Prediction of 1-year mortality in patients with acute coronary syndromes undergoing percutaneous coronary intervention: validation of the logistic clinical SYNTAX (Synergy Between Percutaneous Coronary Interventions With Taxus and Cardiac Surgery) score

OBJECTIVES This study sought to validate the Logistic Clinical SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score in patients with non-ST-segment elevation acute coronary syndromes (ACS), in order to further legitimize its clinical application. BACKGROUND The Logistic Clinical SYNTAX score allows for an individualized prediction of 1-year mortality in patients undergoing contemporary percutaneous coronary intervention. It is composed of a "Core" Model (anatomical SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction), and "Extended" Model (composed of an additional 6 clinical variables), and has previously been cross validated in 7 contemporary stent trials (>6,000 patients). METHODS One-year all-cause death was analyzed in 2,627 patients undergoing percutaneous coronary intervention from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. Mortality predictions from the Core and Extended Models were studied with respect to discrimination, that is, separation of those with and without 1-year all-cause death (assessed by the concordance [C] statistic), and calibration, that is, agreement between observed and predicted outcomes (assessed with validation plots). Decision curve analyses, which weight the harms (false positives) against benefits (true positives) of using a risk score to make mortality predictions, were undertaken to assess clinical usefulness. RESULTS In the ACUITY trial, the median SYNTAX score was 9.0 (interquartile range 5.0 to 16.0); approximately 40% of patients had 3-vessel disease, 29% diabetes, and 85% underwent drug-eluting stent implantation. Validation plots confirmed agreement between observed and predicted mortality. The Core and Extended Models demonstrated substantial improvements in the discriminative ability for 1-year all-cause death compared with the anatomical SYNTAX score in isolation (C-statistics: SYNTAX score: 0.64, 95% confidence interval [CI]: 0.56 to 0.71; Core Model: 0.74, 95% CI: 0.66 to 0.79; Extended Model: 0.77, 95% CI: 0.70 to 0.83). Decision curve analyses confirmed the increasing ability to correctly identify patients who would die at 1 year with the Extended Model versus the Core Model versus the anatomical SYNTAX score, over a wide range of thresholds for mortality risk predictions. CONCLUSIONS Compared to the anatomical SYNTAX score alone, the Core and Extended Models of the Logistic Clinical SYNTAX score more accurately predicted individual 1-year mortality in patients presenting with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention. These findings support the clinical application of the Logistic Clinical SYNTAX score.

Controversies of fetal cardiac intervention

Remarkable advances in ultrasound imaging technology have made it possible to diagnose fetal cardiovascular lesions as early as 12-14 weeks of gestation and to assess their physiological relevance by echocardiography. Moreover, invasive techniques have been developed and refined to relieve significant congenital heart disease (CHD), such as critical aortic and pulmonary stenoses in the pediatric population including neonates. Recognition of the fact that certain CHDs can evolve in utero, and early intervention may improve the outcome by altering the natural history of such conditions has led to the evolution of a new fetal therapy, i.e. fetal cardiac intervention. Two entities, pulmonary valvar atresia and intact ventricular septum (PA/IVS) and hypoplastic left heart syndrome (HLHS), are associated with significant morbidity and mortality even with postnatal surgical therapy. These cases are believed to occur due to restricted blood flow, leading to impaired growth and function of the right or left ventricle. Therefore, several centers started the approach of antenatal intervention with the primary goal of improving the blood flow through the stenotic/atretic valve orifices to allow growth of cardiac structures. Even though centers with a reasonable number of cases seem to have improved the technique and the immediate outcome of fetal interventions, the field is challenged by ethical issues as the intervention puts both the mother and the fetus at risk. Moreover, the perceived benefits of prenatal treatment have to be weighed against steadily improving postnatal surgical and hybrid procedures, which have been shown to reduce morbidity and mortality for these complex heart defects. This review is an attempt to provide a balanced opinion and an update on fetal cardiac intervention.

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival

BACKGROUND: Restrictive lung defects are associated with higher mortality in patients with acquired chronic heart failure. We investigated the prevalence of abnormal lung function, its relation to severity of underlying cardiac defect, its surgical history, and its impact on outcome across the spectrum of adult congenital heart disease. METHODS AND RESULTS: A total of 1188 patients with adult congenital heart disease (age, 33.1+/-13.1 years) undergoing lung function testing between 2000 and 2009 were included. Patients were classified according to the severity of lung dysfunction based on predicted values of forced vital capacity. Lung function was normal in 53% of patients with adult congenital heart disease, mildly impaired in 17%, and moderately to severely impaired in the remainder (30%). Moderate to severe impairment of lung function related to complexity of underlying cardiac defect, enlarged cardiothoracic ratio, previous thoracotomy/ies, body mass index, scoliosis, and diaphragm palsy. Over a median follow-up period of 6.7 years, 106 patients died. Moderate to severe impairment of lung function was an independent predictor of survival in this cohort. Patients with reduced force vital capacity of at least moderate severity had a 1.6-fold increased risk of death compared with patients with normal lung function (P=0.04). CONCLUSIONS: A reduced forced vital capacity is prevalent in patients with adult congenital heart disease; its severity relates to the complexity of the underlying heart defect, surgical history, and scoliosis. Moderate to severe impairment of lung function is an independent predictor of mortality in contemporary patients with adult congenital heart disease.

Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing

OBJECTIVE To perform long QT syndrome and catecholaminergic polymorphic ventricular tachycardia cardiac channel postmortem genetic testing (molecular autopsy) for a large cohort of cases of autopsy-negative sudden unexplained death (SUD). METHODS From September 1, 1998, through October 31, 2010, 173 cases of SUD (106 males; mean ± SD age, 18.4 ± 12.9 years; age range, 1-69 years; 89% white) were referred by medical examiners or coroners for a cardiac channel molecular autopsy. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, a comprehensive mutational analysis of the long QT syndrome susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) and a targeted analysis of the catecholaminergic polymorphic ventricular tachycardia type 1-associated gene (RYR2) were conducted. RESULTS Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%). Females had a higher yield (26/67 [38.8%]) than males (19/106 [17.9%]; P<.005). Among SUD cases with exercise-induced death, the yield trended higher among the 1- to 10-year-olds (8/12 [66.7%]) compared with the 11- to 20-year-olds (4/27 [14.8%]; P=.002). In contrast, for those who died during a period of sleep, the 11- to 20-year-olds had a higher yield (9/25 [36.0%]) than the 1- to 10-year-olds (1/24 [4.2%]; P=.01). CONCLUSION Cardiac channel molecular autopsy should be considered in the evaluation of autopsy-negative SUD. Several interesting genotype-phenotype observations may provide insight into the expected yields of postmortem genetic testing for SUD and assist in selecting cases with the greatest potential for mutation discovery and directing genetic testing efforts.

Unexplained drownings and the cardiac channelopathies: a molecular autopsy series.

OBJECTIVE To determine the prevalence and spectrum of mutations associated with long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) in a seemingly unexplained drowning cohort. PATIENTS AND METHODS From September 1, 1998, through October 31, 2010, 35 unexplained drowning victims (23 male and 12 female; mean ± SD age, 17±12 years [range, 4-69 years]) were referred for a cardiac channel molecular autopsy. Of these, 28 (20 male and 8 female) drowned while swimming, and 7 (3 male and 4 female) were bathtub submersions. Polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing were used for a comprehensive mutational analysis of the 3 major LQTS-susceptibility genes (KCNQ1, KCNH2, and SCN5A), and a targeted analysis of the CPVT1-associated, RYR2-encoded cardiac ryanodine receptor was conducted. RESULTS Of the 28 victims of swimming-related drowning, 8 (28.6%) were mutation positive, including 2 with KCNQ1 mutations (L273F, AAPdel71-73 plus V524G) and 6 with RYR2 mutations (R414C, I419F, R1013Q, V2321A, R2401H, and V2475F). None of the bathtub victims were mutation positive. Of the 28 victims who drowned while swimming, women were more likely to be mutation positive than men (5/8 [62.5%] vs 3/20 [15%]; P=.02). Although none of the mutation-positive, swimming-related drowning victims had a premortem diagnosis of LQTS or CPVT, a family history of cardiac arrest, family history of prior drowning, or QT prolongation was present in 50%. CONCLUSION Nearly 30% of the victims of swimming-related drowning hosted a cardiac channel mutation. Genetic testing should be considered in the postmortem evaluation of an unexplained drowning, especially if a positive personal or family history is elicited.

Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.

BACKGROUND J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L. OBJECTIVE The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes. METHODS Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique. RESULTS One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05). CONCLUSION These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.

Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.

BACKGROUND Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in alpha1-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (I(Na)) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations. METHODS AND RESULTS Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M, and G460S) were identified in 8 (approximately 3%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction-based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells. I(Na) was recorded using the whole-cell method. A significant 1.4- to 1.5-fold increase in peak I(Na) and 2.3- to 2.7-fold increase in late I(Na) compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation, thereby increasing the overlap of the activation and inactivation curves to increase window current. CONCLUSIONS Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins such as alpha1-syntrophin from similarly rare but innocuous ones.

Effects of Gender on the Incidence of Cardiac Tamponade Following Catheter Ablation of Atrial Fibrillation: Results from a Worldwide Survey in 34,943 AF Ablation Procedures.

BACKGROUND -Cardiac tamponade is the most dramatic complication observed during atrial fibrillation (AF) ablation and the leading cause of procedure-related mortality. Female gender is a known risk factor for complications during AF ablation; however, it is unknown whether women have a higher risk of tamponade. METHODS AND RESULTS -A systematic Medline search was used to locate academic electrophysiologic (EP) centers that reported cases of tamponade occurring during AF ablation. Centers were asked to provide information on cases of acute tamponade according to gender and their mode of management including any case of related mortality. Nineteen EP centers provided information on 34,943 ablation procedures involving 25,261 (72%) males. Overall 289 (0.9%) cases of tamponade were reported: 120 (1.24%) in females and 169 (0.67%) in males (odds ratio 1.83, P<0.001). There was a reciprocal association between center volume and the occurrence of tamponade with substantial lower risk in high volume centers. Most cases of tamponade occurred during catheter manipulation or ablation; females tended to develop more tamponades during transseptal catheterization. No gender difference in the mode of management was observed. However, 16% cases of tamponade required surgery with lower rates in high volume centers. Three cases of tamponade (1%) culminated in death. CONCLUSIONS -Tamponade during AF ablation procedures is relatively rare. Women have an almost twofold higher risk for developing this complication. The risk of tamponade among women decreases substantially in high volume centers. Surgical back-up and acute management skills for treating tamponade are important in centers performing AF ablation.