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Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca 2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown. Methods: We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2 , which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies. Results: Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca 2+ indicator Fura-2 showed comparable Ca 2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM. Conclusions: During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.

Among congenital heart diseases, none has undergone a more drastic change in diagnostic approach, management, and outcomes over the last 30 years than hypoplastic left heart syndrome (HLHS), with comfort care replaced as the predominant form of management by a palliative surgical treatment pathway.1 The outcomes of palliative procedures for HLHS have been well documented, but the longer-term picture is less clear. The UK National Congenital Heart Diseases Audit (NCHDA) captures every procedure undertaken for congenital heart disease and updated life status for patients resident in England and Wales from death certifications. From this data set, we identified patients born between 2000 and 2015 who fulfilled the criteria for HLHS: a small left ventricle, stenosis or atresia of the left-sided heart valves, normally aligned great arteries, and no common atrioventricular junction.2 All patients with HLHS require surgical palliation with a traditional Norwood or hybrid pathway or heart transplantation to survive. Hence, we were able to use procedure information in combination with diagnostic information to identify patients with HLHS within the NCHDA data set using the International Paediatric and Congenital Cardiac Codes. Because the NCHDA is a procedure-based data set, patients with HLHS who did not undergo any interventional treatment are not included. Because the hybrid procedure was introduced in the United Kingdom in 2006, we considered 2 eras for …

The principal goals of health care are to help people “live longer and live better,” that is, to optimize both survival and health. In the American Heart Association’s (AHA) special report, “Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond,” the AHA set the following goal: > “By 2020, to improve the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular diseases and stroke by 20%.” 1 The emphasis on improving cardiovascular health is laudable, yet it raises the question of how cardiovascular health is best measured. Indeed, the metrics of cardiovascular health have not been well delineated compared with other cardiovascular mortality and morbidity outcomes. The AHA’s strategic goals primarily focus on ideal health behaviors (eg, not smoking) and ideal health factors (eg, blood pressure control) as metrics of cardiovascular health.1 Although these are of clear import, they do not directly address the World Health Organization’s definition of health as “… a state of complete physical, mental and social well-being.”2 Moreover, the Institute of Medicine identified patient-centered care as 1 of the 6 domains of high-quality health care, wherein patient-centered care supports clinicians in “attending to their patients’ physical and emotional needs, and maintaining or improving their quality of life.”3 The Patient-Centered Outcomes Research Institute emphasizes the goal of “focusing on outcomes that people notice and care about such as survival, function, symptoms, and health related quality of life.”4 Recent concepts of value in health care and the “triple aim” center on improving patients’ health and experience with health care while reducing costs; each reinforces the importance of assessing the impact of disease and medical treatment on patients’ functional status and quality of life.5,6 The definition …

Corin is a cardiac-selective membrane protease that activates pro-ANP and pro-BNP. Emerging evidence suggests that corin may be a key biomarker and modulator of heart failure in dilated cardiomyopathy, but there is little known about the role of corin in myocardial infarction (MI). In acute MI in mice, we found that corin transcript and protein levels were significantly decreased when compared to non-MI controls 24 hrs post MI (1.0±0.1 vs 0.6±0.1, p=0.01; 1.0±0.04 vs 0.5±0.1, p2 , 261±13 vs 106±16, p

Background: Stromal interaction molecules (STIM1 and STIM2) are sarco/endoplasmic calcium sensors ubiquitously expressed in mammalian cells. Upon Ca2+ store discharge STIM proteins oligomerize in proximity of the plasma membrane to activate the Ca2+ selective channels (Orai) and trigger Ca2+ entry. While this mechanism is widely accepted to be the main source of calcium in non-excitable cells, in cardiomyocytes the calcium-induced calcium-release is the major controller of myocardial function, and the presence of STIM in these cells appears somewhat puzzling. Here we investigated the role of STIM in cardiomyocytes and its role in regulating cardiac contractility and intracellular Ca2+ dynamics. Methods: We have generated an inducible cardiac-specific STIM1 knockout (STIM KO) mouse model to elucidate the role of STIM in the myocardium. Echocardiography was used to evaluate structure and function of the left ventricle. Heart rate was monitored continuously in conscious mice by telemetry. Cell dimensions, shortening, and relaxation were determined by videomicroscopy and calcium transients by fura 2. Results: Echocardiographic analyses revealed development of dilated cardiomyopathy with a significant reduction of left ventricular fractional shortening (39.91±4.05% vs. 22.41±7.92%, p Conclusions: Our data demonstrate that STIM proteins play an important role in the maintaining normal cardiac function in the adult heart and reveal that STIM plays an important role during cardiac repolarization.

BACKGROUND The Fontan operation is the usual goal of therapy for children with tricuspid atresia. The influences of morphology and different management strategies on survival and subsequent suitability for this procedure are crucial but unstudied in an unselected population during the Fontan era. METHODS AND RESULTS The fates of 237 consecutive infants with tricuspid atresia were reviewed (1972-1987; median follow-up, 8.0 years). Overall actuarial survival was 72% at 1 year, 53% at 5 years, and 46% at 10 years. Univariate risk factor analysis established that discordant ventriculoarterial connections (24% of the group; relative risk, 2.7), pulmonary atresia (14%, 2.3), aortic arch obstruction (7%, 2.9), and subaortic stenosis (8%, 4.2) were associated with poor survival, whereas pulmonary stenosis (60%, 0.52), balanced pulmonary blood flow (9%, 0.25), and older age at presentation (33%, 0.42) were beneficial. Multivariate analysis allowed the creation of predictive patient-specific survival curves and two additive indexes. Survival was worse for patients who underwent banding of the pulmonary trunk with aortic arch repair than for other individual palliative procedures (p < 0.001). On retrospective review, 204 patients (86%) were judged suitable for a future Fontan procedure at presentation. However, 99 (48%) of these are known to have died before a Fontan operation or became unsuitable for such surgery during follow-up, mostly because of death after palliative surgery (23 patients, 11%), sudden death (18 patients, 9%), and new adverse features (32 patients, 16%) such as subaortic stenosis, pulmonary arterial distortion, and ventricular dysfunction. CONCLUSIONS Management in infancy must aim to ensure survival and maintain suitability for a Fontan-type operation. The accumulating incidence of adverse events with increasing age would argue in favor of undertaking definitive surgery in early childhood in most patients.

Background— Heart failure has an annual mortality rate ranging from 5% to 75%. The purpose of the study was to develop and validate a multivariate risk model to predict 1-, 2-, and 3-year survival in heart failure patients with the use of easily obtainable characteristics relating to clinical status, therapy (pharmacological as well as devices), and laboratory parameters. Methods and Results— The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model. For medications and devices not available in the derivation database, hazard ratios were estimated from published literature. The model was prospectively validated in 5 additional cohorts totaling 9942 heart failure patients and 17 307 person-years of follow-up. The accuracy of the model was excellent, with predicted versus actual 1-year survival rates of 73.4% versus 74.3% in the derivation cohort and 90.5% versus 88.5%, 86.5% versus 86.5%, 83.8% versus 83.3%, 90.9% versus 91.0%, and 89.6% versus 86.7% in the 5 validation cohorts. For the lowest score, the 2-year survival was 92.8% compared with 88.7%, 77.8%, 58.1%, 29.5%, and 10.8% for scores of 0, 1, 2, 3, and 4, respectively. The overall receiver operating characteristic area under the curve was 0.729 (95% CI, 0.714 to 0.744). The model also allowed estimation of the benefit of adding medications or devices to an individual patient’s therapeutic regimen. Conclusions— The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacological, device, and laboratory characteristics.

Background— We have previously suggested that the primary arterial switch operation is a feasible strategy for patients with transposition of the great arteries and intact ventricular septum (TGA-IVS) up to age 2 months. This study reports our current results with this approach and examines whether this policy could be extended beyond age 2 months. Methods and Results— 380 patients who underwent arterial switch for TGA-IVS were reviewed. 275 patients were younger than 3 weeks at the time of surgery (early switch group); 105 patients were 3 weeks or older (range, 21 to 185 days) (late switch group). There was no difference in outcome in terms of in-hospital mortality (5.5% versus 3.8%) or need for mechanical circulatory support (3.6% versus 5.7%) between early and late switch groups. However, duration of postoperative ventilation (4.9 versus 7.1 days, P =0.012) and length of postoperative stay (12.5 versus 18.9 days, P Conclusions— This experience confirms that in TGA-IVS, the left ventricle maintains the potential for systemic work well beyond the first month of life. Consequently, neonates at high risk or late referrals can benefit from delayed arterial switch, even beyond age 2 months. However, the need for mechanical support in some of the older patients may limit the widespread adoption of such a strategy.

Background — The implantable cardioverter-defibrillator (ICD) is an effective but expensive device. We used prospectively collected data from a large randomized clinical trial of secondary prevention of life-threatening ventricular arrhythmias to determine the cost-effectiveness of the ICD compared with antiarrhythmic drug (AAD) therapy, largely with amiodarone. Methods and Results — Charges for initial and repeat hospitalizations, emergency room, and day surgery stays and the costs of antiarrhythmic drugs were collected on 1008 patients. Detailed records of all other medical encounters and expenses were collected on a subgroup of 237 patients. Regression models were then created to attribute these expenses to the rest of the patients. Charges were converted to 1997 costs using standard methods. Costs and life years were discounted at 3% per year. Three-year survival data from the Antiarrhythmics Versus Implantable Defibrillators trail were used to calculate the base-case cost-effectiveness (C/E) ratio. Six-year, twenty-year, and lifetime C/E ratios were also estimated. At 3 years, total costs were $71 421 for a patient taking AADs and $85 522 for a patient using an ICD, and the ICD provided a 0.21-year survival benefit over AAD treatment. The base-case C/E ratio was thus $66 677 per year of life saved by the ICD compared with AAD therapy (95% CI, $30 761 to $154 768). Six- and 20-year C/E ratios remained stable between $68 000 and $80 000 per year of life saved. Conclusions — The ICD is moderately cost-effective for secondary prevention of life-threatening ventricular arrhythmias, as judged from prospectively collected data in a randomized clinical trial.

A20-year-old man presented with a history of acute-onset left-sided chest pain that radiated to the left shoulder and arm. This was associated with breathlessness. He had undergone repair of a “high” perimembranous ventricular septal defect at 2 years of age at this hospital. Since that operation, serial clinical examinations had …

0010 Background: The wealth of data from clinical trials has done as much to diversify standard therapy for acute myocardial infarction (MI) as it has to define it. To better characterize the use of treatments during hospitalization for MI in clinical practice, we analyzed one-year post MI survival in relation to common treatments in the Atherosclerosis Risk in Communities (ARIC) Study. Methods: Between 1987 and 1996 potential cases of MI among men and women, ages 35-74 were identified through hospital surveillance in Forsyth Co. NC, Jackson, MS, Minneapolis, MN, and Washington Co. MD. Diagnosis was validated using a standardized algorithm. Information on treatments was obtained from the medical record. Medication use included those given or continued during the hospitalization or prescribed at discharge. Cox proportional hazards models were used to estimate survival associated with treatments. Results: Of the 15,032 MI events, 34% were female and 18% black. One-year case-fatality of hospitalized MI events ranged from a high of 12% in 1987 to a low of 6.5% in 1994. Between 1987 and 1996, use of thrombolytic therapy (TT) increased from 11% to 16% of patients, beta-blockers (BB) 45% to 66%, and aspirin (AS) 49% to 87%. Coronary artery bypass graft (CABG) surgery increased from 13% to 19% and coronary angioplasty (PTCA) from 11% to 26%. After adjusting for age, race, sex, center, history of MI, severity indicators, complications, and the other therapies, AS (hazard ratio (HR) =0.47, 0.40-0.54) and PTCA (HR=0.47, 0.39-0.57) held the strongest association with survival, followed by CABG (HR=0.61, 0.50-0.75), BB (HR=0.62, 0.53-0.72), and TT (HR=0.71, 0.59-0.87). In 1996, the use of PTCA varied by center from 12% to 36% and AS use varied from 79% to 92%. Conclusions: Although not a randomized trial and therefore subject to selection bias, the ARIC data suggest that established treatments may be associated with better MI survival in community practice. Although no other therapy studied was more strongly associated with survival or has fewer contraindications than aspirin, it is underused in some communities.

To assess the nature and distribution of cardiovascular abnormalities associated with mixed connective tissue disease, we studied 38 patients with overlapping clinical manifestations of systemic lupus erythematosus, progressive systemic sclerosis and polymyositis, and circulating antibodies to nuclear ribonucleoprotein. The protocol included taking a medical history and a physical echocardiogram, and pulmonary function tests. Cardiac catheterization was performed on 17 patients. Postmortem examination was performed on four of the five patients who died during follow-up. Acute pericarditis and/or pericardial effusion was detected in 11 patients (29%) and mitral valve prolapse was identified in 10 patients (26%). Marked intimal hyperplasia of coronary arteries was observed in all four hearts that were autopsied and perivascular and myocardial leukocytic aggregates were present in two hearts. Pulmonary vascular resistance was elevated in 11 of the 17 patients who underwent cardiac catheterization. In summary, cardiovascular abnormalities associated with mixed connective tissue disease include acute pericarditis and/or effusion, mitral valve prolapse, intimal hyperplasia of coronary arteries, perivascular and myocardial leukocytic infiltrates, and pulmonary hypertension.

Between 1979 and 1986, 26 patients with pulmonary atresia, ventricular septal defect, and multifocal pulmonary blood supply underwent surgery (median age, 2 years) to reconnect major aortopulmonary collateral arteries to other collateral arteries or to the central pulmonary arteries in an attempt to prepare the pulmonary circulation for complete repair. In four patients, central pulmonary arteries were found to be absent at exploratory thoracotomy, and therefore, the surgery aimed for optimal palliation. Four (15%) patients died perioperatively. The survivors had symptomatic improvement. At restudy 1 week-110 months (median time, 25 months) postoperatively, modest growth of central pulmonary arteries had occurred [right plus left pulmonary artery diameters/descending aortic diameter from 0.64 +/- 0.61 (mean +/- SD) preoperatively to 0.95 +/- 0.60 postoperatively (p less than 0.01)], with a greater number of bronchopulmonary segments connected to central pulmonary arteries [from 6.3 +/- 4.8 preoperatively to 10.0 +/- 4.5 postoperatively (p less than 0.001)]. However, only seven (27%) patients met the established criteria for repair, of whom three (12%) have undergone definitive surgery. Thirteen (50%) patients are unsuitable for repair, and two (8%) await restudy. Failure of anastomoses involving major aortopulmonary collateral arteries (13 of 33) was higher than for grafts from a systemic artery to the central pulmonary artery (1 of 22, p = 0.003). Failure was not related to the number of anastomoses per operation, suggesting that poor distal runoff may have been responsible. This surgical approach provided reasonable palliation but was rarely effective as a prelude to complete repair.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical presentation, diagnosis, and surgical treatment of 63 patients with doubly committed subarterial ventricular septal defects (DCVSD) were analyzed retrospectively. The patients were divided into three groups. Thirty-one patients had severe congestive heart failure in infancy and presently have a large ventricular septal defect that has no tendency to close or to produce aortic valve regurgitation (Group 1). Ideally, these defects should be closed in infancy, and the transpulmonary approach is recommended to achieve closure. In the first group, there was one death in a patient with a hypoplastic right ventricle. In Group 2, nineteen patients had aortic valve prolapse or aortic valve regurgitation. The DCVSD were moderately large or small. A number of DCVSD in Group 2 patients had maintained the normal offsetting of the arterial valves. These defects must be closed by the time mild aortic valve regurgitation has occurred. In Group 2, there was one late death in a patient who developed subacute bacterial endocarditis. The two patients who had severe aortic valve regurgitation required aortic valve replacement and underwent multiple surgical procedures to replace calcified bioprostheses. Group 3 comprised 13 patients who were diagnosed with tetralogy of Fallot. All of these patients had a large DCVSD with aortic valve overriding. All Group 3 patients survived radical repair of the defect, which required a transannular patch in most cases (76%).