Edward Rowland

Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families

AIMS At least 4% of sudden deaths are unexplained at autopsy [sudden arrhythmic death syndrome (SADS)] and a quarter may be due to inherited cardiac disease. We hypothesized that comprehensive clinical investigation of SADS families would identify more susceptible individuals and causes of death. METHODS AND RESULTS Fifty seven consecutively referred families with SADS death underwent evaluation including resting 12 lead, 24 h and exercise ECG and 2D echocardiography. Other investigations included signal averaged ECG, ajmaline testing, cardiac magnetic resonance imaging, and mutation analysis. First-degree relatives [184/262 (70%)] underwent evaluation, 13 (7%) reporting unexplained syncope. Seventeen (30%) families had a history of additional unexplained premature sudden death(s). Thirty families (53%) were diagnosed with inheritable heart disease: 13 definite long QT syndrome (LQTS), three possible/probable LQTS, five Brugada syndrome, five arrhythmogenic right ventricular cardiomyopathy (ARVC), and four other cardiomyopathies. One SCN5A and four KCNH2 mutations (38%) were identified in 13 definite LQTS families, one SCN5A mutation (20%) in five Brugada syndrome families and one (25%) PKP2 (plakophyllin2) mutation in four ARVC families. CONCLUSION Over half of SADS deaths were likely to be due to inherited heart disease; accurate identification is vital for appropriate prophylaxis amongst relatives who should undergo comprehensive cardiological evaluation, guided and confirmed by mutation analysis.

Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria.

OBJECTIVES We sought to ascertain the prevalence and mode of expression of familial disease in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). BACKGROUND Autosomal-dominant inheritance is recognized in ARVC. The prevalence and mode of expression of familial disease in consecutive, unselected families is uncertain. METHODS First- and second-degree relatives of 67 ARVC index patients underwent cardiac evaluation with history and examination, 12-lead and signal-averaged electrocardiogram (ECG), two-dimensional and Doppler echocardiography, metabolic exercise testing and Holter monitoring. Diagnoses were made in accordance with published criteria. RESULTS Of 298 relatives, 29 (10%; mean age 37.4 +/- 16.4 years) had ARVC. These were from 19 of the 67 families, representing familial involvement in 28%. Of these affected relatives, 72% were asymptomatic, 17% had ventricular tachycardia (sustained VT 10%, nonsustained VT 7%) and 21% had left ventricular involvement. A further 32 relatives (11%; 37.7 +/- 12.4 years) exhibited nondiagnostic ECG, echocardiographic or Holter abnormalities. Fifteen of these relatives were from families with only the proband affected, and inclusion of this subset of relatives would have resulted in familial ARVC in 48% of index cases. Four additional relatives (1% to 3%) fulfilled diagnostic criteria for dilated cardiomyopathy without any features of right ventricular disease. CONCLUSIONS By using current diagnostic criteria, familial disease was present in 28% of index patients. A further 11% of their relatives had minor cardiac abnormalities, which, in the context of a disease whose mode of inheritance is autosomal dominant, are likely to represent early or mild disease expression. We advocate that the current ARVC diagnostic criteria are modified to reflect the broader spectrum of disease that is observed in family members.

Side effects of long-term amiodarone therapy.

Although amiodarone is an effective antiarrhythmic agent, long-term therapy may be associated with unwanted effects. We report our experience in 140 patients treated over 5 years. Important effects were seen particularly in the thyroid gland, liver, lung and skin. Some of these effects are dose-dependent and others may be related to the chemical structure and metabolism of amiodarone. Corneal microdeposits were always found when sought, but did not cause impairment of visual acuity.

Echocardiographic measurement of the normal adult right ventricle.

In studies of the right ventricle the complexities of chamber shape may be overcome by use of multiple tomographic imaging planes. An established protocol for the echocardiographic description of the heart was used to examine the right ventricle in an ordered series of transducer locations and orientations. Diastolic measurements were made of the right ventricular inflow tract, outflow tract, and right ventricular body, and the range and reproducibility of normal values for cavity size and right ventricular free wall thickness were established. These measurements of cavity size in 41 normal subjects were highly reproducible and the views that were used correctly described the truncated and ellipsoidal shape of the right ventricular inflow tract and body with a separately aligned outflow tract. Cavity trabeculation prevented measurement of the free wall thickness in some areas; however, values of nearly twice the previously reported upper limit of normal for anterior regions were measured from the apex or lateral right ventricular wall. These normal data provide a basis for future echocardiographic studies of the right ventricle.

Efficacy and tolerability of transvenous low energy cardioversion of paroxysmal atrial fibrillation in humans

OBJECTIVES This study investigated the efficacy and tolerability of low energy shocks for termination of atrial fibrillation in patients, using an endocardial electrode configuration that embraced both atria. BACKGROUND In animals, low energy biphasic shocks delivered between electrodes in the coronary sinus and right atrium have effectively terminated atrial fibrillation. If human defibrillation thresholds are sufficiently low, atrial defibrillation could be achieved in conscious patients using an implanted device. METHODS Twenty-two consecutive patients with stable atrial fibrillation were studied during electrophysiologic testing. Biphasic R wave synchronous shocks were delivered between large surface area electrodes in the coronary sinus and high right atrium, using a step-up voltage protocol starting at 10 or 20 V and increasing to a maximum of 400 V. Patients were conscious at the start of the study and were asked to report on symptoms but were sedated later if shocks were not tolerated. RESULTS Cardioversion was achieved in all 19 patients who completed the study, with a mean (+/- SD) leading-edge voltage of 237 +/- 55 V (range 140 to 340) and mean energy of 2.16 +/- 1.02 J (range 0.7 to 4.4). The mean maximal shock delivered without sedation was 116 +/- 51 V (range 60 to 180). No proarrhythmia or mechanical complications occurred. CONCLUSIONS The delivery of biphasic R wave synchronous shocks between the high right atrium and coronary sinus can terminate atrial fibrillation with very low energies. General anaesthesia is not required, and a minority of fully conscious patients are able to tolerate this method of cardioversion.

Novel Mutation in Desmoplakin Causes Arrhythmogenic Left Ventricular Cardiomyopathy

Background—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities of the right ventricle (RV). Several disease loci have been identified. Mutations in desmoplakin have recently been isolated in both autosomal-dominant and autosomal-recessive forms of ARVC. Primary left ventricular (LV) variants of the disease are increasingly recognized. We report on a large family with autosomal-dominant left-sided ARVC. Methods and Results—The proband presented with sudden cardiac death and fibrofatty replacement of the LV myocardium. The family was evaluated. Diagnosis was based on modified diagnostic criteria for ARVC. Seven had inferior and/or lateral T-wave inversion on ECG, LV dilatation, and ventricular arrhythmia, predominantly extrasystoles of LV origin. Three had sustained ventricular tachycardia; 7 had late potentials on signal-averaged ECG. Cardiovascular magnetic resonance imaging in 4 patients revealed wall-motion abnormalities of the RV and patchy, late gadolinium enhancement in the LV, suggestive of fibrosis. Linkage confirmed cosegregation to the desmoplakin intragenic marker D6S2975. A heterozygous, single adenine insertion (2034insA) in the desmoplakin gene was identified in affected individuals only. A frameshift introducing a premature stop codon with truncation of the rod and carboxy terminus of desmoplakin was confirmed by Western blot analysis. Conclusions—We have described a new dominant mutation in desmoplakin that causes left-sided ARVC, with arrhythmias of LV origin, lateral T-wave inversion, and late gadolinium enhancement in the LV on magnetic resonance images. Truncation of the carboxy terminus of desmoplakin and consequent disruption of intermediate filament binding may account for the predominant LV phenotype.

Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy.

OBJECTIVES The aim of this study was to evaluate the survival of patients with hypertrophic cardiomyopathy (HCM) after resuscitated ventricular fibrillation or syncopal sustained ventricular tachycardia (VT/VF) when treated with low dose amiodarone or implantable cardioverter defibrillators (ICDs). BACKGROUND Prospective data on clinical outcome in patients with HCM who survive a cardiac arrest are limited, but studies conducted before the widespread use of amiodarone and/or ICD therapy suggest that over a third die within seven years from sudden cardiac death or progressive heart failure. METHODS Sixteen HCM patients with a history of VT/VF (nine male, age at VT/VF 19 +/- 8 years [range 10 to 36]) were studied. Syncopal sustained ventricular tachycardia/ventricular fibrillation occurred during or immediately after exertion in eight patients and was the initial presentation in eight. One patient had disabling neurologic deficit after VT/VF. Before VT/VF, two patients had angina, four had syncope and six had a family history of premature sudden cardiac death. After VT/VF all patients were in New York Heart Association class I or II, three had nonsustained VT during ambulatory electrocardiography and 11 had an abnormal exercise blood pressure response. After VT/VF eight patients were treated with low dose amiodarone and six received an ICD. Prophylactic therapy was declined by two patients. RESULTS Mean follow-up was 6.1 +/- 4.0 years (range 0.5 to 14.5). Cumulative survival (death or ICD discharge) for the entire cohort was 59% at five years (95% confidence interval: 33% to 84%). Thirteen (81%) patients were alive at last follow-up. Two patients died suddenly while taking low dose amiodarone, and one died due to neurologic complications of his initial cardiac arrest. Three patients had one or more appropriate ICD discharges during follow-up; the times to first shock after ICD implantation were 23, 197 and 1,124 days. CONCLUSIONS This study shows that patients with HCM who survive an episode of VT/VF remain at risk for a recurrent event. Implantable cardioverter defibrillator therapy appears to offer the best potential benefit regarding outcome.

PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible atrial fibrillation patients: results from the European PLAATO study

The European PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) study was performed to determine the safety and efficacy of left atrial appendage occlusion by catheter technique. Embolic stroke due to atrial fibrillation is a common observation, especially in the elderly. Most thrombi in atrial fibrillation form in the left atrial appendage (LAA), its occlusion may therefore reduce the incidence of stroke in these patients.

Amiodarone for long-term management of patients with hypertrophic cardiomyopathy.

Fifty-three patients with hypertrophic cardiomyopathy who had serious arrhythmias (45 patients), refractory chest pain (5 patients) or a high risk of sudden death (3 patients) received amiodarone for 6 to 96 months (median 18) after completion of a loading and an initial maintenance period. The dose of amiodarone was altered by 50 to 200 mg/day at 3- to 6-month intervals, guided by electrocardiographic monitoring, plasma drug level measurements and side-effect questionnaires. Ventricular tachycardia was suppressed in 24 patients (92%) with doses of 100 to 400 mg/day (median 300); none died suddenly during a mean follow-up of 27 months. Although symptomatic episodes of frequent or prolonged supraventricular tachycardia or paroxysmal atrial fibrillation/flutter were abolished in 8 of 9 patients on 100 to 600 mg/day (median 300), in 1 patient incessant atrial flutter developed that was relatively refractory to direct-current cardioversion. In 11 patients with atrial fibrillation, sinus rhythm was restored in 7 (after direct-current cardioversion in 3) with doses of 100 to 600 mg/day (median 300) and has been maintained in 5 with associated improvement in symptoms. Despite discontinuation of beta-blocker therapy, chest pain was unchanged in 17 patients, was impaired in 11 and was worse in only 2. Amiodarone was discontinued in 3 patients; in 1 because of hair loss, in 1 because of neurologic symptoms and in 1 because of facial discoloration; in the latter 2 patients, amiodarone was restarted after 1 and 14 months, and was tolerated and effective at the lower dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

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.