Cardiovascular Research Program

New York City, VA, United States

Cardiovascular Research Program

New York City, VA, United States
SEARCH FILTERS
Time filter
Source Type

Aromolaran A.S.,Cardiovascular Research Program | Aromolaran A.S.,New York University | Boutjdir M.,Cardiovascular Research Program | Boutjdir M.,New York University
Frontiers in Physiology | Year: 2017

Obesity and its associated metabolic dysregulation leading to metabolic syndrome is an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese leading to enhanced risk of cardiovascular disease (CVD) incidence and mortality. Obesity predisposes to atrial fibrillation, ventricular, and supraventricular arrhythmias; conditions that are underlain by dysfunction in electrical activity of the heart. To date, current therapeutic options for cardiomyopathy of obesity are limited, suggesting that there is considerable room for development of therapeutic interventions with novel mechanisms of action that will help normalize rhythm in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels/Ca handling proteins remain incompletely understood. Obesity is marked by accumulation of adipose tissue associated with a variety of adverse adaptations including dyslipidemia (or abnormal levels of serum free fatty acids), increased secretion of pro-inflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, that will cause electrical remodeling and thus predispose to arrhythmias. Further, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which are marked by distinct signaling mechanisms. Thus, there may also be functional differences in the outcome of regional distribution of fat deposits on ion channel/Ca handling proteins expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge about the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. The objective of this article is to review cardiac ion channel/Ca handling proteins remodeling that predispose to arrhythmias. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. © 2017 Aromolaran and Boutjdir.


Restivo M.,Cardiovascular Research Program | Restivo M.,SUNY Downstate Medical Center | Kozhevnikov D.O.,Cardiovascular Research Program | Qu Y.S.,Cardiovascular Research Program | And 8 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias. Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30. min stabilization period, 15. min of no-flow ischemia, followed by 20. min reperfusion. Peptides (0.5. μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1). Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P<0.05) and (VF, 70%, P<0.05). However, the highest incidence of VT (100%, P<0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20. min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P<0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P<0.5) of hearts in control. At 20. min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2±9. ms) compared to exacerbated dispersion (115.4 ± 42 ms, P<0.05) in εPKC antagonist and control (67 ± 20. ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control. Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents. © 2012.


Yue Y.,Cardiovascular Research Program | Castrichini M.,University of Siena | Srivastava U.,Cardiovascular Research Program | Srivastava U.,New York University | And 22 more authors.
Circulation | Year: 2015

Background - Emerging clinical evidence demonstrates high prevalence of QTc prolongation and complex ventricular arrhythmias in patients with anti-Ro antibody (anti-Ro Ab)-positive autoimmune diseases. We tested the hypothesis that anti-Ro Abs target the HERG (human ether-a-go-go-related gene) K+ channel, which conducts the rapidly activating delayed K+ current, IKr, thereby causing delayed repolarization seen as QT interval prolongation on the ECG. Methods and Results - Anti-Ro Ab-positive sera, purified IgG, and affinity-purified anti-52kDa Ro Abs from patients with autoimmune diseases and QTc prolongation were tested on IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein. The 52-kDa Ro antigen-immunized Guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro Abs, which inhibited native IKr and cross-reacted with Guinea pig ERG channel. Conclusions - The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit IKr by cross-reacting with the HERG channel likely at the pore region where homology between anti-52-kDa Ro antigen and HERG channel is present. The animal model of autoimmune-associated QTc prolongation is the first to provide strong evidence for a pathogenic role of anti-Ro Abs in the development of QTc prolongation. It is proposed that adult patients with anti-Ro Abs may benefit from routine ECG screening and that those with QTc prolongation should receive counseling about drugs that may increase the risk for life-threatening arrhythmias. © 2015 American Heart Association, Inc.


Puckerin A.,Columbia University | Aromolaran K.A.,Yeshiva University | Chang D.D.,Columbia University | Zukin R.S.,Yeshiva University | And 4 more authors.
Heart Rhythm | Year: 2016

Background The human ether-à-go-go-related gene (hERG 1a) potassium channel is critical for cardiac repolarization. hERG 1b, another variant subunit, co-assembles with hERG 1a, modulates channel biophysical properties and plays an important role in repolarization. Mutations of hERG 1a lead to type 2 long QT syndrome (LQT2), and increased risk for fatal arrhythmias. The functional consequences of these mutations in the presence of hERG 1b are not known. Objective To investigate whether hERG 1a mutants exert dominant negative gating and trafficking defects when co-expressed with hERG 1b. Methods Electrophysiology, co-immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments in HEK293 cells and guinea pig cardiomyocytes were used to assess the mutants on gating and trafficking. Mutations of 1a-G965X and 1a-R1014X, relevant to gating and trafficking were introduced in the C-terminus region. Results The hERG 1a mutants when expressed alone did not result in decreased current amplitude. Compared to wild-type hERG 1a currents, 1a-G965X currents were significantly larger, whereas those produced by the 1a-R1014X mutant were similar in magnitude. Only when co-expressed with wild-type hERG 1a and 1b did a mutant phenotype emerge, with a marked reduction in surface expression, current amplitude, and a corresponding positive shift in the V1/2 of the activation curve. Co-immunoprecipitation and FRET assays confirmed association of mutant and wild-type subunits. Conclusion Heterologously expressed hERG 1a C-terminus truncation mutants, exert a dominant negative gating and trafficking effect only when co-expressed with hERG 1b. These findings may have potentially profound implications for LQT2 therapy. © 2016 Heart Rhythm Society.


Aromolaran A.S.,Columbia University | Colecraft H.M.,Columbia University | Boutjdir M.,Cardiovascular Research Program | Boutjdir M.,New York University
Biochemical and Biophysical Research Communications | Year: 2016

Obesity is associated with hyperlipidemia, electrical remodeling of the heart, and increased risk of supraventricular arrhythmias in both male and female patients. The delayed rectifier K+ current (I K), is an important regulator of atrial repolarization. There is a paucity of studies on the functional role of I K in response to obesity. Here, we assessed the obesity-mediated functional modulation of I K in low-fat diet (LFD), and high-fat diet (HFD) fed adult guinea pigs. Guinea pigs were randomly divided into control and obese groups fed, ad libitum, with a LFD (10 kcal% fat) or a HFD (45 kcal% fat) respectively. Action potential duration (APD), and IK were studied in atrial myocytes and IKr and IKs in HEK293 cells using whole-cell patch clamp electrophysiology. HFD guinea pigs displayed a significant increase in body weight, total cholesterol and total triglycerides within 50 days. Atrial APD at 30% (APD30) and 90% (APD90) repolarization were shorter, while atrial I K density was significantly increased in HFD guinea pigs. Exposure to palmitic acid (PA) increased heterologously expressed I Kr and I Ks densities, while oleic acid (OA), severely reduced I Kr and had no effect on I Ks. The data are first to show that in obese guinea pigs abbreviated APD is due to increased I K density likely through elevations of PA. Our findings may have crucial implications for targeted treatment options for obesity-related arrhythmias. © 2016.


PubMed | VA New York Harbor Healthcare System, Mount Sinai School of Medicine, Cardiovascular Research Program, University of Siena and Laval University
Type: Journal Article | Journal: The Journal of physiology | Year: 2016

Channelopathies of autoimmune origin are novel and are associated with corrected QT (QTc) prolongation and complex ventricular arrhythmias. We have recently demonstrated that anti-SSA/Ro antibodies from patients with autoimmune diseases and with QTc prolongation on the ECG target the human ether--go-go-related gene (HERG) KWe recently demonstrated that anti-SSA/52kDa Ro antibodies (Abs) from patients with autoimmune diseases and corrected QT (QTc) prolongation directly target and inhibit the human ether--go-go-related gene (HERG) K


PubMed | University of Basel, Cardiovascular Research Program, Laval University, University of Québec and University of Zürich
Type: | Journal: The Canadian journal of cardiology | Year: 2016

The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated NaWe generated hiPSC-CM using the recently described monolayer-based differentiation protocol.hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct NaThe findings indicated that hiPSC-CM robustly express Na


PubMed | Cardiovascular Research Program and New York University
Type: | Journal: Biochemical and biophysical research communications | Year: 2016

Ca entry through atrial L-type Calcium channels (


PubMed | Cardiovascular Research Program
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2012

Pervious biochemical and hemodynamic studies have highlighted the important role of PKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of PKC modulation in ischemic hearts. Membrane permeable peptide PKC selective activator and inhibitor were used to investigate the role of PKC modulation in reperfusion arrhythmias.Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30 min stabilization period, 15 min of no-flow ischemia, followed by 20 min reperfusion. Peptides (0.5 M) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled RACK peptide); (b) PKC agonist (TAT-RACK); (c) PKC antagonist (TAT-V1).Hearts treated with PKC agonist RACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P<0.05) and (VF, 70%, P < 0.05). However, the highest incidence of VT (100%, P < 0.05) and VF (80%) occurred in hearts treated with PKC antagonist peptide V1 compared to control and to PKC agonist RACK. Interestingly, at 20 min reperfusion, 100% of hearts treated with PKC agonist RACK exhibited complete recovery of action potentials compared to 40% (P < 0.05) of hearts treated with PKC antagonist peptide, V1 and 65% (P < 0.5) of hearts in control. At 20 min reperfusion, maps of action potential duration from PKC agonist RACK showed minimal dispersion (48.2 9 ms) compared to exacerbated dispersion (115.4 42 ms, P < 0.05) in PKC antagonist and control (67 20 ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control.The results demonstrate that PKC activation by RACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of PKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents.

Loading Cardiovascular Research Program collaborators
Loading Cardiovascular Research Program collaborators