Faculty Bibliography

This study examines acute effect of dual-chamber (DDD) pacing combined with disopyramide for left ventricular outflow tract (LVOT) gradient reduction in obstructive hypertrophic cardiomyopathy (HCM) patients. Among 24 patients refractory to maximal drug therapy, 7 had a significant improvement of LVOT gradient by DDD pacing alone. In the remaining 17 patients, the LVOT gradient reduction was 26+/-19% after DDD pacing alone and 35+/-16% after intravenous disopyramide alone. In contrast, after the combined therapy of DDD pacing and disopyramide, pressure gradient decreased from 102+/-35 to 28+/-23 mm Hg, a reduction of 72+/-21%. We have demonstrated synergy between DDD pacing and disopyramide for LVOT gradient reduction in obstructive HCM. Study of the long-term effects of this combined therapy would be the next step to ascertain clinical utility.

Electrocardiographic (ECG) abnormalities are common in hypertrophic cardiomyopathy (HC) and have been associated with the distribution of left ventricular hypertrophy and myocardial fibrosis. Such abnormalities may predispose patients to electrophysiologic instability, ventricular arrhythmias, and sudden cardiac death (SCD). We studied 330 patients with HC who were judged clinically to be at high risk for SCD and therefore received automatic implantable cardioverter-defibrillators (ICDs). Surface 12-lead electrocardiograms acquired at the time of ICD implantation were analyzed and the ECG characteristics of patients with appropriate device interventions for ventricular tachycardia and fibrillation were compared to those patients without appropriate device interventions. The 330 patients were followed for 3.7 +/- 3.0 years after implantation and 57 patients (17%) had appropriate discharges. No differences in the ECG characteristics of patients with and without appropriate device interventions were identified. Markedly increased ECG voltages, QRS duration, left or rightward QRS axis, abnormal Q waves, and QTc or QT dispersion were not associated with appropriate ICD discharge. Conversely, normal electrocardiograms and electrocardiograms normal except for a repolarization abnormality in only 1 anatomic distribution were not associated with freedom from ICD discharge. Moreover, no combination of ECG variables was associated with the likelihood of an appropriate ICD discharge. In conclusion, in a cohort of patients with HC selected because of their high risk for SCD, 12-lead surface electrocardiogram did not predict subsequent appropriate ICD intervention for ventricular tachyarrhythmias and was not useful in risk stratification for sudden death.

The implantable cardioverter-defibrillator (ICD) therapy is an established intervention for the prevention of sudden cardiac death (SCD) in patients with significant left ventricular dysfunction. Multiple randomized clinical trials have studied the use of ICD for the primary and secondary SCD. These studies were performed in patients with left ventricular dysfunction from coronary artery disease or dilated cardiomyopathy, and the marker of reduced ejection fraction has emerged for selecting patients who would benefit from ICD therapy. Currently, for most of these patients the decision to implant, or not, is determined by relatively straightforward paradigms. The same cannot be said for the genetic cardiac diseases associated with SCD--long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular dysplasia. Indications for ICD in these conditions are very much a work-in-progress.

Arrhythmogenic right ventricular dysplasia (ARVD), also known as arrhythmogenic right ventricular cardiomyopathy, is a genetic cause for sudden cardiac arrest. In ARVD, there is progressive replacement of normal myocytes, with fat and fibrous tissue, predominantly in the right ventricle that predisposes the individual to arrhythmias. Patients who are identified with this condition are risk stratified; those at high risk are recommended to have implanted cardioverter defibrillators.

Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. While these events are relatively few compared to other cardiac deaths, they are tragic in that death occurs in a young, otherwise healthy person. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. As a result of growing awareness that these deaths can be prevented, guidelines have been issued in both Europe and the United States to help screen and determine qualification for young persons who want to participate in competitive athletics. There remains debate on the how extensive screening should be, in particular over the use of the 12-lead electrocardiogram (ECG), with European guidelines mandating ECG and United States guidelines not recommending routine use of the ECG.

Brugada syndrome is a genetic cause of sudden cardiac arrest characterized by abnormal electrocardiographic (ECG) pattern in the right precordial leads either at rest or after provocation. In this condition, sudden death may occur due to polymorphic ventricular tachycardia or ventricular fibrillation. In approximately 30% of patients, sudden cardiac arrest is the initial clinical manifestation of Brugada syndrome. Treatment strategies for Brugada syndrome are evolving. Currently, the implanted cardioverter defibrillator (ICD) is the only proven treatment for Brugada syndrome. Candidates for ICD include patients include those with the type 1 ECG pattern or who have been successfully resuscitated from sudden death or have had unexplained syncope.

Congenital long QT syndrome is a genetic disorder characterized by prolonged QT interval on electrocardiogram and increased risk of sudden cardiac death from ventricular arrhythmias. In long QT syndrome, genes that encode for the various cardiac ion channels or regulatory proteins of these channels are mutated. The various mutations individually lead to a disruption of the normal cardiac myocyte action potential, and thus leading to a propensity for ventricular arrhythmias. Diagnosis can be difficult with patient presentations ranging from palpitations to syncope to sudden cardiac death. The QT interval can also vary over time, often requiring further testing to support the diagnosis. Recently developed genetic testing can be used to identify the responsible genes in patients with known disease. It can also be used to genotype the affected patient's family members. The current test panel only recognizes common mutations resulting in a falsely negative test for those with a rare or unidentified variant. For treatment, beta-blocker therapy is recommended for all patients, and implantable cardioverter-defibrillator (ICD) placement is recommended for those who are at high risk for a cardiac event. Future investigations will concentrate genotype-guided risk stratification for ICD placement and on genotype-specific pharmacological therapy.

BACKGROUND: We analyzed the clinical and quantitative echocardiographic characteristics of patients with sub-basal hypertrophic cardiomyopathy (HCM) to define the characteristics of patients (pts) with severe symptoms. METHODS: Of 444 pts in a referral-based HCM program, 22 (5%) had midventricular or apical HCM. Quality of life (QoL) questionnaire was administered as an independent confirmer of symptomatic state. RESULTS: Ten pts were NYHA III and IV, and 12 pts were NYHA I and II; QoL scores (41 +/- 26 vs. 10 +/- 13, P = 0.001) confirmed a priori division of two groups based on NYHA classification. Pts with more severe symptoms were more likely female (70% vs. 25%, P = 0.001) with atrial fibrillation (40% vs. 0%, P = 0.02). They more frequently had midventricular HCM 60% versus 8% (P = 0.01) (mid-LV thickness 17 +/- 6 vs. 12 +/- 2 mm, P = 0.03) and had much smaller LV diastolic volumes 68 +/- 12 versus 102 +/- 22 ml (39 +/- 4 vs. 53 +/- 12 ml/m(2), P = 0.001). Septal E/E' was higher in the severely symptomatic pts (15 +/- 5 vs. 7 +/- 3, P = 0.001) indicating higher estimated LV filling pressure. Midobstruction with apical akinetic chamber was noted in 4/10 pts who developed refractory symptoms. Cardiac mortality was higher in the severely symptomatic patients, 4/10 who had midventricular HCM as compared to 0/12 in the mildly symptomatic apical HCM group (P = 0.03). CONCLUSIONS: In subbasal HCM, pts with severe symptoms have midventricular hypertrophy, with encroachment of the LV cavity and consequent very small LV volumes that may be complicated by mid-LV obstruction. Pts with mid-LV hypertrophy are more symptomatic than those with apical HCM, are often refractory to therapy, and have higher mortality.

The shape of Doppler velocity tracings in obstructive hypertrophic cardiomyopathy offers insights into its pathophysiology. Inflection points are the points on a curve where its shape changes from concave to convex, or vice versa. These dynamic systolic abnormalities are caused: 1) by the amplifying nature of the obstruction; and 2) by the adverse effect of the sudden imposition of afterload in midsystole. The midsystolic drop in left ventricular ejection velocities and the premature termination of longitudinal shortening are compelling evidence of the deleterious mechanical effect of obstruction on the ventricle. This dynamic systolic dysfunction, demonstrated on the Doppler curves, may contribute to heart failure symptoms and adverse outcome. In outflow obstruction, these abnormalities normalize after abolition of gradient. Therefore, their detection in an individual patient confirms obstruction as a therapeutic target.