The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model.

The transmembrane protein 43 (TMEM43/LUMA) p.S358L mutation causes arrhythmogenic cardiomyopathy named as ARVC5, a fully penetrant disease with high risk of ventricular arrhythmias, sudden death, and heart failure. Male gender and vigorous exercise independently predicted deleterious outcome. Our systems genetics analysis revealed the importance of Tmem43 for cardiac and metabolic pathways associated with elevated lipid absorption from small intestine. This study sought to delineate gender-specific cardiac, intestinal, and metabolic phenotypes in vivo and investigate underlying pathophysiological mechanisms of S358L mutation. Serial echocardiography, surface electrocardiography (ECG), treadmill running, and body EchoMRI have been used in knock-in heterozygous (Tmem43WT/S358L), homozygous (Tmem43S358L), and wildtype (Tmem43WT) littermate mice. Electron microscopy, histology, immunohistochemistry, transcriptome, and protein analysis have been performed in cardiac and intestinal tissues. Systolic dysfunction was apparent in 3-mo-old Tmem43S358L and 6-mo-old Tmem43WT/S358L mutants. Both mutant lines displayed intolerance to acute stress at 6 mo of age, arrhythmias, fibro-fatty infiltration, and subcellular abnormalities in the myocardium. Microarray analysis found significantly differentially expressed genes between left ventricular (LV) and right ventricular (RV) myocardium. Mutants displayed diminished PPARG activities and significantly reduced TMEM43 and ß-catenin expression in the heart, whereas junctional plakoglobin (JUP) translocated into nuclei of mutant cardiomyocytes. Conversely, elongated villi, fatty infiltration, and overexpression of gut epithelial proliferation markers, ß-catenin and Ki-67, were evident in small intestine of mutants. We defined Tmem43 S358L-induced pathological effects on cardiac and intestinal homeostasis via distinctly disturbed WNT-ß-catenin and PPARG signaling thereby contributing to ARVC5 pathophysiology. Results suggest that cardiometabolic assessment in mutation carriers may be important for predictive and personalized care.NEW & NOTEWORTHY This manuscript describes the findings of our investigation of cardiac, small intestine, and metabolic features of Tmem43-S358L mouse model. By investigating interorgan pathologies, we uncovered multiple mechanisms of the S358L-induced disease, and these unique mechanisms likely appear to contribute to the disease pathogenesis. We hope our findings are important and novel and open new avenues in the hunting for additional diagnostic and therapeutic targets in subjects carrying TMEM43 mutation.

Diagnostic and Therapeutic Approach to Arrhythmias in Adult Congenital Heart Disease.

PURPOSE OF REVIEW: Adult survivors of congenital heart disease (CHD) are at increased risk of arrhythmia. The goal of this review is to outline diagnostic and therapeutic approaches to arrhythmia in adult CHD patients. RECENT FINDINGS: Macro-reentrant atrial tachyarrhythmia is the most common arrhythmia encountered in adults with CHD. Approximately 25% of hospitalizations associated with arrhythmia. The risk of ventricular arrhythmia is estimated as high as 25-100 times that for the general population and increased after two decades. Routine ambulatory monitoring is important for arrhythmia risk assessment in adults with CHD. There are limitations, potential adverse effects, and risk of recurrence with antiarrhythmic drugs, catheter ablation, and surgical approaches. Adults with CHD suffer various forms of arrhythmia, are at increased risk of sudden death, and require special consideration for medical and interventional therapy.

Determining left ventricular hypertrophy in overweight-obese youth using electrocardiogram criteria.

BACKGROUND AND PURPOSE: There is an escalating prevalence of obesity in youth that increases the risk for cardiovascular alterations such as left ventricular hypertrophy (LVH). The purpose of this study is to identify the most effective electrical voltage measurement for determining LVH in youth who are overweight and obese. METHODS: A retrospective chart review was conducted to determine sensitivity, specificity, and the receiver operator characteristic (ROC) curve of 4 popular electrical voltage measures. RESULTS: Our findings indicated the sensitivity and specificity for Cornell product (50.0%; 96.2%), Cornell voltage (52.9%; 98.0%), Romhilt Estes (50.0%; 100.0%), and Sokolow-Lyon index (60.0%; 86.4%) consecutively. CONCLUSION: The Romhilt-Estes and Cornell voltage measures displayed the highest specificity and could prove to be beneficial as a screening method to rule out LVH in overweight and obese youth.

Initial experience with conivaptan use in critically ill infants with cardiac disease.

OBJECTIVE: Arginine vasopressin (AVP) is the primary regulator of free water retention through its interactions with the AVP type 2 receptor (V(2)). As opposed to the natriuresis and diuresis that occur with loop and thiazide diuretics, conivaptan is an AVP V(1A)/V(2) receptor antagonist, which enhances free water excretion while minimizing sodium loss. We report our preliminary experience with conivaptan to promote diuresis in infants with functional or structural cardiac disease. METHODS: A retrospective cohort study was conducted of infants who had received conivaptan from August 2007 to January 2008. A loading dose of conivaptan (0.3-0.6 mg/kg) was followed by a continuous infusion of 0.01-0.02 mg/kg/hr for 24 hours. Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, bicarbonate, and urine output were measured prior to the start of conivaptan and at 24 hours after initiation of the infusion. RESULTS: Conivaptan was administered intravenously on 6 occasions to 5 patients with hypervolemic hyponatremia. Patients ranged in age from 8 to179 days, and body weight ranged from 3 to 4.12 kg. Mean sodium concentration increased from 130.17 ± 1.94 mEq/L to 133.67 ± 3.88 mEq/L (p=0.048), and median urine output increased from 4.15 to 5.05 mL/kg/hr (p=0.286). No significant changes were noted in serum potassium, bicarbonate, creatinine, or BUN. No adverse effects were noted during conivaptan infusion. CONCLUSION: Intravenous conivaptan is effective for increasing serum sodium levels and may be a potential adjuvant to enhance diuresis in children with cardiac disease. Given the potential benefits of conivaptan compared to diuretic therapy, with all their potential complications, prospective trials are warranted.

Prediabetes and blood pressure effects on heart rate variability, QT-interval duration, and left ventricular hypertrophy in overweight-obese adolescents.

This ancillary, descriptive correlational study examined the effect of glucose regulation, blood pressure (BP), and their combined effects on cardiac autonomic function in 128 overweight-obese 11-18-year-olds. Measures included body mass index, resting BP, fasting glucose, glucose tolerance, and cardiac autonomic function (heart rate variability, QT, and Cornell voltage). After adjusting for age and gender, multivariate analysis of covariance revealed no differences in cardiac autonomic measures based on glucose regulation (p = .319), BP (p = .286), or the interaction between glucose regulation and BP (p = .132). The additive effect of prediabetes and elevated BP did not impact cardiac autonomic function in overweight-obese youth.

Current Trends in the Management of Neonates With Ebstein's Anomaly.

BACKGROUND: The optimal management strategy for neonates with Ebstein's anomaly is unknown. This analysis was undertaken to assess current trends in the management and prognosis of neonates born with Ebstein's anomaly in the United States, as reflected in an administrative database. METHODS: The Pediatric Health Information System database (40 children's hospitals) was used to review the reported incidence and available data on neonates with Ebstein's anomaly treated in the United States between 2003 and 2007. Primary outcome was hospital survival. Of the 415 patients identified, 257 (62%) did not undergo initial surgical intervention as neonates. Aortopulmonary shunt only was done on 63 patients (15%), single-ventricle palliation on 36 (9%), two-ventricle repair on 16 (4%), heart transplantation in 3 (1%), and a catheter-based intervention or a hybrid palliative approach was applied in 40 (10%). Intergroup comparisons were done using chi-square analyses. RESULTS: Mortality for the entire cohort was 24% (100 of 415). For medically treated patients, this was 22% (56 of 257). For surgically treated and hybrid patients, this was 30% and 23%, respectively (P = NS). CONCLUSIONS: The majority of patients born with Ebstein's anomaly currently do not undergo surgical intervention as neonates. Significant early mortality in this group suggests that certain subsets of patients may benefit from earlier surgical intervention. Among the severely symptomatic neonates who do undergo early surgical intervention, the mortality remains high, irrespective of the surgical approach taken. A multicenter trial may be appropriate to identify strategies to optimize care for these critically ill neonates. Further analysis of risk factors for early mortality is warranted.

Noninvasive cardiac output monitoring in the pediatric cardiac Intensive Care Unit.

PURPOSE OF REVIEW: The present article explores some of the newer noninvasive techniques for monitoring cardiac output in the pediatric population. These new techniques can be utilized in both a wide variety of patient sizes and the unique pathology of congenital cardiopathy. These techniques may assist in optimizing therapy in the intensive care setting. RECENT FINDINGS: Recently, Hoffman et al. found that near-infrared spectroscopy positively correlates with SvO2. Esophageal Doppler is an accurate method only if used by experienced personnel. Both impedance cardiography and electrical cardiometry use thoracic electrical bioimpedance. However, the algorithm differs between the two methods. Cardiometry may be more accurate in patients with a low cardiac output state. Calamandrei et al. found that an analytical method using arterial pulse pressure recording (pressure recording analytical method) shows a high correlation with Doppler echocardiography. Finally, a method like partial CO2 rebreathing was studied by Levy et al., who suggested that this method may be used to trend cardiac output continuously, but not for providing absolute values. SUMMARY: Although promising, studies validating the use of these methods in a variety of real clinical situations are needed before they will be widely used in pediatric practice.The currently available data suggest that pressure recording analytical method and electrical cardiometry will prove to be useful in the pediatric cardiac ICU to monitor trends in cardiac output.

Nesiritide improves hemodynamics in children with dilated cardiomyopathy: a pilot study.

BACKGROUND: This study aimed to obtain hemodynamic measurements of nesiritide in children with dilated cardiomyopathy. METHODS: A prospective, randomized, double-blinded, placebo-controlled pilot study was conducted in the pediatric intensive care unit at the University of California, Los Angeles. All subjects younger than 21 years admitted to the pediatric intensive care unit with a diagnosis of dilated cardiomyopathy and submitted to cardiac catheterization were randomized to receive either nesiritide or placebo. Right heart catheterization with Swan-Ganz catheter placement was performed. Nesiritide was infused over 24 h. Hemodynamic data were obtained before, during, and after the 24-h nesiritide infusion. The measures obtained included pulmonary capillary wedge pressure (PCWP), central venous pressure, mean pulmonary arterial pressure (MPAP), systolic arterial blood pressure (SBP), cardiac index, and systemic vascular resistance. RESULTS: The study included 20 children: 9 randomized to nesiritide and 11 to placebo. At 24 h, the mean decreases in PCWP, MPAP, and SBP were significantly greater for nesiritide than for placebo: PCWP (-5.3 vs. 1.2 mmHg; p = 0.02), MPAP (-8.0 vs. 0.4 mmHg; p = 0.006), SBP (-7.9 vs. 2.6 mmHg; p = 0.04). CONCLUSIONS: Nesiritide significantly decreases PCWP, MPAP, and SBP in children with dilated cardiomyopathy.

Growth and weight gain of prepubertal children after cardiac transplantation.

This study evaluated changes in growth parameters after pediatric heart transplantation and identified factors associated with the changes after pediatric heart transplantation (OHT). We retrospectively evaluated the somatic growth of 46 children <11 yr of age who underwent OHT for changes in weight, height, and BMI. The patient age range was 3.5 months to 10.7 yr. Gain in Z score for weight and BMI was significant at six months post-OHT (mean weight Z score changed from -1.1 to -0.1 and mean BMI Z score changed from -0.1 to 1.3; p < 0.001). After six months post-OHT, there was no further significant change in weight or BMI Z score. Height Z score did not show significant change from pre-OHT at six months, one yr, or two yr post-OHT. Eight patients (17%) became overweight during the two-yr follow-up period as evidenced by a BMI Z score > 2. Multivariate analysis showed length of steroid treatment as a predictor for negative height Z score change, and age at transplant as a predictor for positive height Z score change. Post-OHT, weight significantly increases without proportional increases in height, resulting in a significant proportion of these children becoming obese. Length of steroid therapy is negatively related to the "catch-up" linear growth following OHT.

Muronomab-CD3 for pediatric acute myocarditis.

The treatment of pediatric acute myocarditis that is hemodynamically significant often includes immune modulation with intravenous immunoglobulin (IVIG) and steroids, and supportive measures. In this population, published outcomes include recovery of ventricular function from 6 months to years, transplantation, or death. We studied the effect of the immunosuppressive agent muronomab-CD3 (OKT3) on recovery of heart failure in the treatment of pediatric myocarditis. A retrospective chart review was performed identifying 15 pediatric patients diagnosed with acute myocarditis and depressed left ventricular ejection fraction (LVEF) or arrhythmias to which OKT3 was added to the immunosuppressive regimen. All patients were treated with supportive care, intravenous immunoglobulin, and steroids. LVEF by echocardiogram was plotted for each patient versus time. Outcomes included recovery of left ventricular function (as defined by an LVEF > or = 45%), death, or listing for transplant. The diagnosis of acute myocarditis was made by a positive endomyocardial biopsy in 8 patients. Nine patients required extracorporeal membrane oxygenation (ECMO) or LV assist device. After treatment with OKT3, 9 patients made a significant recovery of LVEF within 17 days, and 1 recovered by 60 days. Six of the patients requiring mechanical assistance recovered within this time period. There were 4 deaths--3 due to ECMO complications and 1 due to underlying gastrointestinal illness. One patient diagnosed with chronic myocarditis on biopsy underwent transplantation. No significant side effects attributable to OKT3 occurred. By decreasing the autoimmune inflammatory response, OKT3 may hasten recovery of ventricular function and be a useful adjunct therapy for hemodynamically significant acute pediatric myocarditis.

B-type natriuretic peptide in children after cardiac transplantation.

BACKGROUND: The normal B-type natriuretic peptide (BNP) concentration and the significance of increased BNP concentration in children after orthotopic heart transplant (OHT) remain unknown. We sought to determine plasma BNP concentrations in relation to post-transplant time and to explore factors associated with increased BNP in pediatric OHT recipients. METHODS: We obtained plasma BNP concentrations in 44 pediatric patients at 1 to 171 months after OHT. All patients underwent endomyocardial biopsies and echocardiography. We analyzed the association between BNP and post-transplant time, as well as the association between BNP concentration and left ventricular end-diastolic dimension (LVEDD) after transplantation. RESULTS: The age of study patients ranged from 0.9 to 21.2 years (mean, 11.4 +/- 6.2 years; median, 10.5 years). We evaluated BNP concentrations immediately after transplantation. The mean BNP concentration decreased exponentially to 100 pg/ml by 14 weeks after OHT. Although BNP concentration relative to time after OHT varied among individuals, all patients with multiple measurements showed predictable rates of decrease. This decrease in BNP concentration was not associated with changes in LVEDD. CONCLUSIONS: Plasma BNP concentration was elevated in children after OHT and decreased exponentially in time to 100 pg/ml by 14 weeks after OHT. The decrease in BNP concentration was unrelated to left ventricular dimension.

The yield of surveillance endomyocardial biopsies as a screen for cellular rejection in pediatric heart transplant patients.

Endomyocardial biopsy is commonly used to screen for cellular rejection in pediatric heart transplant patients. The yield of EMBs when combined with newly developed immunohistochemical techniques and modern immunosuppression in pediatric heart transplant patients is unknown. After OHT, surveillance biopsies were performed on a routine basis on all pediatric patients. EMBs were also performed on symptomatic OHT patients suspected to have rejection. All positive results (greater than ISHLT grade 1B) were confirmed with immunohistochemical staining. A retrospective review of consecutive EMBs performed in this institution from January 1995 to January 2003 was performed. The echocardiographic results, clinical history and treatment changes at the time of every biopsy were also catalogued. Of the 1093 EMB results from 136 pediatric heart transplant grafts (127 patients, 64 male) reviewed, 825 biopsies were performed on patients managed with tacrolimus and 268 were performed on patients managed with cyclosporine. The patients managed with tacrolimus had an incidence of 0.85% (7/825) for significant rejection (greater than ISHLT grade 1B rejection) vs. an incidence of 4.1% (11/268) for the patients on cyclosporine (p < 0.0005). In the asymptomatic tacrolimus patients, only two screening biopsies (0.26%) manifest significant rejection, and both of these were performed within the first month after transplantation. Of the symptomatic tacrolimus patients, 9.1% (n = 5) had findings on biopsy consistent with significant cellular rejection. There were 25 patients with grade 1B rejection. Twenty-two of these patients were not treated, and all cases of grade 1B rejection resolved without clinical sequelae. For pediatric patients more than 30 days after OHT, EMB has failed to reveal significant episodes of cellular rejection in asymptomatic patients managed with tacrolimus.

Usefulness of B-type natriuretic peptide as a noninvasive screening tool for cardiac allograft pathology in pediatric heart transplant recipients.

We examined the utility of B-type natriuretic peptide (BNP) in the evaluation of pediatric orthotopic heart transplant recipients for allograft pathology by measuring the serum BNP levels at the time of either screening echocardiography and biopsy, or at the time of clinical rejection. There was a significant difference (p <0.0001) in the BNP levels in 37 patients in the group with evidence of pathology compared with those without evidence. There was also 100% sensitivity and 100% negative predictive value of BNP levels >100 pg/ml for identifying graft pathology.

Postoperative arrhythmia.

Postoperative arrhythmia is a major cause of morbidity and mortality after cardiac surgery for congenital heart disease. Rhythm disturbances that may be well tolerated in a normal heart often cause hemodynamic instability when they occur in the immediate postoperative period. In the face of pre-existing myocardial dysfunction resulting from preoperative pressure or volume overload, patients with congenital heart conditions are especially vulnerable to rhythm disturbances after cardiac surgery. Cardiopulmonary bypass, intraoperative injury to the conduction system and myocardium, postoperative metabolic abnormalities, electrolyte disturbances, and increased adrenergic tone in response to the stress of the surgery or inotropic agents are also known factors associated with increased risk of arrhythmia in the immediate postoperative period. Surgically related arrhythmia can also present in the late postoperative period, particularly in association with surgical incision sites and surgically induced hemodynamic abnormalities. Early and late postoperative arrhythmias are important risk factors for morbidity and mortality after surgical treatment of many forms of congenital heart disease. This review describes the incidence of the most common forms of arrhythmia and recent advances in their diagnosis and treatment.

Azimilide inhibits multiple cardiac potassium currents in human atrial myocytes.

BACKGROUND: Studies in animal cell preparations suggest that azimilide may produce a more desirable rate-dependent profile of class III action as a result of its effects on both the slowly (I(Ks)) and rapidly (I(Kr)) activating components of potassium current (I(K)). However, relatively little is known about the effects of azimilide on K(+) currents in human atrial cells. The present study investigated the effect of azimilide on the inward rectifier potassium current (I(K1)), delayed rectifier potassium current (I(K)), ultrarapid delayed rectifier current (I(Kur)), and transient outward potassium current (I(to)) in isolated single human atrial myocytes. METHODS: The tight-seal, whole-cell voltage clamp technique was used to investigate the acute effects of azimilide on K(+) currents in single human atrial myocytes. The cells were isolated enzymatically from atrial tissues that were obtained from patients undergoing open-heart surgeries, with the approval of the local Institutional Review Board. RESULTS: The average cell capacitance of the human atrial myocytes was 77.5 +/- 2.8 pF (Mean +/- standard error of mean, total 28 cells from 17 patients). We found that 100 microM of azimilide in the extracellular solution significantly inhibited the inward rectifier potassium current (12.3 +/- 3.1 vs 6.7 +/- 2.0 pA/pF, n = 12, P < 0.05) at the testing potential of -100 mV. Superfusion with 100 microM of azimilide for 10 minutes inhibited I(K) by 51.7 +/- 5.1% (from 3.4 +/- 0.5 to 1.6 +/- 0.2 pA/pF, n = 9, P < 0.01) at the clamping membrane potential of +40 mV. Human atrial cell I(Kur) was inhibited with 100 microM of azimilide by 38.6 +/- 4.4% (from 3.9 +/- 0.5 to 2.3 +/- 0.2 pA/pF, n = 9, P < 0.01, test potential = 40 mV). We also found that the average peak current amplitude of I(to) in these cells was significantly inhibited with 100 microM of azimilide by 60.3 +/- 5.9% (from 10.3 +/- 1.5 to 3.6 +/- 0.3 pA/pF, n = 6, P < 0.01, test potential = 50 mV). CONCLUSION: The present study provides direct evidence that azimilide inhibits multiple cellular transmembrane K(+) currents in freshly isolated human atrial myocytes. Inhibition of these K(+) currents by azimilide, especially of I(Ks) and I(Kur) is likely to be the electrophysiologic basis for the prolongation of the action potential duration in the human atria which mediates its known antifibrillatory effects in atrial fibrillation and flutter.

HIV type 1 glycoprotein 120 inhibits cardiac myocyte contraction.

Cardiomyopathy is a common, life-threatening, but poorly understood complication of HIV infection. The purpose of the present study is to study the effects of an HIV surface envelope protein, glycoprotein 120 (gp120), on cell contraction and L-type Ca(2+) current in rabbit ventricular myocytes. Rabbit ventricular cells were isolated by an enzyme dissociation method. Cell contractions were induced by electric field stimulation. Whole cell L-type Ca(2+) channel currents were measured by the whole cell voltage-clamp technique. We found that perfusion with solution containing gp120 (0.1 microg/ml) derived from HIV-1(SF2) significantly inhibited field-stimulated contractions and L-type Ca(2+) current in rabbit ventricular myocytes as compared with perfusion with buffer alone. These results suggest that HIV-1 gp120 may directly contribute to cardiac dysfunction as seen in many HIV patients.