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PurposeHigh calorie intake leads to obesity, a global socio-economic and health problem, reaching epidemic proportion in children and adolescents. Saturated and monounsaturated fatty acids from animal (lard) fat are major components of the western-pattern diet and its regular consumption leads to obesity, a risk factor for cardiovascular disease. However, no clear evidence exists whether consumption of diet rich in saturated (SFAs) and monounsaturated (MUFAs) fatty acids has detrimental effects on cardiac structure and energetics primarily due to excessive calories. We, therefore, sought to determine the impact of high calories versus fat content in diet on cardiac structure and mitochondrial energetics.MethodsSix-week-old C57BL/6J mice were fed with high calorie, high lard fat-based diet (60% fat, HFD), high-calorie and low lard fat-based diet (10% fat, LFD), and lower-calorie and fat diet (standard chow, 12% fat, SCD) for 10 weeks.ResultsThe HFD- and LFD-fed mice had higher body weight, ventricular mass and thickness of posterior and septal wall with increased cardiomyocytes diameter compared to the SCD-fed mice. These changes were associated with a reduction in the mitochondrial oxidative phosphorylation (OXPHOS) complexes I and III activity compared to the SCD-fed mice without significant differences between the HFD- and LFD-fed animals. The HFD-fed animals had higher level of malondialdehyde (MDA) than LFD and SCD-fed mice.ConclusionsWe assume that changes in cardiac morphology and selective reduction of the OXPHOS complexes activity observed in the HFD- and LFD-fed mice might be related to excessive calories with additional effect of fat content on oxidative stress.

BackgroundThe risk of thromboembolism and bleeding before initiation of oral anticoagulant (OAC) in atrial fibrillation patients is estimated by CHA2DS2-VASc and HAS-BLED scoring system, respectively. Patients’ socioeconomic status (SES) could influence these risks, but its impact on the two risk scores’ predictive performance with respect to clinical events remains unknown. Our objective was to determine if patient SES defined by area deprivation index (ADI), in conjunction with CHA2DS2-VASc and HAS-BLED scores, could guide oral anticoagulation therapy.Methods and findingsThe study cohort included newly diagnosed patients with AF who were treated with warfarin. The cohort was stratified by the time in therapeutic range of INR (TTR), ADI, CHA2DS2-VASc, and HAS-BLED risk scores. TTR and ischemic and bleeding events during the first year of therapy were compared across subpopulations. Among 7274 patients, those living in the two most deprived quintiles (ADI ≥60%) had a significantly higher risk of ischemic events and those in the most deprived quintile (ADI≥80%) had a significantly increased risk of bleeding events. ADI significantly improved the predictive performance of CHA2DS2-VASc but not HAS-BLED risk scores.ConclusionADI can predict increased risk for ischemic and bleeding events in the first year of warfarin therapy in patients with incident AF.

Purpose: Excessive fibrosis has been suggested to result from persistence of fibroblasts in injured tissue due to impaired apoptosis, but signaling pathways are not fully defined. Methods: Suppression of apoptotic cell death following transforming growth factor-β1 (TGF-β1) exposure was studied using the culture of NIH/3T3 mouse embryonic fibroblasts. Caspase-3 activity, propidium iodide staining and annexin V binding induced by Fas-ligand (FasL) in NIH/3T3 fibroblasts in the absence and presence of TGF-β1 was determined, and relative contribution of signaling through Smad2/3 and noncanonical Erk1/2 and Akt pathways was dissected by assessing phosphorylation status of these kinases and caspase activity in the absence and presence of specific inhibitors (SB431542, PD0325901 and LY294002), respectively. Results: TGF-β1 treatment suppressed FasL-mediated fibroblasts apoptosis with a greater than threefold reduction of caspase-3 activity (from 894 ± 186 to 195 ± 56 nmol AFC/min/106 cells at 250 ng/mL of FasL) and reductions in cleaved caspase-8 and caspase-3 by 3.2-fold and 4.3-fold, respectively. The reduction in caspase activation was accompanied by a decrease in annexin V-positive cells by ~80%. TGF-β1 treatment phosphorylated Smad2/3, Erk1/2 and Akt, which were reduced by their selective inhibitors. Inhibition of Smad2/3 and Erk1/2 alone partially reduced the protective effect of TGF-β1 on caspase-3 activation, whereas inhibition of the Akt pathway had no significant effect. Concomitant inhibition of Smad2/3 and Erk1/2 completely reversed the protection by TGF-β1. Conclusions: TGF-β1-mediated suppression of apoptosis in fibroblasts involves both Smad2/3 and Erk1/2 pathways, but not the Akt pathway. A combined approach inhibiting Smad2/3 and Erk1/2 pathways can completely reverse the protective effect of TGF-β1 on apoptosis. These findings are proof of concept to help define strategies to reduce progression of fibrosis and resultant morbidities associated with conditions causing excessive fibrosis, including but not limited to keloid formation, transplant fibrosis and aging-associated fibrosis of the heart.

The increasing prevalence of stroke, with an estimated annual cost of $71.5 billion, has made it a major health problem that increases disability and death, particularly in patients with atrial fibrillation. Although advanced age and atrial fibrillation are recognized as strong risk factors for stroke, the basis for this susceptibility are not well defined. Aging or associated diseases are accompanied by changes in rheostatic, humoral, metabolic and hemodynamic factors that may contribute more to stroke predisposition than rhythm abnormality alone. Several thromboembolism-predisposing clinical characteristics and serum biomarkers with prognostic significance have been identified in patients with atrial fibrillation. Although anticoagulation decreases the risk of thromboembolism, management in the elderly remains complex due to major concerns about bleeding. New anticoagulants and nonpharmacologic strategies are helpful to reduce the risk of bleeding, particularly in older-elderly patients. Herein, we review the pathogenesis and management of select issues of thromboembolism in the elderly with atrial fibrillation.

In an aged population, cardiovascular disease is the leading cause of fatality and morbidity. Age-related fibrotic remodeling of the heart contributes to progressive myocardial dysfunction. Cardiac fibroblasts (CF), responsible for the maintenance of extracellular matrix and fibrosis process, play an important role in cardiac health and disease. CFs influence myocardial function by their chemical, electrical and mechanical interactions with cardiomyocytes through extracellular matrix deposition or secretion of cytokines and growth factors. These, in turn, are modulated by ion channels, macromolecular pores in the plasma membrane that allow selective ionic fluxes of major ions like K+, Ca2+, Na+ or Cl-, which affect membrane potential and cellular signal transduction. The importance of ion channels in modulating various functions of CFs, including proliferation, differentiation, secretion and apoptosis, is being recognized from recent studies of CFs from animal models and tissue from patients with various cardiac pathologies. Understanding the role of ion channels in CFs under physiological conditions and their alterations in age-related cardiac diseases may help facilitate development of novel therapeutic strategies to limit cardiac fibrosis and its adverse effect on myocardial function. This narrative review summarizes the knowledge gained thus far on ion channels in CFs and their relationship with cardiac diseases in human and experimental animal models.

Fibroblasts, the most abundant cells in the heart, contribute to cardiac fibrosis, the substrate for the development of arrythmogenesis, and therefore are potential targets for preventing arrhythmic cardiac remodeling. A chamber-specific difference in the responsiveness of fibroblasts from the atria and ventricles toward cytokine and growth factors has been described in animal models, but it is unclear whether similar differences exist in human cardiac fibroblasts (HCFs) and whether drugs affect their proliferation differentially. Using cardiac fibroblasts from humans, differences between atrial and ventricular fibroblasts in serum-induced proliferation, DNA synthesis, cell cycle progression, cyclin gene expression, and their inhibition by simvastatin were determined. The serum-induced proliferation rate of human atrial fibroblasts was more than threefold greater than ventricular fibroblasts with faster DNA synthesis and higher mRNA levels of cyclin genes. Simvastatin predominantly decreased the rate of proliferation of atrial fibroblasts, with inhibition of cell cycle progression and an increase in the G0/G1 phase in atrial fibroblasts with a higher sensitivity toward inhibition compared with ventricular fibroblasts. The DNA synthesis and mRNA levels of cyclin A, D, and E were significantly reduced by simvastatin in atrial but not in ventricular fibroblasts. The inhibitory effect of simvastatin on atrial fibroblasts was abrogated by mevalonic acid (500 μM) that bypasses 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition. Chamber-specific differences exist in the human heart because atrial fibroblasts have a higher proliferative capacity and are more sensitive to simvastatin-mediated inhibition through HMG-CoA reductase pathway. This mechanism may be useful in selectively preventing excessive atrial fibrosis without inhibiting adaptive ventricular remodeling during cardiac injury.

Objectives This study reports on a novel method to prevent coagulum formation by continuously delivering a negative charge to the catheter tip to repel negatively charged fibrinogen molecules during RF ablation. Background Radiofrequency (RF) ablation for cardiac arrhythmias is associated with a 70% incidence of coagulum formation on the catheter tip during ablation and a 10% incidence of thromboembolic events. Catheter tip thrombus can impede RF energy to the tissue, reducing efficacy and increasing procedure times. Methods A novel circuit was built to deliver a negative, fixed-offset, direct current-based charge using a 9-V battery, placed in parallel with an RF delivery unit during RF ablation. In in vivo canine experiments, standard ablation catheters were advanced into atria and ventricles under fluoroscopic guidance. The presence of thrombus with and without RF delivery was identified with intracardiac echocardiography. Results Scanning electron microscopy of the catheter tips showed clot coverage of the catheter tip to be 90% for noncharged catheters compared to 0% (p Conclusions Negative-charge delivery to ablation catheter tips and tissue during RF ablation is feasible and safe and can eliminate coagulum formation, potentially reducing thromboembolic complications.

Postoperative atrial fibrillation (PoAF), a common complication of cardiac surgery, contributes significantly to morbidity, mortality, and increasing healthcare costs. Despite advances in surgical and medical management, the overall incidence of PoAF has not changed significantly, partly because of the limited understanding of mechanisms underlying acute surgery-related factors, such as myocardial injury, inflammation, sympathetic activation, and oxidative stress, which play an important role in the initiation of PoAF, whereas a preexisting atrial substrate appears to be more important in the maintenance of this dysrhythmia. Thus, in a majority of patients, PoAF becomes a manifestation of an underlying arrhythmogenic substrate that is unmasked after acute surgical stress. As such, the ability to identify which patients have this proarrhythmic substrate and are, therefore, at high risk for developing AF postoperatively, is important for the improved selection for prophylactic interventions, closer monitoring for complications, and establishing the probability of AF in the long term. This review highlights the role of the underlying substrate in promoting PoAF, proposed mechanisms, and the potential role of serum biomarkers to identify patients at risk for PoAF.

Purpose: Access site complications following peripheral vascular intervention (PVI) are associated with prolonged hospitalization and increased mortality. Prediction of access site complication risk may optimize PVI care; however, there is no tool designed for this. We aimed to create a clinical scoring tool to stratify patients according to their risk of developing access site complications after PVI. Methods: The Society for Vascular Surgery’s Vascular Quality Initiative database yielded 27,997 patients who had undergone PVI at 131 North American centers. Clinically and statistically significant preprocedural risk factors associated with in-hospital, post-PVI access site complications were included in a multivariate logistic regression model, with access site complications as the outcome variable. A predictive model was developed with a random sample of 19,683 (70%) PVI procedures and validated in 8,314 (30%). Results: Access site complications occurred in 939 (3.4%) patients. The risk tool predictors are female gender, age > 70 years, white race, bedridden ambulatory status, insulin-treated diabetes mellitus, prior minor amputation, procedural indication of claudication, and nonfemoral arterial access site (model c-statistic = 0.638). Of these predictors, insulin-treated diabetes mellitus and prior minor amputation were protective of access site complications. The discriminatory power of the risk model was confirmed by the validation dataset (c-statistic = 0.6139). Higher risk scores correlated with increased frequency of access site complications: 1.9% for low risk, 3.4% for moderate risk and 5.1% for high risk. Conclusions: The proposed clinical risk score based on eight preprocedural characteristics is a tool to stratify patients at risk for post-PVI access site complications. The risk score may assist physicians in identifying patients at risk for access site complications and selection of patients who may benefit from bleeding avoidance strategies.

Natural history of mitral valve prolapse (MVP) in the community is widely heterogeneous [(1)][1]. Prognosis in MVP ranges from normal life expectancy to subsets with high morbidity/excess mortality, including sudden cardiac death [(2)][2]. Although MVP is identified in a significant number of

Importance Malignant arrhythmic mitral valve prolapse (MVP) phenotype poses a substantial risk of sudden cardiac death (SCD), and an estimated 26 000 individuals in the United States are at risk of SCD per year. Thus, identifying risk-stratification strategies for SCD is imperative. Observations Patients with MVP have a heterogenous clinical spectrum, ranging from a benign course to a devastating complication such as SCD. Some of the high-risk markers of MVP, which are identified electrocardiographically, include inverted or biphasic T waves, QT dispersion, QT prolongation, and premature ventricular contractions originating from the left ventricular outflow tract and papillary muscles. Morphofunctional characteristics of SCD are leaflet thickness of 5 mm or greater, mitral annulus disjunction, paradoxical systolic increase of the mitral annulus diameter, increased tissue Doppler velocity of the mitral annulus, and higher mechanical dispersion on echocardiography and fibrosis identified by late gadolinium enhancement on cardiac magnetic resonance imaging. Conclusions and Relevance Findings from this review suggest that SCD can occur earlier in the course of MVP from complex arrhythmias that are triggered by the repeated tugging and traction of the chordopapillary muscle unit and basal mid-myocardium, even before macrofibrosis can be identified in these regions by late gadolinium enhancement on cardiac magnetic resonance imaging. Some of the newer markers identified by speckle-tracking Doppler, such as mechanical dispersion, myocardial work index, and postsystolic shortening, need further validation in a larger population.

High-degree atrioventricular (HD-AVB) block is frequently seen post transcatheter aortic valve replacement (TAVR) with right ventricular pacing induced cardiomyopathy being a potential long-term complication. A retrospective review of 59 patients (32 women, 27 men) who underwent permanent pacemaker

Vagal nerve stimulators (VNS) are used for medically refractory epilepsy. The device provides electrical stimulation to the left vagus nerve. The right vagus nerve has greater effect on the sinoatrial node, while the left vagus nerve affects the atrioventricular node. A 33-year-old female was

Several studies have been reported in various domains from induction methods to utilities of somatic cell pluripotent reprogramming. However, one of the major struggles facing the research field of induced pluripotent stem cell (iPSC)-derived target cells is the lack of consistency in observations. This could be due to variety of reasons including varied culture periods post-differentiation. The cardiomyocytes (CMs) derived from iPSCs are commonly studied and proposed to be utilized in the comprehensive in vitro proarrhythmia initiative for drug safety screening. As the influence of varied culture periods on the electrophysiological properties of iPSC-CMs is not clearly known, using whole-cell patch clamp technique, we compared two groups of differentiated ventricular-like iPSC-CMs that are cultured for 10 to 15 days (D10-15) and more than 30 days (≥ D30) both under current and voltage clamps. The prolonged culture imparts increased excitability with high-frequency spontaneous action potentials, robust increase in the magnitude of peak Na

Introduction: ICD implantation is recommended in patients with LVEF Hypothesis: Prolonged repolarization is a marker of electrical instability and JTc interval on ECG could provide prognostic information in patients with LVEF 35-40% incremental to that from LVEF. Methods: Patients ≥18 yr with no history of VA and an ECG and echocardiogram obtained at initial encounter between 11/2011 to 12/2016 with long-term follow-up were identified. The incremental predictive ability of JTc interval on improvement in risk stratification for VA was determined by receiver operating characteristics (ROC) curve, integrated discrimination improvement (IDA) and net reclassification improvement (NRI) analysis. All tests were performed at a 5% level of significance. Results: Out of 29,700 pts that met inclusion criteria, 1,102 (3.7%) had LVEF 35-40% (mean age 70.5±14.6 yrs, 49% males, CAD 67%) and 24,894 (84%) LVEF >40% (65.9±16.3 yrs , 61.8% M). Over the mean follow-up of 4.6±4.2 years, the incidence of VT/VF/cardiac arrest was 16.1% in patients with LVEF 35-40% compared to 4.1% with LVEF >40%. For every 50 ms increase in JTc interval above 300 ms, the risk for arrhythmic event in LVEF 35-40% increased two-fold (Odds Ratio=1.83 (95 % CI 1.72-1.94, P=0.013). Incorporation of JTc to LVEF improved the C statistics (95% Confidence Limit) in the model with only LVEF from 0.56 (0.54-0.57) to 0.72 (0.70-0.73) for the model combining LVEF and JTc. In addition, NRI was estimated at 0.57, which was statistically significant with p values Conclusions: In patients with LVEF 35-40% considered low risk for life threatening VA by EF, incorporating JTc interval information improved risk stratification and identified those who subsequently developed VT/VF or cardiac arrest and thus identifies a subgroup that can benefit from prophylactic ICD implantation.

Background: Yearly trends and prevalence of alcoholic cardiomyopathy (ACMP) hospitalizations and its associated in-hospital mortality, arrhythmia, complications and outcomes are not well studied on a national level. Methods: We used Nationwide Inpatient Sample database (2005-14) and identified 25402 hospitalizations for adults (≥18 yrs) with a primary or secondary diagnosis of ACMP . Since ACMP is a diagnosis of exclusion, all patients with a co-diagnosis of CAD or other causes of cardiomyopathy were excluded. Results: Taking the growth of the US general population into account, there was a decreasing number of ACMP hospital stays per 100,000 persons (4.38 in 2005 vs 3.62 in 2014; p < 0.001). Arrhythmias were present in in 48.7% of hospital stays. In-hospital mortality was 4.2% down-trending over years (4.3% 2005 vs 3.7% 2014) but this was not statistically significant (p = 0.78). Approximately 2.1% experienced cardiac arrest(uptrend from 1.4% to 3.2% in 2005-14; p Conclusion: There was a decreasing number of ACMP hospitalizations per 100,000 of US population. Despite the increased prevalence of arrhythmias in this population over years, the in-hospital mortality has not change, but rate of cardiac arrest has increased. The Median length of hospital stay has not changed, but the healthcare cost has significantly increased. This could be explained by the increased utilization of inpatient cardiac procedures.

Background: Circulating microRNAs have recently been identified as biomarkers predicting A-Fib and heart failure. Yet, their role in identifying those at risk for postoperative atrial fibrillation (PoAF) in a gender-specific manner has not been studied. Methods: Preoperative blood from patients undergoing cardiac surgery with no prior history of AF, supraventricular/ventricular tachycardia was used for RNA isolation. Differences in the relative levels of miRNA between those who did/did not develop PoAF were assessed using qPCR. Principal component analysis and receiver operative characteristics were performed to predict miRNA associated with PoAF. Results: Out of 56 patients, 29 developed PoAF (52%, mean age 70.4± 9y, 51% males), while 27 (mean age 63y ± 10) remained free of AF. Patients who developed PoAF were older (P Conclusion: This indicates the existence of different substrate/precipitating factors reflected in miRNAs profile in male and female patients who developed PoAF. Gender differences exist in circulatory miRNA levels can help in predicting the development of new-onset AF after cardiac surgery.

Introduction: Right and left atria have different susceptibilities toward developing atrial fibrillation (AF). The molecular bases of these differences are not well characterized. Given the complexity of AF development and progression, understanding AF-associated changes in myocardial energetics between the atria will help improve mechanistic insights and therapeutics for better clinical management of AF. The aim was to compare changes in mitochondrial oxidative phosphorylation system (OXPHOS), glycolysis and Krebs cycle metabolites in right atrial (RAA) and left atrial (LAA) appendage tissue from patients with (AF) and without (non-AF) AF. Methods: RAA and LAA from well-matched AF (n=54) and non-AF (n=58) patients undergoing elective open heart surgery was collected. Functional activity of OXPHOS complexes I-V was measured spectrophotometrically. Protein expression level of OXPHOS complexes was determined by Western blot. OXPHOS gene expression level was performed using RT-PCR. Metabolites were profiled using high performance liquid chromatography coupled to tandem mass spectrometry. Comparison between groups was done applying the 2 sample t - and Wilcoxon rank sum tests with 5% level of significance. Results: The most significant AF-associated alterations in myocardial energetics were observed in RAA. In AF patients, out of 84 OXPHOS genes, expression of 14 genes was significantly reduced in RAA (p+ (p=0.03), GDP (p=0.05), citrate (p=0.03), total pool of adenine nucleotides (p=0.02) and glutathione (p=0.03) level in RAA without changes in LAA. Conclusion: AF is associated with different energetic remodeling in right and left atria, suggesting that dissimilar mechanisms may contribute to development and progression of AF.

Background: Cardiomyocytes (CM), derived from human induced-pluripotent stem cells (iPSC-CM), are promising tools for in vitro proarrhythmia screening for drug safety. However, among various challenges with interpretation of iPSC-CM experimental results, the influence of varied culture periods post-differentiation on the electrophysiological properties of iPSC-CMs is unclear. Objective: To test the hypothesis that prolonged post-differentiation culture of iPSC-CMs will influence the biophysical characteristics of Na + - and Ca 2+ -channels. Methods: Using whole-cell patch clamp, we compared the electrophysiological properties of differentiated ventricular-like iPSC-CMs (APD 30-40 /APD 70-80 >1.5) cultured for 10 to 15 days (D10-15) to those cultured for more than 30 days (≥ D30) both under current- and voltage- clamp configurations. Quantitative real-time PCR was used to quantify the mRNA expression of voltage-gated Na channel subunits SCN1A, SCN5A and Ca channel subunits CACNA1C, CACNA1G and CACNA1I. Fold change was calculated by 2 -ΔΔCt method. Data were analyzed by Student’s t test, and P value Results: Post-differentiation prolonged culture imparts increased cellular excitability with high frequency spontaneous action potentials, robust increase in the magnitude of peak Na + -current level, relatively shallow inactivation kinetics of Na + channels, faster recovery from inactivation, and augmented Ca 2+ current density compared to early cultured iPSC-CM. This was associated with a greatly enhanced mRNA expression of α-subunit transcripts of SCN1A (7.5 fold) and SCN5A (38 fold) Na channel subtypes while less robust elevation in the mRNA expression of CACNA1C (0.5 fold), CACNA1G (2 fold) and CACNA1I (2 fold) subunits in prolonged culture compared to early cultured iPSC-CM. Conclusion: Prolonged culture of ventricular-like iPSC-CMs affects the excitability, single-cell electrophysiological properties and differential ion channels subunit expression. Standardization of post-differentiation period for ventricular-like iPSC-CMs culture is crucial for in vitro proarrhythmia screening, health/disease modelling to study cellular mechanisms or test high-throughput drugs’ efficacy and toxicity.

CoreValve is widely used in transcatheter aortic valve replacement, but the impact of its deployment location on hemodynamics is unexplored despite a potential role in subsequent aortic and coronary artery pathologies. The objectives of this investigation were to perform fluid-structure interaction (FSI) simulations for a 29 mm CoreValve deployed in annular vs supra-annular locations, and characterize resulting hemodynamics including velocity and wall shear stress (WSS). Patient-specific geometry was reconstructed from computed tomography scans and CoreValve was deployed using a finite element approach. FSI simulations were then performed using a boundary conforming method and realistic boundary conditions. Results showed that CoreValve deployment location impacts hemodynamics in the ascending aorta and flow patterns in the coronary arteries. During peak-systole, annularly deployed CoreValve produced a jet-like flow structure impinging on the outer-curvature of the ascending aorta. Supra-annularly deployed CoreValve having a lateral tilt of 10° led to a more centered jet impinging further downstream. At mid-systole, valve leaflets of the annularly deployed CoreValve closed asymmetrically leading to disorganized flow patterns in the ascending aorta vs those from the supra-annular position. Supra-annularly deployed CoreValve also led to high-velocity para-valvular flow supplying the coronary arteries. CoreValve in the supra-annular position significantly (P

As the number of individuals, particularly the elderly, using herbal products with prescription drugs continues to grow, the risk for adverse interactions increases but remains poorly recognized. The true incidence and nature of adverse herb reactions or herb-drug interactions remains unknown since no postmarketing surveillance mechanism exists. Adverse events are greatly underreported, and information regarding safety mainly comes from case reports and suboptimally conducted studies in a limited number of healthy young volunteers or patients with limited comorbidities. Therefore, convincing evidence for the safety of herbal products in the elderly is lacking, and the true magnitude of problems that herb-drug interactions pose to public health, particularly in elderly patients with cardiovascular diseases, is not known. Since cardiovascular diseases themselves are life-threatening, necessitate use of multiple medications and occur in a population with extensive comorbidities, the risk of herb-drug and herb-disease interactions is not minor and cannot be ignored. This review addresses these concerns in an effort to raise awareness about the use of herbal medicine by the elderly and its potential adverse impact on the efficacy of prescription medications that can increase predisposition to catastrophic events such as major bleeding, inadequate anticoagulation leading to undesired clotting, transplant organ rejection and life-threatening cardiac arrhythmias. (J Patient-Centered Res Rev. 2015;2:174-191.)

Diabetes mellitus is a major risk factor for arrhythmogenesis and is associated with a two-fold increase in all-cause mortality and a four-fold increase in cardiovascular mortality including sudden cardiac death when compared with nondiabetics. Implantable cardioverter defibrillators (ICD) have been shown to effectively reduce arrhythmic death and all-cause mortality in patients with severe myocardial dysfunction. With a high competing risk of nonarrhythmic cardiac and noncardiac death, survival benefit of ICD in patients with diabetes mellitus could be reduced, but the subanalysis of diabetic patients in randomized clinical trials provides reassurance regarding a similar beneficial survival effect of ICD and cardiac resynchronization therapy in diabetics, as observed in the overall population with advanced heart disease. In this article, the authors highlight some of the clinical issues related to diabetes, summarize the data on the efficacy of ICD in diabetics when compared with nondiabetics and discuss concerns related to ICD implantation in patients with diabetes.

Introduction: Although generations of reactive oxygen species and mitochondrial dysfunction have been implicated in pathogenesis of alcoholic cardiomyopathy (ACM), molecular target(s) responsible for myocardial dysfunction in ACM are not well known. Objective: To determine the impact of chronic alcohol exposure on mitochondrial oxidative phosphorylation system (OXPHOS), permeability transition pore (mPTP) opening, and oxidative stress using a rat model of ACM. Methods: Sprague Dawley male rats (1 mo old) were exposed to alcohol (7.5% ethanol) for 3 months to develop ACM. Activity of OXPHOS was assessed enzymatically and by measuring mitochondrial oxygen consumption rate (OCR). The mPTP opening was determined by monitoring abrupt release of Ca 2+ after exposure of mitochondria to Ca 2+ . Western blot and RT-PCR were used to assess the expression of OXPHOS and mPTP protein components and corresponding genes. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were determined in heart tissue homogenates. Results: There was no significant change in OCR or activity of OXPHOS complexes I-V, despite a decrease in complex V protein and Atp6v1e2 gene expression (-1.7-fold, p2+ -induced mPTP opening. This was associated with increase in protein expression level of adenine nucleotide translocase 1/2 and voltage dependent anion channel 1. There was no difference in MDA or 4-HNE levels. Conclusion: Increased sensitivity of mitochondria to mPTP opening during long-term alcohol consumption may compromise cardiac energetic reserves and contractility, leading to ACM development and progression.

Background: AF, a common sustained arrhythmia that predisposes heart failure and stroke, is associated with cardiac fibrosis and oxidative stress. Peroxisome proliferator-activated receptor (PPAR)-α, important for ROS and lipid degradation, is reported to negatively correlate with kidney, liver, and lung fibrosis, but its role in cardiac fibrosis is less clear. We hypothesize that reduced expression of PPARα in AF contributes to oxidative stress and interferes with TGFβ signaling, a cytokine implicated in cardiac fibrosis. Methods: Myocardial fibrosis was detected (Masson trichrome) in right atrial appendages of AF and non-AF patients. Levels of 4-hydroxynonenal (4-HNE) (ELISA) and superoxide production (MitoSOX) were assayed in patients’ atrial tissue homogenates and cardiac myofibers respectively. Using atrial fibroblasts (hAF) from AF and non-AF patients, α-SMA, COL1A1 and c-Jun/c-Fos expressions were determined (RT-PCR and/or Western Blot) in the absence and presence of TGF-β (5 ng) with or without ciprofibrate (200 μM), a PPARα agonist. Results: Increased atrial fibrosis, levels of 4-HNE (101.7 vs 7.4 ng/mg protein; p=0.02(n=6)) and oxidative stress (8.7 fold; p=0.04) correlated with reduced PPAR-α mRNA (2.1 fold; p Conclusion: Reduced expression of PPARα is associated with impaired cardiac mitochondrial metabolism and promotes TGFβ-induced profibrotic pathway. Preliminary data suggest PPARα agonist might confer therapeutic benefits for patients with cardiac fibrosis and oxidative stress in AF.

Introduction: The mechanical and electrical dysfunction in heart failure (HF) is associated with excessive cardiac fibrosis (CF). Activation of human ventricular fibroblasts (hVF) and transdifferentiation to myofibroblasts underlies the increased CF. We recently reported that statin therapy reduced differentiation of hVF in HF patients. However, the underlying mechanism is not known. Therefore, we studied the effect of statin therapy on the transcriptome of hVF from HF patients. Hypothesis: We tested the hypothesis that statin therapy alters the expression of differentiation-associated transcription factors (TF) in hVFs from HF patients. Methods: Primary cultures of hVF obtained from HF patients undergoing left ventricular assist device implantation either under statin therapy for at least 1 year (n=3) or not (n=3). The extent of transcriptomic changes induced by statin therapy in hVFs was studied from total RNA using RT 2 Profiler TM PCR array - human transcription factors (Qiagen, Catalog No: PAHS-075Z ) run on Roche LightCycler 96-well block. Fold change was calculated by 2 -ΔΔCt method. Data were analyzed by Student’s t test, and P value Results: Out of the 84 related genes profiled, statin therapy upregulated significantly (P Conclusion: Statin therapy mitigates differentiation of hVFs from human failing heart patients by associated changes in the transcriptome. Selective targeting of hVF transcription factor may be a potential therapeutic strategy to de-differentiate myofibroblasts and mitigate the progression of CF and HF.

Weight loss after bariatric surgery is associated with reduction in adverse cardiovascular outcomes; however, the impact of obstructive sleep apnea (OSA) on reduction of cardiovascular outcomes after bariatric surgery in morbidly obese patients is not known. We retrospectively assessed differences in cardiovascular events after laparoscopic adjustable gastric banding (LAGB)-induced weight loss in patients with and without OSA before and after propensity score matching for age, sex, body mass index (BMI), and major comorbidities between the two groups and determined predictors of poor outcomes. OSA was present in 222 out of 830 patients (27 per cent) who underwent LAGB between 2001 and 2011. Despite a similar reduction in BMI (20.0 and 20.8 per cent), a significantly higher percentage of cardiovascular events were observed in patients with than without OSA (35.6 vs 6.9 per cent; p < 0.001) at 3 years (mean follow-up 6.0 ± 3.2; range: 0.5 to 13 years). The differences in the cumulative endpoint of new onset stroke, heart failure, myocardial infarction, venous thrombosis, and pulmonary embolism between the OSA and non-OSA groups were maintained after propensity matching. Patients with OSA treated with continuous positive airway pressure (CPAP) during sleep [n = 66] had lower cardiovascular event rates at 30 months compared with those not treated (p < 0.041). OSA (hazard ratio: 6.92, 95% CI: 3.39-14.13, p < 0.001) remained an independent predictor of cardiovascular events after multivariate analysis. Thus, patients with OSA, despite a similar initial weight loss after LAGB, had a higher incidence of cardiovascular events compared with a propensity-matched group without OSA. Treatment with CPAP appears to reduce such events.

Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights.

Introduction Danon disease is an X-linked lysosomal condition that causes a deficiency of lysosome-associated membrane protein 2 (LAMP2) gene. It is characterized clinically by a triad of skeletal myopathy, cardiomyopathy, and intellectual disability. Methods We examined clinical, echocardiographic, and genetic data on 5 patients with Danon disease, highlighting their clinical course and outcomes. Results All patients presented phenotypically with hypertrophic cardiomyopathy and later developed systolic dysfunction. The mean age at diagnosis was 19years (11–31years). All patients had diastolic dysfunction (mean e' of 5cm/s [3.5–6cm/s], mean E/e′ of 17 [15–21]). Three patients required cardiac transplantation (ages 15, 27, and 42). Of the two deaths in this group, both were in women. Conclusion We highlight the aggressive cardiac phenotype of Danon disease in our clinical experience with rapid progression to end-stage cardiomyopathy; this progression occurred in both men and women. A timely diagnosis and an early referral for cardiac transplantation is crucial for improved outcomes.

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.

Excessive cardiac fibrosis, characterized by increased collagen-rich extracellular matrix (ECM) deposition, is a major predisposing factor for mechanical and electrical dysfunction in heart failure (HF). The human ventricular fibroblast (hVF) remodeling mechanisms that cause excessive collagen deposition in HF are unclear, although reports suggest a role for [Ca2+]i in fibrosis. Therefore, we determined the association of differences in cellular Ca2+ dynamics and collagen secretion/deposition between hVFs from failing and normal (control) hearts. Histology of left ventricle sections (Masson trichrome) confirmed excessive fibrosis in HF vs normal. In vitro, hVFs from HF showed increased secretion/deposition of soluble collagen in 48 hours of culture compared with control [85.9±7.4 μg/106 vs 58.5±8.8 μg/106 cells, P

Background The trends in the incidence of different arrhythmias, consequent hospitalizations & electrophysiological (EP) studies in heart transplant recipients have not been reported on a national level. Methods Nationwide Inpatient Sample NIS database (2005-2014) was used to identify hospital stays for adults (gt 18-year-old) who had a previous heart transplant using ICD 9 code (V421). Hospital stays for heart transplant surgery were excluded. We compared the number of hospitalizations for different arrhythmias & EP procedures, between two periods: 2005-2009 & 2010-2014 using Chi-square test. Results Overall, there were 137,016 hospital stays for heart transplant recipients over the study period (10 years), arrhythmia was the cause of hospitalization in 2625 hospitalizations (1.9%). The most common type of arrhythmias were atrial fibrillation (19.4%), atrial flutter (18%), complete heart block (6.2%), sinus node dysfunction (5.7%) & cardiac arrest or VFib (3.3%). A total of 2916 EP procedures were performed during these hospitalizations. Most common EP procedures were: pacemaker related (63.9%), diagnostic EP procedure (9.7%), catheter ablation (6.9%), ICD related (4.5%), & cardiac resynchronization therapy (1.8%) (Figure 1). Complications were seen in 14% of procedures. The most common complications were mechanical complications requiring device revision/replacement (6%), infection (5.5%), & death (1.9%). There were no significant differences in the number of hospitalizations for arrhythmias, utilization of EP procedures or rate of procedural complications between the two periods. Conclusion Arrhythmias are responsible for about 2% of hospital admissions in heart transplant recipients. The most common arrhythmia was atrial fibrillation, & the most common EP procedure was pacemaker placement, revision or replacement. There were no significant differences in the incidence of individual arrhythmias as reasons for admission or number of performed EP procedures between 2005-2009 & 2010-2014.

Long QT syndrome (LQTS) is a heterogeneous disorder of prolonged repolarization that increases the risk for life-threatening arrhythmias. The diagnosis, based on a scoring system of clinical and electrocardiographic parameters is aided by genetic testing that allows classification into subtypes centered on mutations in genes coding for ion channel subunits or associated proteins (1). At least 15 different genes are implicated in LQTS, but the common subtypes are due to mutations in 3 genes coding for pore-forming subunits of 2 potassium (KCNQ1 and KCNH2 coding for IKs and IKr, respectively) and a sodium (SCN5a for Nav1.5) channel giving rise to what is known as LQTS1, LQTS2 and LQTS3, respectively. Despite advances in genotype characterization, it is difficult to predict the clinical presentation even within the same family, as members carrying the same mutation may present differently, from asymptomatic to more malignant course with recurrent syncope or cardiac arrest (1). Genotype-phenotype studies have correlated functional effects of gene mutations on ECG parameters, clinical presentation, triggers for arrhythmogenesis and responsiveness to therapy (2). Although spatial and temporal differences in repolarization due to individual ion channel defects and its heterogeneous distribution within the myocardium have been described (2), its impact on cardiac electrical and mechanical coupling has not been fully explored (3-6).

Background Sudden death may occur after radiofrequency catheter ablation of the atrioventricular node (AVN) and permanent pacemaker implantation. It is unclear whether a faster initial heart rate with gradual rate reduction decreases the risk of sudden death. Objective To evaluate the effects of initial pacing at a faster rate after AVN ablation, with a gradual rate decrease over 3 months, on the rate of sudden death in patients with atrial fibrillation. Methods We compared the rate of likely or possible procedure-related sudden death in 2 groups of patients who had AVN ablation and pacemaker implantation. The study cohort was treated between January 2005 and December 2009, and pacemakers were programmed to a lower rate of 90 beats/min after the procedure, with a monthly decrement of 10 beats/min until 60 beats/min was reached. The control group was treated between July 1990 and December 1998 when pacemakers were programmed to a lower rate of 60 beats/min immediately after ablation. Results The study cohort included 520 patients (mean age 73.6±10.3 years), and the control cohort comprised 334 patients (mean age 68.1±1.1 years). Sudden death deemed likely or possibly related to ablation and pacemaker implantation occurred in 1 patient in the study cohort (0.2%) and in 7 patients (2.1%) in the control group ( P = .007). Conclusions Sudden death was significantly decreased in the study cohort compared to controls. The faster lower pacing rate immediately after AVN ablation with a gradual decrease is a plausible mechanism for the improved clinical outcome.

Introduction: Excessive cardiac fibrosis (CF) underlies mechanical and electrical dysfunction in heart failure (HF). However, the underlying mechanisms of increased CF are unclear. Recently, we reported increased Orai1 expression and I CRAC (calcium release-activated channels) -Ca 2+ influx in failing heart ventricular fibroblasts (hVF). Therefore, we studied the magnitude of collagen secretion/deposition by hVF from failing hearts and the involvement of Ca 2+ influx through I CRAC channels in this process. Hypothesis: We tested the hypothesis that collagen secretion/deposition by hVFs from failing hearts will be high and sensitive to inhibition of I CRAC channels, compared to normal hearts. Methods: Primary cultures of hVF obtained from HF patients undergoing LV assist device implantation (n=9) were compared to non-diseased hVF from trauma victims (n=4). The degree of fibrosis was analyzed by histology of LV tissue sections (5μm) with Masson’s trichrome staining. Collagen secretion/deposition after 48 h culture of hVFs from failing or normal hearts in the presence or absence of I CRAC inhibitor, YM-58483(10 μM), was assayed calorimetrically using Sircol™ kit. Data were analyzed by unpaired Student’s t-test. Results: Histology of the failing heart LV sections with Masson’s trichome staining showed severe fibrosis compared to control sections. The percentage of positive staining area to total area, measured using custom-developed ImageJ macro, was significantly (p6 cells) than normal heart hVF (58.4±8.8 μg/10 6 cells). Incubation of fibroblasts with the I CRAC inhibitor YM58486 (10 μM) for 48 h eliminated the increase in collagen secretion of HF fibroblasts (55.8± 7 μg/10 6 cells vs 66.8± 6 μg/10 6 cells, p=0.27). Conclusion: LV fibrosis is severe in HF patients. The magnitude of pro-fibrotic collagen secretion/deposition by hVF from HF patients is significantly high but sensitive to I CRAC inhibition. Selective targeting of fibroblast I CRAC may be a potential therapeutic tool to mitigate progression of CF and HF.