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Abstract 1 of 8 (Circulation. 2009;120:286-294.)

Arrhythmia/Electrophysiology
Systematic Assessment of Patients With Unexplained Cardiac Arrest
Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)
Background— Cardiac arrest without evident cardiac disease may be caused by subclinical genetic conditions. Provocative testing to unmask a phenotype is often necessary to detect primary electrical disease, direct genetic testing, and perform family screening.
Methods and Results— Patients with apparently unexplained cardiac arrest and no evident cardiac disease (normal cardiac function on echocardiogram, no evidence of coronary artery disease, and a normal ECG) underwent systematic evaluation that included cardiac magnetic resonance imaging, signal-averaged ECG, exercise testing, drug challenge, and selective electrophysiological testing. Diagnostic criteria were based on accepted criteria or provocation of the characteristic clinical features for long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarization, arrhythmogenic right ventricular cardiomyopathy, coronary spasm, and myocarditis. Sixty-three patients in 9 centers were enrolled (age 43.0±13.4 years, 29 women). A diagnosis was obtained in 35 patients (56%): Long-QT syndrome in 8, catecholaminergic polymorphic ventricular tachycardia in 8, arrhythmogenic right ventricular cardiomyopathy in 6, early repolarization in 5, coronary spasm in 4, Brugada syndrome in 3, and myocarditis in 1. Targeted genetic testing demonstrated evidence of causative mutations in 9 (47%) of 19 patients. Screening of 64 family members of these patients identified 15 affected individuals who were treated (24%). The remaining 28 patients (44%) were considered to have idiopathic ventricular fibrillation.
Conclusions— Systematic clinical testing, including drug provocation and advanced imaging, results in unmasking of the cause of apparently unexplained cardiac arrest in >50% of patients. This approach assists in directing genetic testing to diagnose genetically mediated arrhythmia syndromes, which results in successful family screening.

Abstract 2 of 8 (Circulation. 2009;120:286-294.)
Spinal Cord Stimulation Improves Ventricular Function and Reduces Ventricular Arrhythmias in a Canine Postinfarction Heart Failure Model
Background— Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model.
Methods and Results— In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65±5% at baseline, 17±3% at the end of stage 1, and 47±7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61±4% at baseline, 18±3% at the end of stage 1, and 34±4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64±5% at baseline, 19±5% at the end of stage 1, and 28±3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (P<0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27±17 and 27%, respectively; P<0.03) and MED (58±42 and 33%; P<0.05) versus CTRL (88±52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52±5%) and SCS+MEDS (46±4%) groups compared with the MEDS (38±2%) and CTRL (31±4%) groups.
Conclusion— SCS significantly improved cardiac contractile function and decreased ventricular arrhythmias in canine heart failure.

Abstract 3 of 8 (Circulation. 2009;120:295-301.)

Congenital Heart Disease
Recurrence of Congenital Heart Defects in Families
Background— Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse. We estimated an individual’s risk of CHD given a family history of CHD, as well as the contribution of CHD family history to the total number of CHD cases in the population.
Methods and Results— In a national cohort study, we linked all Danish residents to the National Patient Register, the Causes of Death Register, the Danish Central Cytogenetic Register, and the Danish Family Relations Database, yielding 1 763 591 persons born in Denmark between 1977 and 2005, of whom 18 708 had CHD. Individuals with CHD were classified by phenotype. We estimated recurrence risk ratios and population-attributable risk. Among first-degree relatives, the recurrence risk ratio was 79.1 (95% confidence interval [CI] 32.9 to 190) for heterotaxia, 11.7 (95% CI, 8.0 to 17.0) for conotruncal defects, 24.3 (95% CI,12.2 to 48.7) for atrioventricular septal defect, 12.9 (95% CI, 7.48 to 22.2) for left ventricular outflow tract obstruction, 48.6 (95% CI, 27.5 to 85.6) for right ventricular outflow tract obstruction, 7.1 (95% CI, 4.5 to 11.1) for isolated atrial septal defect, and 3.4 (95% CI, 2.2 to 5.3) for isolated ventricular septal defect. The overall recurrence risk ratio for the same defect was 8.15 (95% CI, 6.95 to 9.55), whereas it was 2.68 (95% CI, 2.43 to 2.97) for different heart defects. Only 2.2% of heart defect cases in the population (4.2% after the exclusion of chromosomal aberrations) were attributed to CHD family history in first-degree relatives.
Conclusions— Specific CHDs showed highly variable but strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared with the population prevalence, whereas the crossover risks between dissimilar cases of CHD were weaker. Family history of any CHD among first-degree relatives accounted for a small proportion of CHD cases in the population.

Abstract 4 of 8 (Circulation. 2009;120:302-309.)

Congenital Heart Disease
Children and Adults With Congenital Heart Disease Lost to Follow-Up
Who and When?
Background— Many patients with congenital heart disease (CHD) require lifelong care. However, the duration of cardiology follow-up in children and adults with CHD is unknown. We sought to determine the proportion of children and young adults with CHD receiving outpatient cardiology care and to identify predictors of lack of follow-up.
Methods and Results— The study population consisted of individuals born in 1983 and alive at age 22 years who were diagnosed with CHD in Quebec, Canada, before 6 years of age (n=643). Patients and outpatient visits were identified with the use of the provincial physician’s claims database. Three age groups were examined for the presence of outpatient cardiology follow-up: 6 to 12, 13 to 17, and 18 to 22 years. CHD lesions were classified as severe (n=84; 13%), simple shunts (n=390; 61%), and \"other\" lesions (n=169; 26%). Failure to receive cardiac follow-up after the 6th, 13th, and 18th birthday occurred in 28%, 47%, and 61%, respectively. Among those with severe lesions, only 79% were seen after the 18th birthday. However, the majority of subjects visited primary care physicians in all age groups, and 93% remained in contact with the healthcare system into early adulthood. Predictors of lack of cardiology follow-up in adulthood included male sex, a nonsevere lesion, and a history of follow-up outside a university hospital setting.
Conclusions— Lack of cardiology follow-up begins during childhood, even among those with severe lesions. This occurs despite patients being in contact with other healthcare providers. Improved communication with primary care physicians may reduce the proportion of patients lost to cardiac follow-up.



Abstract 5 of 8 (Circulation. 2009;120:310-317.)

Heart Failure
Neuregulin-1β Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure
Background— Neuregulin-1 (NRG-1) is a paracrine factor released by microvascular endothelial cells that has cardioprotective effects in animal models of heart failure. However, circulating NRG-1 has not been studied in human heart disease. We used a novel immunoassay to test whether circulating NRG-1β is associated with disease severity and clinical outcomes in chronic heart failure.
Methods and Results— Serum NRG-1β was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1β was significantly elevated in patients with worse disease severity (median, 6.2 ng/mL for New York Heart Association class IV versus 4.4 ng/mL for class I; P=0.002). In adjusted models, NRG-1β was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted hazard ratio, 1.58; 95% confidence interval, 1.04 to 2.39; P=0.03 comparing fourth versus first NRG-1β quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction P=0.008) and New York Heart Association class III/IV symptoms (interaction P=0.01). These findings were all independent of brain natriuretic peptide, and assessment of NRG-1β and brain natriuretic peptide jointly provided better risk stratification than each biomarker individually in patients with ischemic or New York Heart Association class III/IV heart failure.
Conclusions— Circulating NRG-1β is independently associated with heart failure severity and risk of death or cardiac transplantation. These findings support a role for NRG-1/ErbB signaling in human heart failure and identify serum NRG-1β as a novel biomarker that may have clinical applications.

Abstract 6 of 8 (Circulation. 2009;120:318-325.)

Molecular Cardiology
Loss of Cardiac Phosphoinositide 3-Kinase p110 Results in Contractile Dysfunction
Background— Phosphoinositide 3-kinase (PI3K) p110 plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca2+ current (ICa,L) through the voltage-dependent L-type Ca2+ channel (LTCC). The aim of this study was to evaluate whether p110 also controls cardiac contractility by regulating the LTCC.
Methods and Results— Genetic ablation of p110 (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced ICa,L and blocked insulin signaling in the heart. p110 -null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110 decreased ICa,L and contractility in canine myocytes. Inhibition of p110β did not reduce ICa,L.
Conclusions— PI3K p110 but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110 reduces the number of LTCCs on the cell surface and thus attenuates ICa,L and contractility.

Abstract 7 of 8 (Circulation. 2009;120:326-333.)

Valvular Heart Disease
Percutaneous Mitral Annuloplasty for Functional Mitral Regurgitation
Results of the CARILLON Mitral Annuloplasty Device European Union Study
Background— Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care.
Methods and Results— Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction <40%, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307±87 m at baseline to 403±137 m at 6 months (P<0.001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47±16 points at baseline to 69±15 points at 6 months (P<0.001).
Conclusions— Percutaneous reduction in FMR with a novel coronary sinus–based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.

Abstract 8 of 8 (Circulation. 2009;120:334-342.)

Valvular Heart Disease
Active Adaptation of the Tethered Mitral Valve
Insights Into a Compensatory Mechanism for Functional Mitral Regurgitation
Background— In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching.
Methods and Results— Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61±6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4±1.3 cm2 (17±10%) from 14.3±1.9 to 16.7±1.9 cm2 (P=0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.14 versus 0.42±0.14 mm; P<0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31+) coexpressing -smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41±19% versus 9±5%; P=0.02), indicating endothelial-mesenchymal transdifferentiation. -Smooth muscle actin–positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial -smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells.
Conclusions— Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation.