Efficacy of Different Beta-Blockers in the Treatment of Long QT Syndrome

AbstractBackgroundIn LQTS, β-blocker therapy is effective in reducing the risk of cardiac events (syncope, aborted cardiac arrest, sudden cardiac death). Limited studies have compared the efficacy of different β-blockers.ObjectivesThe goal of this study was to compare the efficacy of different β-blockers in long QT syndrome (LQTS) and in genotype-positive patients with LQT1 and LQT2.MethodsThe study included 1,530 patients from the Rochester, New York–based LQTS Registry who were prescribed common β-blockers (atenolol, metoprolol, propranolol, or nadolol). Time-dependent Cox regression analyses were used to compare the efficacy of different β-blockers with the risk of cardiac events in LQTS.ResultsRelative to being off β-blockers, the hazard ratios and 95% confidence intervals (CIs) for first cardiac events for atenolol, metoprolol, propranolol, and nadolol were 0.71 (0.50 to 1.01), 0.70 (0.43 to 1.15) 0.65 (0.46 to 0.90), and 0.51 (0.35 to 0.74), respectively. In LQT1, the risk reduction for first cardiac events was similar among the 4 β-blockers, but in LQT2, nadolol provided the only significant risk reduction (hazard ratio: 0.40 [0.16 to 0.98]). Among patients who had a prior cardiac event while taking β-blockers, efficacy for recurrent events differed by drug (p = 0.004), and propranolol was the least effective compared with the other β-blockers.ConclusionsAlthough the 4 β-blockers are equally effective in reducing the risk of a first cardiac event in LQTS, their efficacy differed by genotype; nadolol was the only β-blocker associated with a significant risk reduction in patients with LQT2. Patients experiencing cardiac events during β-blocker therapy are at high risk for subsequent cardiac events, and propranolol is the least effective drug in this high-risk group

Metabolic syndrome is associated with different clinical outcome after cardiac resynchronization therapy in patients with ischemic and non-ischemic cardiomyopathy

Background: Although association of metabolic syndrome (MS) and ischemic heart disease is strongly established, it is not known whether presence of MS may differently influence clinical responses to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the associations between obesity and metabolic features and the clinical outcome after cardiac resynchronization with defibrillator therapy (CRT-D), compared to an implantable cardioverter defibrillator (ICD). Methods: The risk of heart failure (HF) or death and death alone was evaluated in 829 non-obese patients, 156 obese patients without MS, and 277 obese patients with MS (all with left bundle branch block), who were enrolled in the Multicenter Automatic Defibrillator Implanta­tion Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Results: Obese patients with MS (HR 0.50, 95% CI 0.32–0.77, p = 0.002), obese patients without MS (HR 0.57, 95% CI 0.30–1.06, p = 0.077), and non-obese patients (HR 0.48, 95% CI 0.37–0.62, p < 0.001) had a similar risk reduction of HF/death in response to CRT-D therapy when compared to ICD patients. However, among those with non-ischemic cardiomyo­pathy, obese patients with MS experienced a 90% reduction for HF/death (HR 0.11, 95% CI 0.04–0.32, p < 0.001), whereas obese patients without MS had no reduction (HR 0.98, 95% CI 0.48–1.98, p = 0.951; interaction p < 0.001). The reverse was observed in ischemic car­diomyopathy patients: obese patients with MS had no reduction in the risk of HF/death (HR 0.80, 95% CI 0.48–1.34, p = 0.402), while obese patients without MS showed a significant reduction in the risk of events (HR 0.15, 95% CI 0.04–0.65, p = 0.011; interaction p = 0.036). Similar trends were observed for the endpoint of death. Conclusions: Presence of MS differentiates the response to CRT in obese patients with is­chemic and non-ischemic etiology for HF

Effectiveness of cardiac resynchronization therapy by the frequency of revascularization procedures in ischemic cardiomyopathy patients

Background: It is not known whether the number of revascularizations modifies clinical outcomes in patients with ischemic cardiomyopathy (ICM) implanted with cardiac resynchronization therapy defibrillator (CRT-D) vs. an implantable cardioverter-defibrillator (ICD)-only. Methods: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), we evaluated the effect of CRT-D vs. ICD-only on heart failure (HF) or death, on ventricular tachycardia (VT), ventricular fibrillation (VF) or death, and on reverse remodeling in 592 ICM patients with left bundle branch block, by the number of pre-enrollment revascularizations (0, 1 or ≥ 2 revascularizations). Results: There was a risk reduction of HF/death with CRT-D vs. ICD-only in all three sub-groups: ICM with no need for revascularization (HR 0.51 [0.26–1.02]; p = 0.055), ICM with 1 revascularization (HR 0.45 [0.30–0.70]; p < 0.001), and ICM with 2 or more revas­cularizations (HR 0.37 [0.20–0.66]; p < 0.001). Similarly, there was a risk reduction of VT/ /VF/death with CRT-D vs. ICD-only in patients with no need for revascularization (HR 0.55 [0.31–0.99]; p = 0.044); with 1 revascularization (HR 0.77 [0.51–1.18]; p = 0.23); or with ≥ 2 revascularizations (HR 0.63 [0.34–1.17]; p = 0.14). There was a similar degree of left ventricular reverse remodeling in all three subgroups (p > 0.05 for LVESV, LVEDV, and LAV percent change at 1-year follow-up). Conclusions: In ICM patients, CRT-D is associated with a reduction in HF or death and VT/VF or death — irrespective of the frequency of pre-enrollment revascularization procedures — and is accompanied by a similar degree of beneficial left ventricular reverse remodeling.

Clinical presentation at first heart failure hospitalization does not predict recurrent heart failure admission

Abstract Aims There are limited data on whether clinical presentation at first heart failure (HF) hospitalization predicts recurrent HF events. We aimed to assess predictors of recurrent HF hospitalizations in mild HF patients with an implantable cardioverter defibrillator or cardiac resynchronization therapy with defibrillator. Methods and results Data on HF hospitalizations were prospectively collected for patients enrolled in MADIT‐CRT. Predictors of recurrent HF hospitalization (HF2) after the first HF hospitalization were assessed using Cox proportional hazards regression models including baseline covariates and clinical presentation or management at first HF hospitalization. There were 193 patients with first HF hospitalization, and 156 patients with recurrent HF events. Recurrent HF rate after the first HF hospitalization was 43% at 1 year, 52% at 2 years, and 55% at 2.5 years. Clinical signs and symptoms, medical treatment, or clinical management of HF at first HF admission was not predictive for HF2. Baseline covariates predicting recurrent HF hospitalization included prior HF hospitalization (HR = 1.59, 95% CI: 1.15–2.20, P = 0.005), digitalis therapy (HR = 1.58, 95% CI: 1.13–2.20, P = 0.008), and left ventricular end‐diastolic volume >240 mL (HR = 1.62, 95% CI: 1.17–2.25, P = 0.004). Conclusions: Recurrent HF events are frequent following the first HF hospitalization in patients with implanted implantable cardioverter defibrillator or cardiac resynchronization therapy with defibrillator. Neither clinical presentation nor clinical management during first HF admission was predictive of recurrent HF. Prior HF hospitalization, digitalis therapy, and left ventricular end‐diastolic volume at enrolment predicted recurrent HF hospitalization, and these covariates could be used as surrogate markers for identifying a high‐risk cohort

Primary prevention implantable cardioverter defibrillator in cardiac resynchronization therapy recipients with advanced chronic kidney disease

IntroductionThe implantable cardioverter defibrillator (ICD) is effective for the prevention of sudden cardiac death (SCD) in patients with heart failure and a reduced ejection fraction (HFrEF). The benefit of the ICD in patients with advanced CKD, remains elusive. Moreover, the benefit of the ICD in patients with advanced chronic kidney disease (CKD) and HFrEF who are cardiac resynchronization therapy (CRT) recipients may be attenuated.HypothesisWe hypothesized that patients with CKD who are CRT recipients may derive less benefit from the ICD due to the competing risk of dying prior to experiencing an arrhythmia.MethodsThe study population included 1,015 patients receiving CRT with defibrillator (CRT-D) device for primary prevention of SCD who were enrolled in either (Multicenter Automated Defibrillator Implantation Trial) MADIT-CRT trial or the Ranolazine in High-Risk Patients with Implanted Cardioverter Defibrillator (RAID) trial. The cohort was divided into two groups based on the stage of CKD: those with Stage 1 to 3a KD, labeled as (S1-S3a)KD. The second group included patients with Stage 3b to stage 5 kidney disease, labeled as (S3b-S5)KD. The primary endpoint was any ventricular tachycardia (VT) or ventricular fibrillation (VF) (Any VT/VF).ResultsThe cumulative incidence of Any VT/VF was 23.5% in patients with (S1-S3a)KD and 12.6% in those with (S3b-S5)KD (p < 0.001) The incidence of Death without Any VT/VF was 6.6% in patients with (S1-S3a)KD and 21.6% in patients with (S3b-S5)KD (p < 0.001). A Fine and Gray multivariate competing risk regression model showed that Patients with (S3b-S5)KD had a 43% less risk of experiencing Any VT/VF when compared to those with (S1-S3a)KD (HR = 0.56, 95% CI [0.33–0.94] p = 0.03. After two years of follow up, there was almost a 5-fold increased risk of Death without Any VT/VF among patients with (S3b-S5)KD when compared to those with (S1-S3a)KD [HR = 4.63, 95% CI (2.46–8.72), p for interaction with time = 0.012].ConclusionDue to their lower incidence of arrhythmias and higher risk of dying prior to experiencing an arrhythmia, the benefit of the ICD may be attenuated in CRT recipients with advanced CKD. Future prospective trials should evaluate whether CRT without a defibrillator may be more appropriate for these patients

Atrial Fibrillation in Long QT Syndrome by Genotype

BACKGROUND: Long QT syndrome (LQTS) is caused by the abnormal function of ion channels, which may also affect atrial electrophysiology and be associated with the risk of atrial fibrillation (AF). However, large-scale studies of AF risk among patients with LQTS and its relation to LQTS manifestations are lacking. We aimed to assess the risk of AF and its relationship to the LQTS genotype and the long-term prognosis in patients with LQTS. METHODS: Genotype-positive patients with LQTS (784 LQT1, 746 LQT2, and 233 LQT3) were compared with 2043 genotype-negative family members. Information on the occurrence of AF was based on physician-reported ECG-verified events. Multivariate Cox proportional hazards regression analyses were performed for ages 0 to 60 and after 60 years (reflecting an early and late-onset of AF) to assess the risk of incident AF by genotype and the relationship of AF to the risk of cardiac events defined as syncope, documented torsades de pointes, and aborted cardiac arrest or sudden cardiac death. RESULTS: In patients followed from birth to 60 years of age, patients with LQT3 had an increased risk of AF compared with genotype-negative family members (hazard ratio=6.62; 95% CI, 2.04-21.49; P<0.001), while neither LQT1 nor LQT2 demonstrated increased AF risk. After the age of 60 years, patients with LQT2 had significantly lower risk of AF compared with genotype-negative controls (hazard ratio=0.07; 95% CI, 0.01-0.53, P=0.011). AF was a significant predictor of cardiac events in patients with LQT3 through the age of 60 (hazard ratio=5.38; 95% CI, 1.17-24.82; P=0.031). CONCLUSIONS: Our data demonstrate an increased risk of early age AF in patients with LQT3 and also indicate a protective effect of the LQT2 genotype in it's association with a decreased risk of AF after the age of 60

Quantitative T-wave morphology assessment from surface ECG is linked with cardiac events risk in genotype-positive KCNH2 mutation carriers with normal QTc values

Introduction: Long QT syndrome (LQTS) mutation carriers have elevated the risk of cardiac events even in the absence of QTc prolongation; however, mutation penetrance in patients with normal QTc may be reflected in abnormal T-wave shape, particularly in KCNH2 mutation carriers. We aimed to assess whether the magnitude of a three-dimensional T-wave vector (TwVM) will identify KCNH2-mutation carriers with normal QTc at risk for cardiac events. Methods: Adult LQT2 patients with QTc < 460 ms in men and <470 ms in women (n = 113, age 42 ± 16 years, 43% male) were compared with genotype-negative family members (n = 1007). The TwVM was calculated using T-wave amplitudes in leads V6, II, and V2 as the square root of (TV62 + TII2 + (0.5*TV2)2). Cox regression analysis adjusted for gender and time-dependent beta-blocker use was performed to assess cardiac event (CE) risk, defined as syncope, aborted cardiac arrest, implantable cardioverter-defibrillator therapy, or sudden death. Results: Dichotomized by median of 0.30 mV, lower TwVM was associated with elevated CE risk compared to those with high TwVM (HR = 2.95, 95% CI, 1.25-6.98, P =.014) and also remained significant after including sex and time-dependent beta-blocker usage in the Cox regression analysis (HR = 2.64, 95% CI, 1.64-4.24, P <.001). However, these associations were found only in women but not in men who had low event rates. Conclusion: T-wave morphology quantified as repolarization vector magnitude using T-wave amplitudes retrieved from standard 12-lead electrocardiogram predicts cardiac events risk in LQT2 women and appears useful for risk stratification of KCNH2-mutation carriers without QTc prolongation