Sudden cardiac death in congenital heart disease.

Sudden cardiac death (SCD) accounts for up to 25% of deaths in patients with congenital heart disease (CHD). To date, research has largely been driven by observational studies and real-world experience. Drawbacks include varying definitions, incomplete taxonomy that considers SCD as a unitary diagnosis as opposed to a terminal event with diverse causes, inconsistent outcome ascertainment, and limited data granularity. Notwithstanding these constraints, identified higher-risk substrates include tetralogy of Fallot, transposition of the great arteries, cyanotic heart disease, Ebstein anomaly, and Fontan circulation. Without autopsies, it is often impossible to distinguish SCD from non-cardiac sudden deaths. Asystole and pulseless electrical activity account for a high proportion of SCDs, particularly in patients with heart failure. High-quality cardiopulmonary resuscitation is essential to improve outcomes. Pulmonary hypertension and CHD complexity are associated with lower likelihood of successful resuscitation. Risk stratification for primary prevention implantable cardioverter-defibrillators (ICDs) should consider the probability of SCD due to a shockable rhythm, competing causes of mortality, complications of ICD therapy, and associated costs. Risk scores to better estimate probabilities of SCD and CHD-specific guidelines and consensus-based recommendations have been proposed. The subcutaneous ICD has emerged as an attractive alternative to transvenous systems in those with vascular access limitations, prior device infections, intra-cardiac shunts, or a Fontan circulation. Further improving SCD-related outcomes will require a multidimensional approach to research that addresses disease processes and triggers, taxonomy to better reflect underlying pathophysiology, high-risk features, early warning signs, access to high-quality cardiopulmonary resuscitation and specialized care, and preventive therapies tailored to underlying mechanisms.

Edoxaban versus warfarin in patients with atrial fibrillation in relation to the risk of stroke: A secondary analysis of the ENGAGE AF-TIMI 48 study.

INTRODUCTION: The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA2DS2VASc scores have not been described. METHODS: The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA2DS2VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin. RESULTS: The distribution CHA2DS2VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA2DS2VASc score increased. The hazard ratios per unit increase of CHA2DS2VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA2DS2VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA2DS2VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA2DS2VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA2DS2VASc scores. CONCLUSION: The benefit and safety of edoxaban versus warfarin is maintained across CHA2DS2VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA2DS2VASc scores.

J Curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets: An Experimental Approach to an Observational Paradigm.

BACKGROUND: Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so-called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events, and all-cause mortality in patients randomized to different SBP targets. METHODS: Data from 2 large randomized trials that randomly allocated hypertensive patients at high risk for cardiovascular disease to intensive (SBP<120 mm Hg) or conventional (SBP<140 mm Hg) treatment were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, we plotted the hazard ratio for all-cause mortality and cardiovascular events against the mean on-treatment SBP per treatment group. RESULTS: The pooled data consisted of 194 875 on-treatment SBP measurements in 13 946 patients (98.9%). During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%), and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J curve was present, with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher body mass index, smoked more often, and had a higher frequency of diabetes mellitus and cardiovascular events. CONCLUSIONS: Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure-lowering treatment can be established only via randomized clinical trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01206062 and NCT00000620.

Sudden cardiac death in adults with congenital heart disease: does QRS-complex fragmentation discriminate in structurally abnormal hearts?

Aims: Sudden cardiac death (SCD) causes a large portion of all mortality in adult congenital heart disease (ACHD) patients. However, identification of high-risk patients remains challenging. Fragmented QRS-complexes (fQRS) are a marker for SCD in patients with acquired heart disease but data in ACHD patients are lacking. We therefore aim to evaluate the prognostic value of fQRS for SCD in ACHD patients. Methods and results: From a multicentre cohort of 25 790 ACHD patients, we included tachyarrhythmic SCD cases (n = 147), and controls (n = 266) matched by age, gender, congenital defect and (surgical) intervention. fQRS was defined as ≥1 discontinuous deflection in narrow QRS-complexes, and ≥2 in wide QRS-complexes (>120 ms), in two contiguous ECG leads. We calculated odds ratios (OR) using univariable and multivariable conditional logistic regression models correcting for impaired systemic ventricular function, heart failure and QRS duration >120 ms. ECGs of 147 SCD cases (65% male, median age of death 34 years) and of 266 controls were assessed. fQRS was present in 51% of cases and 34% of controls (OR 2.0, P = 0.003). In multivariable analysis, fQRS was independently associated with SCD (OR 1.9, P = 0.01). The most common diagnose of SCD cases was tetralogy of Fallot (ToF, 34 cases). In ToF, fQRS was present in 71% of cases vs. 43% of controls (OR for SCD 2.8, P = 0.03). Conclusions: fQRS was independently associated with SCD in ACHD patients in a cohort of SCD patients and matched controls. fQRS may therefore contribute to the decision when evaluating ACHD patients for primary prevention of SCD.

Implantable cardioverter-defibrillators in adults with congenital heart disease: a systematic review and meta-analysis.

AIMS: Sudden cardiac death is a major cause of mortality in adult congenital heart disease (ACHD) patients. The indications for implantable cardioverter-defibrillator (ICD) implantation in ACHD patients are still not well established. We aim to systematically review the literature on indications and outcome of ICD implantation in ACHD patients. METHODS AND RESULTS: We performed a comprehensive search in EMBASE, MEDLINE, and Google Scholar to identify all studies on ICD implantation in ACHD patients. We used random effects models to calculate proportions and 95% confidence intervals. Of 1356 articles, 24 studies with 2162 patients were included, with a mean follow-up of 3.6 ± 0.9 years. Half of patients had tetralogy of Fallot. Mean age at implantation was 36.5 ± 5.5 years old and 66% was male. Implantable cardioverter-defibrillators were implanted for primary prevention in 53% (43.5-62.7). Overall, 24% (18.6-31.3) of patients received one or more appropriate ICD interventions (anti-tachycardia pacing or shocks) during 3.7 ± 0.9 years: 22% (16.9-28.8) of patients with primary prevention in 3.3 ± 0.3 years and 35% (26.6-45.2) of patients with secondary prevention in 4.3 ± 1.2 years. Inappropriate shocks occurred in 25% (20.1-31.0) in 3.7 ± 0.8 years and other, particularly lead-related complications in 26% (18.9-33.6) of patients in 3.8 ± 0.8 years. All-cause mortality was 10% during 3.7 ± 0.9 years. CONCLUSIONS: In ACHD, remarkably high rates of appropriate ICD therapy were reported, both in primary and secondary prevention. Because of the young age and lower death rates, the cumulative beneficial effects are likely greater in ACHD patients than in acquired heart disease patients. However, considering the high rates of inappropriate shocks and complications, case-by-case weighing of costs and benefits, remains essential.

Management of Heart Failure With Arrhythmia in Adults With Congenital Heart Disease: JACC State-of-the-Art Review.

Together, heart failure and arrhythmia represent the most important cardiovascular sources of morbidity and mortality among adults with congenital heart disease (ACHDs). Although traditionally conceptualized as operating within 2 distinct clinical silos, these scenarios frequently coexist within the same individual; consequently the mechanistic, therapeutic, and prognostic overlap between them demands increased recognition. In fact, given the near ubiquity of heart failure and arrhythmia among ACHDs, there is perhaps no other arena within cardiology where this critical intersection is more frequently observed. Optimal care for ACHDs therefore requires a heightened awareness of the relevant interactions as well as the pharmacologic and interventional resources that are increasingly available to the treating cardiologist. This review explores and highlights the overlap between these 2 fields to recommend a parallel, yet interactive, multidisciplinary approach to clinical management. Congenital heart disease categories are broken down into their archetypal subtypes to highlight subtleties of the pathophysiology, evaluation, and therapeutic approach.

Identification of patients at risk of sudden cardiac death in congenital heart disease: The PRospEctiVE study on implaNTable cardIOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD).

BACKGROUND: Sudden cardiac death (SCD) is the main preventable cause of death in patients with adult congenital heart disease (ACHD). Since robust risk stratification methods are lacking, we developed a risk score model to predict SCD in patients with ACHD: the PRospEctiVE study on implaNTable cardIOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD) risk score model. OBJECTIVE: The purpose of this study was to prospectively study predicted SCD risk using the PREVENTION-ACHD risk score model and actual SCD and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) rates in patients with ACHD. METHODS: The PREVENTION-ACHD risk score model assigns 1 point each to coronary artery disease, New York Heart Association class II/III heart failure, supraventricular tachycardia, systemic ejection fraction < 40%, subpulmonary ejection fraction < 40%, QRS duration ≥ 120 ms, and QT dispersion ≥ 70 ms. SCD risk was calculated for each patient. An annual predicted risk of ≥3% constituted high risk. The primary outcome was SCD or VT/VF after 2 years. The secondary outcome was SCD. RESULTS: The study included 783 consecutive patients with ACHD (n=239 (31%) left-sided lesions; n=138 (18%) tetralogy of Fallot; n=108 (14%) closed atrial septal defect; median age 36 years; interquartile range 28-47 years; n=401 (51%) men). The PREVENTION-ACHD risk score model identified 58 high-risk patients. Eight patients (4 at high risk) experienced the primary outcome. The Kaplan-Meier estimates were 7% (95% confidence interval [CI] 0.1%-13.3%) in the high-risk group and 0.6% (95% CI 0.0%-1.1%) in the low-risk group (hazard ratio 12.5; 95% CI 3.1-50.9; P < .001). The risk score model's sensitivity was 0.5 and specificity 0.93, resulting in a C-statistic of 0.75 (95% CI 0.57-0.90). The hazard ratio for SCD was 12.4 (95% CI 1.8-88.1) (P = .01); the sensitivity and specificity were 0.5 and 0.92, and the C-statistic was 0.81 (95% CI 0.67-0.95). CONCLUSION: The PREVENTION-ACHD risk score model provides greater accuracy in SCD or VT/VF risk stratification as compared with current guideline indications and identifies patients with ACHD who may benefit from preventive implantable cardioverter-defibrillator implantation.

Prolonged Tpeak -Tend interval is a risk factor for sudden cardiac death in adults with congenital heart disease.

OBJECTIVE: Adult congenital heart disease (ACHD) patients are at risk of sudden cardiac death (SCD). However, methods for risk stratification are not yet well-defined. The Tpeak -Tend (TpTe) interval, a measure of dispersion of ventricular repolarization, is a risk factor for SCD in non-ACHD patients. We aim to evaluate whether TpTe can be used in risk stratification for SCD in ACHD patients. DESIGN: From an international multicenter cohort of 25 790 ACHD patients, we identified all SCD cases. Cases were matched to controls by age, gender, congenital defect, and (surgical) intervention. OUTCOME MEASURES: TpTe was measured on a standard 12-lead ECG. The maximum TpTe of all ECG leads (TpTe-max), mean (TpTe-mean), and TpTe dispersion (maximum minus minimum) were obtained. Odds ratios (OR) for SCD cases vs controls were calculated using conditional logistic regression analysis. RESULTS: ECGs were available for 147 cases (median age at death 33.5 years (quartiles 26.2, 48.7), 66% male) and 267 controls. The mean TpTe-max was 97 ± 24 ms in cases vs 84 ± 17 ms in controls (P < .001); TpTe-mean was 70 ± 16 vs 63 ± 10 ms (P < .001); and dispersion was 51 ± 22 ms vs 41 ± 16 ms (P = .02), respectively. Assessing each ECG lead separately, TpTe in lead aVR predicted SCD most accurately. TpTe in lead aVR was 71 ± 23 ms in cases vs 61 ± 13 ms in controls (P < .001). After adjusting for impaired ventricular function, heart failure symptoms, and prolonged QRS duration, the OR of SCD of TpTe in lead aVR at an optimal cutoff of 80 ms was 5.8 (95% CI 2.7-12.4, P < .001). CONCLUSIONS: The TpTe interval is associated with SCD in ACHD patients. Particularly, TpTe in lead aVR can be used as an independent risk factor for SCD in ACHD patients and may, therefore, add precision to current risk prediction models.

Resuscitation for out-of-hospital cardiac arrest in adults with congenital heart disease.

AIMS: Adult congenital heart disease (ACHD) patients are at increased risk of sudden cardiac death and out-of-hospital cardiac arrest (OHCA). Currently, insufficient data exist on outcome, causes and circumstances of OHCA of ACHD patients resuscitated for OHCA. We investigate these parameters in ACHD patients in comparison to OHCA in the general population. METHODS AND RESULTS: We identified ACHD patients with OHCA by linking data from a Dutch nationwide registry of ACHD patients (CONCOR, n = 15,727), and ARREST, a cohort of OHCA cases (n = 17,868). 62 ACHD patients with OHCA were identified. Ventricular septal defect (n = 11), bicuspid aortic valve (n = 10) and atrial septal defect (n = 8) were the most common diagnoses. We included OHCA cases from the general population as controls. ACHD patients were younger than controls (n = 11,624) at the time of OHCA (47 (SD ±â€¯17) years vs. 66 (SD ±â€¯15) years, respectively, p < 0.001), and more often had a shockable initial rhythm (67% vs 40%, respectively, p < 0.001). A cardiac cause of OHCA was identified in 76% of ACHD patients, with only 7% due to myocardial infarction or ischemia. Survival was better in ACHD patients than in controls (44% vs. 19%, p < 0.001), but this difference disappeared after correction for age, gender, witnessed arrest, bystander resuscitation, public location and shockable rhythm. CONCLUSIONS: OHCA in ACHD patients occurs at young age, is rarely caused by ischemia and occurs mainly in patients with simple congenital defects. Risk stratification efforts should therefore not be restricted to ACHD patients with severe congenital defects.

Feasibility of An Entirely Extracardiac, Minimally Invasive,Temporary Pacing System.

BACKGROUND: A completely extracardiac pacing system provides the potential for clinical advantages over existing device alternatives that require intravascular, endocardial, or epicardial contact. Preliminary studies evaluating the feasibility of cardiac pacing with a lead in the anterior mediastinum, outside the pericardium and circulatory system have been completed. These studies examined (1) the anatomic access route, (2) the usability of a delivery tool to facilitate lead placement, and (3) the pacing performance of the extracardiac lead. METHODS: Feasibility evaluations included (1) a retrospective computed tomography analysis to characterize anatomic variations related to lead access, (2) accessing the anterior mediastinum in cadavers and human subjects using a custom delivery tool, and (3) acute clinical pacing performance. RESULTS: Major findings: (1) A total of 166 (95%) out of 174 patients had a viable lead access path through the fourth, fifth, or sixth intercostal space. (2) Access to the targeted implant location using a delivery tool was successful in all 5 cadavers and 3 humans without use of fluoroscopy and with an average lead delivery time of 121±52 s. No damage to the lung, pericardium, heart, or internal thoracic vessels occurred. (3) Pacing performance was tested in 6 human subjects showing a threshold voltage of 4.7 V (2.7-6.7), threshold pulse width of 1.8 ms (1.0-2.5), and an impedance of 1205 Ω (894-1786). R-wave amplitudes measured 9.6 mV (5.6-12.0). CONCLUSIONS: Results support the feasibility for this completely extracardiac pacing method in a heterogeneous patient population, using a minimally invasive, parasternal, delivery approach and with adequate sensing and thresholds suited for temporary pacing.

Current state of risk stratification for sudden cardiac death in adults with congenital heart disease.

Sudden cardiac death (SCD), mainly caused by ventricular arrhythmias, is one of the leading causes of mortality in adult congenital heart disease (ACHD) patients. An implantable cardioverter defibrillator (ICD) may prevent SCD, but risk stratification remains challenging. In this review, we will address the current guideline recommendations for ICD implantation in ACHD patients, as well as review a recent study in which the discriminative ability for SCD of these guidelines is evaluated. In this study, the guideline recommendations were applied to patients who died of SCD and living controls. Among SCD cases, 35%-41% of patients were recommended ICD, whereas 16%-17% of controls were recommended ICD. The discriminative ability for SCD of the guidelines was poor, with an area under the receiver operating characteristic curve of 0.61-0.63. Risk stratification for SCD in ACHD patients, therefore, remains to be a work-in-progress.

Intensive Blood Pressure Lowering in Patients With and Patients Without Type 2 Diabetes: A Pooled Analysis From Two Randomized Trials.

OBJECTIVE: The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study did not find a significant beneficial effect of intensive systolic blood pressure (SBP) lowering on cardiovascular events in hypertensive patients with type 2 diabetes mellitus (T2DM), while the Systolic Blood Pressure Intervention Trial (SPRINT) did find a significant beneficial effect in patients without T2DM. The objective of this analysis was to assess the effect of both T2DM and baseline cardiovascular disease risk on the treatment effect of intensive blood pressure lowering. RESEARCH DESIGN AND METHODS: The individual patient data from the ACCORD-BP and SPRINT studies were pooled and follow-up durations harmonized. Both studies randomized hypertensive patients to an SBP target of <120 mmHg or a target of <140 mmHg. The composite primary end point consisted of unstable angina, myocardial infarction, acute heart failure, stroke, and cardiovascular death. The interaction between intensive blood pressure lowering and both T2DM and 10-year cardiovascular risk was assessed using Cox proportional hazards models. RESULTS: The cohort consisted of 14,094 patients with mean age 66 ± 8.9 years and mean baseline SBP 139.5 ± 15.6 mmHg; 33.6% had T2DM. The hazard ratio for the primary composite end point was 0.82 (95% CI 0.73-0.93), P = 0.0017. The interaction between intensive blood pressure lowering and T2DM was nonsignificant (P = 0.13). The 10-year cardiovascular risk was higher in primary prevention patients with T2DM, but risk did not interact with the treatment effect (P = 0.84). CONCLUSIONS: Intensive blood pressure lowering may have a similar favorable effect and appears to decrease cardiovascular events in both patients with and patients without T2DM.

Prevention of Sudden Cardiac Death in Adults With Congenital Heart Disease: Do the Guidelines Fall Short?

BACKGROUND: Sudden cardiac death (SCD) is a major cause of mortality in adult congenital heart disease (ACHD) patients. SCD may be prevented by implantable cardioverter-defibrillator (ICD) implantation, but patient stratification remains troublesome. The 2014 Consensus Statement on Arrhythmias in ACHD patients and the 2015 European Society of Cardiology Guidelines specified recommendations for ICD implantation in ACHD patients for the first time. We assess the discriminative ability of these ICD recommendations for SCD in ACHD patients. METHODS AND RESULTS: Of 25 790 ACHD patients in an international multicenter registry, we identified all SCD cases, matched to living controls by age, sex, congenital defect, and surgical repair. We assessed all primary prevention ICD recommendations listed in both documents. We used conditional logistic regression models to calculate odds ratios and receiver operating characteristic curves with area under the curve. Consensus Statement: One hundred twenty-four cases (median age at death, 33 years [26-44]; 67% men) and 230 controls were studied. In total, 41% of SCD cases and 17% of controls had an ICD recommendation (odds ratio, 5.9; P<0.001). European Society of Cardiology Guidelines: Of one hundred fifty-seven cases (median age at death, 33 years [26-48]; 64% men) and 292 controls, 35% and 14% had an ICD recommendation, respectively (odds ratio, 4.8; P<0.001). CONCLUSIONS: A minority of SCD cases had an ICD recommendation according to these guidelines, whereas the majority of SCD victims remained unrecognized. With an area under the curve of 0.6 to 0.7, the discriminative ability of both guidelines was mediocre. Critical clinical reasoning when deciding on ICD implantation in ACHD patients, therefore, remains vital.

QRS fragmentation is superior to QRS duration in predicting mortality in adults with tetralogy of Fallot.

BACKGROUND: Although QRS duration >180 ms has prognostic value in adults with tetralogy of Fallot (TOF), its sensitivity to predict mortality is low. Fragmented QRS complexes, a simple measurement on ECG, are related to myocardial fibrosis and dysfunction in patients with TOF. Our objective was to determine whether QRS fragmentation predicts major outcomes in TOF. METHODS: This multicentre study included adult patients with TOF from a prospective registry. Notches in the QRS complex in ≥2 contiguous leads on a 12-lead ECG, not related to bundle branch block, were defined as QRS fragmentation, which was classified as none, moderate (≤4 leads) or severe (≥5 leads). The primary and secondary outcomes were all-cause mortality and clinical ventricular arrhythmia, respectively. RESULTS: A total of 794 adult patients with TOF (median age 27 years, 55% male; 52% no QRS fragmentation, 32% moderate, 16% severe) were included. During long-term (median 10.4 years) follow-up, 46 (6%) patients died and 35 (4%) patients had ventricular arrhythmias. Overall, 10-year survival was 98% in patients without fragmented QRS complexes, 93% in patients with moderate QRS fragmentation and 81% in patients with severe QRS fragmentation. In multivariable Cox hazards regression analysis, extent of QRS fragmentation (HR: 2.24/class, 95% CI 1.48 to 3.40, p<0.001) remained independently predictive for mortality, whereas QRS duration was not predictive (p=0.85). The extent of QRS fragmentation was also independently predictive for ventricular arrhythmia (HR: 2.00/class, 95% CI 1.26 to 3.16, p=0.003). CONCLUSIONS: The extent of QRS fragmentation is superior to QRS duration in predicting mortality in adult patients with TOF and may be used in risk stratification.