SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes

The cardiac sodium channel Na(v)1.5 plays a key role in excitability and conduction. The 3 last residues of Na(v)1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na(v)1.5 could potentially interact with other, yet unknown, proteins at this site.

Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death.

The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric impulse. Emerging evidence over the past 20 years strongly suggests that the normal electric function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post-translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electric function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.

Evidence of cardiac injury and arrhythmias in dogs with acute kidney injury

OBJECTIVES Cardiac involvement in the course of acute kidney injury is described in humans as cardiorenal syndrome type 3 but has received only limited attention in dogs. This study was designed to evaluate cardiac injury and dysfunction in acute kidney injury in dogs and its association with outcome. METHODS This prospective cohort study enrolled 24 client-owned dogs with acute kidney injury. Cardiac disorders were evaluated with thoracic radiographs, echocardiography, 24-hour Holter monitoring and cardiac troponin I concentrations within 2 days of admission and 7 to 10 days later. RESULTS Most dogs were diagnosed with leptospirosis (n=18, 75%) and presented with moderate-to-severe acute kidney injury, International Renal Interest Society grades III to V. Dogs with ê100 ventricular premature complexes per 24 hour in the first examination (n=8) had significantly higher initial cTnI concentrations (P=0·007) compared to dogs with fewer than 100. In receiver operating characteristic curve analysis, the number of ventricular premature complexes was predictive of outcome (AUC 0·83, P<0·001). CLINICAL SIGNIFICANCE Acute kidney injury seems to be associated with cardiac injury and arrhythmias in dogs. The data do not indicate a cardiac cause of poor outcome in dogs with increased number of ventricular premature complexes but the association may reflect the severity of disease.

Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology

The cardiac voltage-gated Na(+) channel Na(v)1.5 generates the cardiac Na(+) current (INa). Mutations in SCN5A, the gene encoding Na(v)1.5, have been linked to many cardiac phenotypes, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. The mutations in SCN5A define a sub-group of Na(v)1.5/SCN5A-related phenotypes among cardiac genetic channelopathies. Several research groups have proposed that Na(v)1.5 may be part of multi-protein complexes composed of Na(v)1.5-interacting proteins which regulate channel expression and function. The genes encoding these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Na(v)1.5 may be classified as (1) anchoring/adaptor proteins, (2) enzymes interacting with and modifying the channel, and (3) proteins modulating the biophysical properties of Na(v)1.5 upon binding. The aim of this article is to review these Na(v)1.5 partner proteins and to discuss how they may regulate the channel's biology and function. These recent investigations have revealed that the expression level, cellular localization, and activity of Na(v)1.5 are finely regulated by complex molecular and cellular mechanisms that we are only beginning to understand.

Long-term cardiac remodeling and arrhythmias in nonelite marathon runners

Long-term endurance sports are associated with atrial remodeling and atrial arrhythmias. More importantly, high-level endurance training may promote right ventricular (RV) dysfunction and complex ventricular arrhythmias. We investigated the long-term consequences of marathon running on cardiac remodeling as a potential substrate for arrhythmias with a focus on the right heart. We invited runners of the 2010 Grand Prix of Bern, a 10-mile race. Of 873 marathon and nonmarathon runners who applied, 122 (61 women) entered the final analysis. Subjects were stratified according to former marathon participations: control group (nonmarathon runners, n = 34), group 1 (1 marathon to 5 marathons, mean 2.7, n = 46), and group 2 (≥6 marathons, mean 12.8, n = 42). Mean age was 42 ± 7 years. Results were adjusted for gender, age, and lifetime training hours. Right and left atrial sizes increased with marathon participations. In group 2, right and left atrial enlargements were present in 60% and 74% of athletes, respectively. RV and left ventricular (LV) dimensions showed no differences among groups, and RV or LV dilatation was present in only 2.4% or 4.3% of marathon runners, respectively. In multiple linear regression analysis, marathon participation was an independent predictor of right and left atrial sizes but had no effect on RV and LV dimensions and function. Atrial and ventricular ectopic complexes during 24-hour Holter monitoring were low and equally distributed among groups. In conclusion, in nonelite athletes, marathon running was not associated with RV enlargement, dysfunction, or ventricular ectopy. Marathon running promoted biatrial remodeling.

Cardiomegaly in a premature neonate after venous umbilical catheterization

Umbilical venous catheters allow rapid central access in neonates, but may be associated with various complications. We present a case of a newborn with pericardial effusion following umbilical venous catheterization. An extremely low birth weight infant was intubated for respiratory distress syndrome and had umbilical venous and arterial lines in place. Massive cardiomegaly was noted on the subsequent chest X-ray. Echocardiography revealed a large pericardial effusion without signs of tamponade. After removing the catheter, the effusion gradually resolved. While pericardial effusion is a well-known complication of percutaneous long central lines, only a few case reports have documented sudden cardiovascular compromise associated with umbilical venous catheters. Pericardial effusion may be asymptomatic and should be suspected in infants with central catheters and progressive cardiomegaly. The prompt removal of catheters and, if signs of cardiac tamponade are present, emergency pericardiocentesis may prove to be life-saving.

Idiopathic ventricular outflow tract arrhythmias from the great cardiac vein: Challenges and risks of catheter ablation

INTRODUCTION Catheter ablation for idiopathic ventricular arrhythmia is well established but epicardial origin, proximity to coronary arteries, and limited accessibility may complicate ablation from the venous system in particular from the great cardiac vein (GCV). METHODS Between April 2009 and October 2010 14 patients (56 ± 15 years; 9 male) out of a total group of 117 patients with idiopathic outflow tract tachycardias were included undergoing ablation for idiopathic VT or premature ventricular contractions (PVC) originating from GCV. All patients in whom the PVC arose from the GCV were subject to the study. In these patients angiography of the left coronary system was performed with the ablation catheter at the site of earliest activation. RESULTS Successful ablation was performed in 6/14 (43%) and long-term success was achieved in 5/14 (36%) patients. In 4/14 patients (28.6%) ablation was not performed. In another 4 patients (26.7%), ablation did not abolish the PVC/VT. In the majority, the anatomical proximity to the left coronary system prohibited effective RF application. In 3 patients RF application resulted in a coronary spasm with complete regression as revealed in repeat coronary angiography. CONCLUSION A relevant proportion idiopathic VT/PVC can safely be ablated from the GCV without significant permanent coronary artery stenosis after RF application. Our data furthermore demonstrate that damage to the coronary artery system is likely to be transient.

A-kinase anchoring protein Lbc coordinates a p38 activating signaling complex controlling compensatory cardiac hypertrophy

In response to stress, the heart undergoes a remodeling process associated with cardiac hypertrophy that eventually leads to heart failure. A-kinase anchoring proteins (AKAPs) have been shown to coordinate numerous prohypertrophic signaling pathways in cultured cardiomyocytes. However, it remains to be established whether AKAP-based signaling complexes control cardiac hypertrophy and remodeling in vivo. In the current study, we show that AKAP-Lbc assembles a signaling complex composed of the kinases PKN, MLTK, MKK3, and p38α that mediates the activation of p38 in cardiomyocytes in response to stress signals. To address the role of this complex in cardiac remodeling, we generated transgenic mice displaying cardiomyocyte-specific overexpression of a molecular inhibitor of the interaction between AKAP-Lbc and the p38-activating module. Our results indicate that disruption of the AKAP-Lbc/p38 signaling complex inhibits compensatory cardiomyocyte hypertrophy in response to aortic banding-induced pressure overload and promotes early cardiac dysfunction associated with increased myocardial apoptosis, stress gene activation, and ventricular dilation. Attenuation of hypertrophy results from a reduced protein synthesis capacity, as indicated by decreased phosphorylation of 4E-binding protein 1 and ribosomal protein S6. These results indicate that AKAP-Lbc enhances p38-mediated hypertrophic signaling in the heart in response to abrupt increases in the afterload.

Depression and disease severity in patients with premature acute coronary syndrome

OBJECTIVES The association between depression and cardiovascular disease severity in younger patients has not been assessed, and sex differences are unknown. We assessed whether major depression and depressive symptoms were associated with worse cardiovascular disease severity in patients with premature acute coronary syndrome, and we assessed sex differences in these relationships. METHODS We enrolled 1023 patients (aged ≤ 55 years) hospitalized with acute coronary syndrome from 26 centers in Canada, the United States, and Switzerland, through the GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary Syndrome study. Left ventricular ejection fraction, Killip class, cardiac troponin I, and Global Registry of Acute Coronary Events score data were collected through chart review. RESULTS The sample comprised 248 patients with major depression and 302 women. In univariate analyses, major depression was associated with a lower likelihood of having an abnormal left ventricular ejection fraction (odds ratio, 0.70; 95% confidence interval, 0.51-0.97; P = .03) and lower troponin I levels (estimate, -4.04; 95% confidence interval, -8.01 to -0.06; P = .05). After adjustment for sociodemographic and clinical characteristics, neither major depression nor depressive symptoms were associated with disease severity indices, and there were no sex differences. CONCLUSION The increased risk of adverse events in depressed patients with premature acute coronary syndrome is not explained by disease severity.

Sex-related differences in access to care among patients with premature acute coronary syndrome

BACKGROUND Access to care may be implicated in disparities between men and women in death after acute coronary syndrome, especially among younger adults. We aimed to assess sex-related differences in access to care among patients with premature acute coronary syndrome and to identify clinical and gender-related determinants of access to care. METHODS We studied 1123 patients (18-55 yr) admitted to hospital for acute coronary syndrome and enrolled in the GENESIS-PRAXY cohort study. Outcome measures were door-to-electrocardiography, door-to-needle and door-to-balloon times, as well as proportions of patients undergoing cardiac catheterization, reperfusion or nonprimary percutaneous coronary intervention. We performed univariable and multivariable logistic regression analyses to identify clinical and gender-related determinants of timely procedures and use of invasive procedures. RESULTS Women were less likely than men to receive care within benchmark times for electrocardiography (≤ 10 min: 29% v. 38%, p = 0.02) or fibrinolysis (≤ 30 min: 32% v. 57%, p = 0.01). Women with ST-segment elevation myocardial infarction (MI) were less likely than men to undergo reperfusion therapy (primary percutaneous coronary intervention or fibrinolysis) (83% v. 91%, p = 0.01), and women with non-ST-segment elevation MI or unstable angina were less likely to undergo nonprimary percutaneous coronary intervention (48% v. 66%, p < 0.001). Clinical determinants of poorer access to care included anxiety, increased number of risk factors and absence of chest pain. Gender-related determinants included feminine traits of personality and responsibility for housework. INTERPRETATION Among younger adults with acute coronary syndrome, women and men had different access to care. Moreover, fewer than half of men and women with ST-segment elevation MI received timely primary coronary intervention. Our results also highlight that men and women with no chest pain and those with anxiety, several traditional risk factors and feminine personality traits were at particularly increased risk of poorer access to care.