Carla Giustetto

Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG

Background—Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results—Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. Conclusions—We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Short QT Syndrome: a familial cause of sudden death.

Background—A prolonged QT interval is associated with a risk for life-threatening events. However, little is known about prognostic implications of the reverse—a short QT interval. Several members of 2 different families were referred for syncope, palpitations, and resuscitated cardiac arrest in the presence of a positive family history for sudden cardiac death. Autopsy did not reveal any structural heart disease. All patients had a constantly and uniformly short QT interval at ECG. Methods and Results—Six patients from both families were submitted to extensive noninvasive and invasive work-up, including serial resting ECGs, echocardiogram, cardiac MRI, exercise testing, Holter ECG, and signal-averaged ECG. Four of 6 patients underwent electrophysiological evaluation including programmed ventricular stimulation. In all subjects, a structural heart disease was excluded. At baseline ECG, all patients exhibited a QT interval ≤280 ms (QTc ≤300 ms). During electrophysiological study, short atrial and ventricular refractory periods were documented in all and increased ventricular vulnerability to fibrillation in 3 of 4 patients. Conclusions—The short QT syndrome is characterized by familial sudden death, short refractory periods, and inducible ventricular fibrillation. It is important to recognize this ECG pattern because it is related to a high risk of sudden death in young, otherwise healthy subjects.

Long-Term Prognosis of Patients Diagnosed With Brugada Syndrome Results From the FINGER Brugada Syndrome Registry

Background— Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. Methods and Results— Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. Conclusions— In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.

Long-term follow-up of patients with short QT syndrome.

OBJECTIVES The aim of this study was to investigate the clinical characteristics and the long-term course of a large cohort of patients with short QT syndrome (SQTS). BACKGROUND SQTS is a rare channelopathy characterized by an increased risk of sudden death. Data on the long-term outcome of SQTS patients are not available. METHODS Fifty-three patients from the European Short QT Registry (75% males; median age: 26 years) were followed up for 64 ± 27 months. RESULTS A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an implantable cardioverter defibrillator, and 12 patients received long-term prophylaxis with hydroquinidine (HQ), which was effective in preventing the induction of ventricular arrhythmias. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2 already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1 had syncope. Nonsustained polymorphic ventricular tachycardia was recorded in 3 patients. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events occurred in patients receiving HQ. CONCLUSIONS SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up.

Long-Term Clinical Results of 2 Different Ablation Strategies in Patients With Paroxysmal and Persistent Atrial Fibrillation

Background—Data regarding the long-term efficacy of atrial fibrillation (AF) ablation are still lacking. Methods and Results—Two hundred four consecutive patients symptomatic for paroxysmal or persistent/permanent AF were randomly assigned to 2 different ablation schemes: pulmonary vein isolation (PVI) and PVI plus left linear lesions (LL). Primary end point was to assess the maintenance of sinus rhythm (SR) after procedures 1 and 2 in the absence of antiarrhythmic drugs in a long-term follow-up of at least 3 years. Paroxysmal AF—With a single procedure at 12-month follow-up, 46% of patients treated with PVI maintained SR, whereas at 3-year follow-up, 29% were in SR; using the “PVI plus LL” at the 12-month follow-up, 57% of patients were in SR, whereas at the 3-year follow-up, 53% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 62% with PVI and 85% with PVI plus LL. Persistent/Permanent AF—With a single procedure at the 12-month follow-up, 27% of patients treated with PVI were in SR, whereas at the 3-year follow-up, 19% maintained SR; using the PVI plus LL with a single procedure at the 12-month follow-up 45% of patients were in SR, whereas at the 3-year follow-up, 41% remained in SR. After a second procedure, the long-term overall success rate without antiarrhythmic drugs was 39% with PVI and 75% with PVI plus LL. Conclusions—A long-term follow-up of AF ablation shows that short-term results cannot be considered permanent because AF recurrences are still present after the first year especially in patients who have had “PVI” strategy. PVI isolation plus LL is superior to the PVI strategy in maintaining SR without antiarrhythmic drugs after procedures 1 and 2 both in paroxysmal and persistent AF.

Long-term follow-up of right ventricular monomorphic extrasystoles.

OBJECTIVES The purpose of this study was to verify in a long-term follow-up whether frequent monomorphic right ventricle extrasystoles may progress to arrhythmogenic right ventricular dysplasia (ARVD). BACKGROUND Frequent monomorphic right ventricle extrasystoles are generally considered benign. However, in patients with this pattern, cardiac magnetic resonance (MR) has recently shown anatomical and functional abnormalities of the right ventricle. METHODS Sixty-one patients who had been classified by noninvasive examinations as having frequent idiopathic right ventricle ectopy were contacted after 15 +/- 2 years (12 to 20) and submitted to clinical examination, electrocardiogram (ECG), Holter monitoring, stress test, signal averaged ECG, echocardiography and, in 11 patients, cardiac MR. The primary end point was to ascertain the presence of cases of sudden death or progression to ARVD. RESULTS At the end of the follow-up, 55 patients were alive; six died, none of sudden death; eight stated to be well but refused further examinations. The 47 patients examined had normal ECG; in 24 patients (51%), extrasystoles were no longer present at Holter monitoring; late potentials were present in up to 15% of the patients; the right ventricle was normal at echocardiography. In 8 of 11 patients (73%), cardiac MR showed focal fatty replacement and other abnormalities of the right ventricle. CONCLUSIONS In this long-term follow-up study, no patient died of sudden death nor developed ARVD; two-thirds of the patients were asymptomatic, and, in half of the patients, ectopy had disappeared. Focal fatty replacement in the right ventricle was present in most.

Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach

Aims Risk stratification in individuals with type 1 Brugada electrocardiogram (ECG) pattern (type 1 ECG) for primary prevention of sudden death (SD). Methods and results Three hundred and twenty patients (258 males, median age 43 years) with type 1 ECG were enrolled. No patient had previous cardiac arrest. Fifty-four per cent of patients had a spontaneous and 46% a drug-induced type 1 ECG. One-third had syncope, two-thirds were asymptomatic. Two hundred and forty-five patients underwent electrophysiologic study (EPS) and 110 patients received an implantable cardiac defibrillator (ICD). During follow-up [median length 40 months (IQ20-67)], 17 patients had major arrhythmic events (MAE) (14 resuscitated ventricular fibrillation (VF) and three SD). Both a spontaneous type 1 ECG and syncope significantly increased the risk (2.6 and 3.0% event rate per year vs. 0.4 and 0.8%). Major arrhythmic events occurred in 14% of subjects with positive EPS, in no subjects with negative EPS and in 5.3% of subjects without EPS. All MAE occurred in subjects who had at least two potential risk factors (syncope, family history of SD, and positive EPS). Among these patients, those with spontaneous type 1 ECG had a 30% event rate. Conclusion (1) In subjects with the Brugada type 1 ECG, no single clinical risk factor, nor EPS alone, is able to identify subjects at highest risk; (2) a multiparametric approach (including syncope, family history of SD, and positive EPS) helps to identify populations at highest risk; (3) subjects at highest risk are those with a spontaneous type 1 ECG and at least two risk factors; (4) the remainder are at low risk.

Risk stratification of the patients with Brugada type electrocardiogram: a community-based prospective study

AIMS Risk stratification of patients with Brugada electrocardiogram (ECG) is being strongly debated. Conflicting results have been suggested from international registries, which enrolled non-consecutive cases, studied with different programmed electrical stimulation (PES) protocols. The aim of this study was to prospectively evaluate the incidence of arrhythmic events and the prognostic role of clinical presentation, ECG, and of a standardized PES protocol in consecutive cases from a community-based population. METHODS AND RESULTS A total of 166 consecutive patients (45 +/- 14 years) with Brugada ECG were enrolled. Type 1 ECG was observed spontaneously in 72 (43%) and after pharmacological testing in 94 (57%). One hundred and three (62%) were asymptomatic, 58 (35%) had syncope, and five (3%) had a prior cardiac arrest. One hundred and thirty-five (81%) underwent PES with two extra stimuli up to ventricular refractoriness and 34% had ventricular fibrillation (VF) induced. Arrhythmic events occurred in nine patients at a mean follow-up of 30 +/- 21 months (2.2 events per 100 person-year): in three (60%) patients with aborted sudden death (aSD), five (8.6%) of those with syncope, and one (1%) of the asymptomatic. The only predictors of events were a history of syncope or aSD (P = 0.02) and induction at PES (P = 0.004). CONCLUSION Clinical presentation is the most important parameter in the risk stratification of patients with Brugada ECG. Programmed electrical stimulation seems valuable, particularly in patients with previous syncope.

Electromechanical coupling in patients with the short QT syndrome: further insights into the mechanoelectrical hypothesis of the U wave.

BACKGROUND Patients with a short QT syndrome (SQTS) are at risk of sudden cardiac death (SCD). It is not known whether abbreviation of cardiac repolarization alters mechanical function in SQTS. Controversies persist regarding whether the U wave is a purely electrical or mechanoelectrical phenomenon. OBJECTIVE The present study uses echocardiographic measurements to discriminate between the hypotheses for the origin of the U wave. METHODS Diagnostic work-up including echocardiography and electrocardiogram was performed in 5 SQTS patients (39 +/- 19 years old) from 2 unrelated families with a history of SCD and 5 age-matched and gender-matched control subjects. RESULTS QT intervals were 268 +/- 18 ms (QTc 285 +/- 28 ms) in SQTS versus 386 +/- 20 ms (QTc 420 +/- 22 ms) in control subjects (P < .005). In SQTS patients, the end of the T wave preceded aortic valve closure by 111 +/- 30 ms versus -12 +/- 11 ms in control subjects (P < .005). The interval from aortic valve closure to the beginning of the U wave was 8 +/- 4 ms in patients and 15 +/- 11 ms in control subjects (P = .25). Thus, the inscription of the U wave in SQTS patients coincided with aortic valve closure and isovolumic relaxation, supporting the hypothesis that the U wave is related to mechanical stretch. CONCLUSION Our data show for the first time a significant dissociation between the ventricular repolarization and the end of mechanical systole in SQTS patients. Coincidence of the U wave with termination of mechanical systole provides support for the mechanoelectrical hypothesis for the origin of the U wave.

Associated cardiac lesions in patients with radiation-induced complete heart block

We investigated the clinical, electrophysiological, haemodynamic and angiographic aspects of four patients (two men and two women, aged 31-46 years) who developed complete heart block 13-20 years after therapeutic irradiation of the chest for Hodgkins disease. The initial cardiac symptom was syncope in three, effort intolerance in one. The electrocardiogram recorded third-degree atrioventricular block in three patients, right bundle branch block and posterior fascicular block in one. The electrophysiological study, performed in three cases, showed that the block was infranodal in two. Three patients had significant coronary arterial stenoses, that involved the ostia in two. All patients had mild-to-moderate aortic and mitral regurgitation. One patient had haemodynamic signs of constriction. Another patient had recurrent pericardial effusions. All had echocardiographic evidence of a thickened pericardium. Cardiac involvement can be extensive in patient with radiation-induced heart block. Because coronary artery disease can be particularly severe, coronary angiography appears to be warranted in such patients.