David M. Gilligan

A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy

OBJECTIVESnThe aim of this study was to determine whether therapy with a beta-adrenergic or calcium channel blocking agent can improve the functional capacity and quality of life of patients with mild or moderately symptomatic hypertrophic cardiomyopathy.nnnBACKGROUNDnBoth beta-blockers and calcium channel blockers may alleviate symptoms in hypertrophic cardiomyopathy, but previous studies have been performed in hospitalized patients or have been open studies without control subjects.nnnMETHODSnA randomized, double-blind crossover trial of nadolol, verapamil and placebo, administered for periods of 4 weeks each, was performed in 18 patients with mild or moderately symptomatic hypertrophic cardiomyopathy (10 men, 8 women; mean age +/- SD 39 +/- 17 years). A detailed symptom assessment, bicycle exercise testing, echocardiography and Holter monitoring were performed in each period.nnnRESULTSnTwo patients withdrew from the study owing to symptomatic sinus bradycardia during nadolol therapy. Neither drug improved maximal oxygen consumption (placebo 26 +/- 8, verapamil 23 +/- 6, nadolol 21 +/- 7 ml/kg per min; p = 0.1). Peak exercise work load was reduced by > or = 10 W in 13 patients (81%) during nadolol therapy and in 4 patients (25%) during verapamil therapy (p = 0.005, nadolol vs. verapamil). Despite the effects on exercise capacity, 13 patients (81%) preferred drug treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001). Verapamil improved reported performance at work compared with nadolol (p = 0.01) and tended to improve other measures of health-related behavior and symptoms compared with nadolol and placebo.nnnCONCLUSIONSnIn patients with mild or moderately symptomatic hypertrophic cardiomyopathy, exercise capacity was not improved by nadolol or verapamil, and individuals were more often impaired by nadolol than with verapamil. Nevertheless, many patients derived symptomatic benefit from drug therapy, especially with verapamil.

Investigation of a hemodynamic basis for syncope in hypertrophic cardiomyopathy. Use of a head-up tilt test.

BackgroundSyncope and sudden death in hypertrophic cardiomyopathy may have a hemodynamic basis. The presence of a small ventricular cavity with high intracavity pressures may activate left ventricular baroreceptors and cause reflex hypotension as described in other populations with syncope. Methods and ResultsTo investigate this potential mechanism of syncope in hypertrophic cardiomyopathy, we studied 17 patients with a history of syncope (syncopal), 19 without syncope (nonsyncopal), and nine normal control subjects by using a head-up tilt test. Head-up tilt at 60° for 45 minutes was followed by 10-minute tilts during incremental doses of isoprenaline. Heart rate, blood pressure, and twodimensional and Doppler echocardiography were monitored throughout. On tilting, hypertrophic cardiomyopathy patients showed a decline in mean arterial pressure of −5±6 mm Hg (p<0.001) compared with no change in control subjects (0.2±6 mm Hg, p=0.9). Left ventricular outflow tract velocity decreased on tilting in control subjects (−8±6 cm/sec, p=0.004) but increased in the syncopal and nonsyncopal patients (20±50 cm/sec, p=0.05). Reflex hypotension with or without bradycardia, associated with syncope or presyncope, was induced in seven syncopal patients, two nonsyncopal patients, and two control subjects (p=0.05). The early response to tilt in these subjects was characterized by maintenance of blood pressure but a greater increase in left ventricular fractional shortening than in the other subjects (10±8% versus 1±1%, p=0.002). The onset of hypotension was associated with a trend toward further decreases in left ventricular diameters, outflow tract velocity, and transmitral flow velocities. In the remaining patients who had a negative test, transient hypotension (systolic pressure <100 mm Hg) occurred in seven syncopal patients and three nonsyncopal patients compared with none of the control subjects (p=0.01). In total, hypotension was demonstrated in 82% of syncopal patients compared with 26% of nonsyncopal patients and 22% of control subjects (p=0.001). ConclusionsPatients with hypertrophic cardiomyopathy and a history of syncope frequently display hypotension during head-up tilt. In some cases, sudden hypotension occurs and is usually associated with bradycardia and a reduced cavity size, findings compatible with activation of a ventricular baroreflex. In other cases, transient hypotension occurs and could be explained by an impairment of baroreceptor function. These mechanisms may contribute to the occurrence of syncope in daily life.

Amiodarone reduces QT dispersion in patients with hypertrophic cardiomyopathy

To compare QT interlead variability (dispersion) in patients who receive a class III antiarrhythmic with those not on antiarrhythmic therapy, we measured QT in all 12 leads of a standard ECG in 24 patients with hypertrophic cardiomyopathy, 12 (50%) of whom were on amiodarone monotherapy and 12 (50%) who were not on amiodarone or other cardioactive medication which could affect QT. Age, functional class, chamber dimension or the degree of left ventricular hypertrophy expressed by maximal wall thickness (21 +/- 5 vs 20 +/- 4 mm; p = NS) was not different between the amiodarone and the non-amiodarone group. Maximal corrected QT (QTc) was greater in patients receiving (488 +/- 25 ms) compared to those not receiving amiodarone (451 +/- 23 ms) (p less than 0.001). However, QTc dispersion defined as the difference of maximum minus minimum QTc was decreased in the amiodarone (48 +/- 10 ms) compared to the non-amiodarone group (78 +/- 17 ms) (p less than 0.001). We conclude that in patients with hypertrophic cardiomyopathy, amiodarone prolongs QTc but reduces QTc dispersion. These results agree with expected changes in ventricular recovery time in patients who receive Class III antiarrhythmic agents and provide further support to the theory that QTc dispersion reflects regional differences in ventricular recovery time.

Effects of a meal on hemodynamic function at rest and during exercise in patients with hypertrophic cardiomyopathy

Many patients with hypertrophic cardiomyopathy experience postprandial exacerbation of their symptoms. The vasodilation associated with eating may be deleterious in hypertrophic cardiomyopathy, especially during exercise. To examine the hemodynamic effects of a meal in hypertrophic cardiomyopathy, 11 patients were studied with invasive hemodynamic monitoring during exercise testing in the fasting state and 45 min after a 740 kcal (3,100 J) meal. The meal induced a decrease in systemic vascular resistance index at rest (mean +/- SD, -17 +/- 14%), increases in mean right atrial (31 +/- 21%), mean pulmonary artery (14 +/- 14%) and mean pulmonary capillary wedge (17 +/- 14%) pressures and an increase in cardiac index (18 +/- 10%) due to an increased heart rate without any significant change in stroke volume. During postprandial exercise, heart rate, rate-pressure product, cardiac index and cardiac filling pressures were higher than during fasting exercise and one patient had a decrease in exercise blood pressure compared with the fasting test. Five patients with postprandial exacerbation of symptoms in everyday life had a lesser increase in systemic arterial pressure and stroke volume during both exercise tests and a smaller increase in cardiac index after the meal than did the six patients without postprandial symptom exacerbation, suggesting more severe cardiac disease. It is concluded that patients with hypertrophic cardiomyopathy have an abnormal hemodynamic response to food, in which stroke volume fails to increase and pulmonary capillary wedge and pulmonary artery pressures increase. These adverse changes persist during postprandial exercise and may predispose to exertional collapse in certain patients.

Adrenergic hypersensitivity after beta-blocker withdrawal in hypertrophic cardiomyopathy

Withdrawal of beta-blocker therapy has been associated with the development of adrenergic hypersensitivity and adverse clinical effects in patients with coronary artery disease and hypertension. The aim of this study was to establish the occurrence and clinical significance of adrenergic hypersensitivity after abrupt withdrawal of long-term beta blockade in hypertrophic cardiomyopathy. Beta-adrenergic sensitivity was measured using the isoprenaline chronotropic dose25. Symptom assessment chronotropic dose25 calculation, bicycle exercise, echocardiography and Holter monitoring were performed while the patient received beta-blocker therapy and repeated on days 2, 4, 6, 8 (acute withdrawal period) and on day 21 after abrupt withdrawal. The study was terminated after 7 patients had been studied because all patients experienced a marked deterioration in symptoms and several clinical events had occurred. The chronotropic dose25 (mean +/- standard deviation) demonstrated beta 1-adrenergic hypersensitivity with a minimal value of 1.6 +/- 0.8 micrograms during the acute withdrawal period compared with 3.8 +/- 1.7 micrograms on day 21 (p = 0.003). Heart rates during rest and exercise showed an overshoot increase during the acute withdrawal period. The maximal 24-hour ventricular ectopic count was higher during the acute withdrawal period than during day 21 (p = 0.04). Of 3 patients with inducible outflow tract gradients, 2 developed resting gradients greater than 30 mm Hg during the acute withdrawal period. There was an increase in peak late filling velocity of mitral inflow after beta-blocker withdrawal. In conclusion, transient beta-adrenergic hypersensitivity occurs after beta-blocker withdrawal in hypertrophic cardiomyopathy and is associated with significant physiologic changes and adverse clinical consequences.

Sudden death due to ventricular tachycardia during amiodarone therapy in familial hypertrophic cardiomyopathy

Abstract The potential modes of sudden death in hypertrophic cardiomyopathy (HC) can be broadly divided into those in which arrhythmia is the primary cause and those in which initial hemodynamic deterioration or ischemia are followed by secondary arrhythmia. Fortuitous electrocardiographic monitoring at the time of cardiac arrest may elucidate the mechanism responsible in individual patients and improve our understanding of sudden death in this condition. We report on 1 patient from a family with HC who died suddenly during amiodarone therapy and who was wearing a Holter monitor at the time of death. Death was due to primary ventricular tachycardia progressing to ventricular fibrillation.

Effect of preload change on resting and exercise cardiac performance in hypertrophic cardiomyopathy

The purpose of this study was to investigate the hemodynamic responses, at rest and on exercise, of patients with hypertrophic cardiomyopathy to changes in circulating volume. After Swan-Ganz and radial arterial cannulation, 13 patients with hypertrophic cardiomyopathy performed maximal exercise tests after diuretic (frusemide 20 mg intravenously) and after fluid loading (0.9% saline at 10 ml/kg body weight intravenously) on different days. At rest, right atrial and pulmonary capillary wedge pressures increased with volume loading and decreased with a diuretic. There were no significant changes in the resting, supine cardiac or stroke indexes but in the upright position, the cardiac index and stroke index were higher after volume loading (2.5 +/- 0.7 vs 2.2 +/- 0.5 liters/min/m2, p less than 0.05; 33 +/- 11 vs 27 +/- 9 ml/m2, p less than 0.005, respectively). Although the right atrial, pulmonary arterial and pulmonary capillary wedge pressures were higher during exercise after volume loading, there were no significant differences in exercise heart rate, systemic blood pressure, cardiac index, stroke index, systemic vascular resistance index or overall exercise capacity compared to exercise after diuresis. The data show that the cardiac index and stroke index, at supine rest and during upright exercise, were not influenced by the preload changes induced in these patients with hypertrophic cardiomyopathy. The results suggest that these patients are operating on the plateau of left ventricular Frank-Starling function (filling pressure/output) curve.

Cardiac responses assessed by echocardiography to changes in preload in hypertrophic cardiomyopathy

Abstract The features of a small left ventricle with diastolic dysfunction and variable left ventricular outflow tract obstruction 1 suggest that cardiac function in hypertrophic cardiomyopathy (HC) may be particularly sensitive to change in preload. However, there is little information concerning clinically relevant fluid manipulation in HC. We have previously shown that stroke volume, at supine rest and during upright exercise, did not change despite significant changes in preload, indicating that patients with HC were functioning on the plateau of the Frank-Starling curve. 2 The current study extends these observations by examining the effect of the same fluid manipulations on 2-dimensional and Doppler echocardiography measurements of cardiac function in patients with HC compared with normal subjects.

Influence of left ventricular hypertrophy and function on the occurrence of ventricular tachycardia in hypertrophic cardiomyopathy

Sixty-nine patients with hypertrophic cardiomyopathy were studied by 2-dimensional and Doppler echocardiography and 72-hour Holter monitoring to examine the relation between the degree of left ventricular (LV) hypertrophy and dysfunction and the occurrence of ventricular tachycardia (VT). Episodes of nonsustained VT were detected in 20 patients (29%). Maximal wall thickness was not different between patients with (22 +/- 5 mm) and without (21 +/- 5 mm) VT. Total hypertrophy score, calculated as the sum of 10 segmental wall thicknesses, was also similar in both groups (157 +/- 22 and 153 +/- 32 mm, respectively; p = not significant). Furthermore, no significant differences were found between the 2 groups in LV end-diastolic dimension (41 +/- 7 vs 40 +/- 6 mm), fractional shortening (33 +/- 7 vs 34 +/- 10%) and left atrial size (40 +/- 10 vs 41 +/- 11 mm). An LV outflow tract gradient was detected in 25% of patients with and 35% without VT (p = not significant). One or more Doppler indexes of diastolic function were abnormal in 70% of patients, but no difference in any of these indexes was found between those with and without VT. In summary, the occurrence of VT in hypertrophic cardiomyopathy is not related to the degree of LV hypertrophy, outflow tract gradient or dysfunction. This finding suggests a dissociation between the arrhythmogenic substrate and echocardiographic features of the disease.

Intraventricular Systolic Flow Mapping in Hypertrophic Cardiomyopathy

Ninety‐two consecutive patients with hypertrophic cardiomyopathy were studied with pulsed and continuous‐wave Doppler and color flow imaging to assess the intraventricular systolic flow profile from apex to base and compare it with that obtained in normals and in patients with aortic stenosis and systemic hypertension. Hypertrophic cardiomyopathy patients had higher intraventricular blood flow velocities (cm/sec) from apex to base compared with normals and aortic stenosis and systemic hypertension patients (apex: 41.5 ± 17.3 vs 24 ± 1.9,26.1 ± 2.9, and 26.4 ± 3.3; papillary muscles: 95.4 ± 66.5 vs 41.9 ± 4.9, 46.2 ± 3.4, and 46.4 ± 5.7; outflow tract: 249.3 ± 176.2 vs 66.9 ± 8.4, 64.1 ± 10.8, and 66 ± 9.5, respectively) (P < 0.001). Eighty‐six (93%) hypertrophic cardiomyopathy patients showed an abnormal intraventricular systolic color flow pattern at one or more sites but none of the patients with aortic stenosis or systemic hypertension or normal controls. Of those, 65 (71%) showed one or more variant (mosaic) flow, all of whom had intraventricular gradients, while 75 showed abnormal aliased flow at a site other than the subaortic area. It is concluded that patients with hypertrophic cardiomyopathy often exhibit an abnormal spatial distribution of the intraventricular systolic flow velocity profile compared with normals and patients with secondary forms of ventricular hypertrophy that can readily be recognized with color flow imaging. This could improve the sometimes difficult separation of hypertrophic cardiomyopathy patients from secondary hypertrophy.