 mmHg (mean +/- SEM) in the clipped group and 150 +/- 2 mmHg in the sham-operated group (P less than 0.001). 4. When the clips were removed blood pressure in the hypertensive group fell to 144 +/- 4 mmHg. 5. On the first day after removal of the clip NaE was significantly lower in the clipped group than in the sham-operated group, but there were no significant differences thereafter. 6. Total body sodium (TBNa), measured at death, was consistently higher than NaE by a mean of 1.25 +/- 0.08 mmol, in hypertensive and control rats alike. 7. We conclude that changes in sodium balance are not a necessary accompaniment of of the development of hypertension in this two-kidney one-clip rat model.

Papilloedema and hepatic dysfunction apparently induced by perhexiline maleate (Pexid).

A patient developed papilloedema and hepatic dysfunction while being treated with perhexiline maleate. These later regressed when the drug was withdrawn. Patients should be monitored for these potentially serious side-effects while on this drug.