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Barry London

Publications and source records attributed to Barry London.

At least 19 recordsLinked to original sources
PubMed2025

Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Humans↗
PubMed2012

Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression.

The calcium pump SERCA2a (sarcoplasmic reticulum calcium ATPase 2a), which plays a central role in cardiac contraction, shows decreased expression in heart failure (HF). Increasing SERCA2a expression in HF models improves cardiac function. We used direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in HF and normal canine models to study safety, efficacy, and the effects of immunosuppression. Tachycardic-paced dogs received left ventricle (LV) wall injection of AAV6-hSERCA2a or solvent. Pacing continued postinjection for 2 or 6 weeks, until euthanasia. Tissue/serum samples were analyzed for hSERCA2a expression (Western blot) and immune responses (histology and AAV6-neutralizing antibodies). Nonpaced dogs received AAV6-hSERCA2a and were analyzed at 12 weeks; a parallel cohort received AAV-hSERCA2a and immunosuppression. AAV-mediated cardiac expression of hSERCA2a peaked at 2 weeks and then declined (to ~50%; p<0.03, 6 vs. 2 weeks). LV end diastolic and end systolic diameters decreased in 6-week dogs treated with AAV6-hSERCA2a (p<0.05) whereas LV diameters increased in control dogs. Dogs receiving AAV6-hSERCA2a developed neutralizing antibodies (titer &#x2265;1:120) and cardiac cellular infiltration. Immunosuppression dramatically reduced immune responses (reduced inflammation and neutralizing antibody titers <1:20), and maintained hSERCA2a expression. Thus cardiac injection of AAV6-hSERCA2a promotes local hSERCA2a expression and improves cardiac function. However, the hSERCA2a protein level is reduced by host immune responses. Immunosuppression alleviates immune responses and sustains transgene expression, and may be an important adjuvant for clinical gene therapy trials.

Animals↗
PubMed2006

Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT.

Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, I(to,f), have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4-/-) that lack the slow component of I(to) (I(to,s)), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN x Kv1.4-/-) mice that lack both I(to,f) and I(to,s), have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 +/- 2.5 ms, P < 0.01, n = 6), Kv1.4-/- (28.4 +/- 0.4 ms, P < 0.01, n = 5) and Kv4.2DN x Kv1.4-/- (34.3 +/- 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 +/- 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 +/- 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4-/- (14.2 +/- 2.0 ms, n = 5, P < 0.05) and Kv4.2DN x Kv1.4(-/-) (15.0 +/- 3 ms, n = 5, P < 0.5) mice compared with controls (10 +/- 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4-/- (n = 4/5) and Kv4.2DN x Kv1.4-/- hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that I(to,f) was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.

Action Potentials↗
PubMed2006

Mouse models of long QT syndrome.

Congenital long QT syndrome is a rare inherited condition characterized by prolongation of action potential duration (APD) in cardiac myocytes, prolongation of the QT interval on the surface electrocardiogram (ECG), and an increased risk of syncope and sudden death due to ventricular tachyarrhythmias. Mutations of cardiac ion channel genes that affect repolarization cause the majority of the congenital cases. Despite detailed characterizations of the mutated ion channels at the molecular level, a complete understanding of the mechanisms by which individual mutations may lead to arrhythmias and sudden death requires study of the intact heart and its modulation by the autonomic nervous system. Here, we will review studies of molecularly engineered mice with mutations in the genes (a) known to cause long QT syndrome in humans and (b) specific to cardiac repolarization in the mouse. Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models.

Animals↗
PubMed2006

A sodium channel pore mutation causing Brugada syndrome.

BACKGROUND: Brugada and long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine-to-isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5A) in a family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type electrocardiogram changes, and have relatively normal corrected QT intervals. OBJECTIVES: To characterize the properties of the newly identified cardiac sodium channel (SCN5A) mutation at the cellular level. RESULTS: Using whole-cell voltage clamp, we found that heterologous expression of SCN5A containing the T353I mutation resulted in 74% +/- 6% less peak macroscopic sodium current when compared with wild-type channels. A construct of the T353I mutant channel fused with green fluorescent protein failed to traffic properly to the sarcolemma, with a large proportion of channels sequestered intracellularly. Overnight exposure to 0.1 mM mexiletine, a Na(+) channel blocking agent, increased T353I channel trafficking to the membrane to near normal levels, but the mutant channels showed a significant late current that was 1.6% +/- 0.2% of peak sodium current at 200 ms, a finding seen with long QT mutations. CONCLUSIONS: The clinical presentation of patients carrying the T353I mutation is that of Brugada syndrome and could be explained by a cardiac Na(+) channel trafficking defect. However, when the defect was ameliorated, the mutated channels had biophysical properties consistent with long QT syndrome. The lack of phenotypic changes associated with the long QT syndrome could be explained by a T353I-induced trafficking defect reducing the number of mutant channels with persistent currents present at the sarcolemma.

Action Potentials↗
PubMed2006

Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans.

BACKGROUND: Analysis of repolarization instability, manifested by T-wave alternans (TWA), has proved useful for arrhythmia risk assessment. However, temporal relations between TWA and the spontaneous initiation of ventricular tachyarrhythmias (VTA) in humans are unknown. We examined continuous dynamics of repolarization in Holter electrocardiograms with spontaneous sustained (>30 seconds) VTA. METHODS AND RESULTS: Ambulatory electrocardiograms from 42 patients (79% with ischemic heart disease; left ventricular ejection fraction, 37+/-15%) were digitized, and the lead with the highest magnitude of the T wave was selected for analysis. TWA was examined by the modified moving average and intrabeat average analyses. To examine non-TWA (longer-period) oscillations in the repolarization segment, spectral energy of oscillations of consecutive T-wave amplitudes was calculated with the use of the short-time Fourier transform. Heart rate variability was assessed with the Fourier transform as well. TWA increased before the onset of VTA and reached a peak value of 23.6+/-11.7 microV 10 minutes before the event (P=0.0007). Spectral power of the oscillations of consecutive T-wave amplitudes increased nonuniformly, with the greatest increase in the respiratory range (2.6 microV2; P=0.005). In the TWA range, the change was smaller but highly pronounced relative to the 60- to 120-minute level (65%; P=0.003). The low-frequency and high-frequency heart rate variability power declined before the arrhythmia (P=0.04 and P=0.06, respectively). CONCLUSIONS: The magnitude of repolarization instability, manifested by TWA and beat-to-beat oscillations of T-wave amplitudes at other frequencies, increased before the onset of VTA. Tracking of these dynamics can facilitate timely detection of high-risk periods and may be useful for initiation of preventive treatments.

Aged↗
PubMed2006

Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway.

Skeletal muscle atrophy results from an imbalance in protein degradation and protein synthesis and occurs in response to injury, various disease states, disuse, and normal aging. Current treatments for this debilitating condition are inadequate. More information about mechanisms involved in the onset and progression of muscle atrophy is necessary for development of more effective therapies. Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse. Further, ectopic expression of Merg1a in vivo induces atrophy in healthy wt-bearing mice, while expression of a dysfunctional Merg1a mutant suppresses atrophy in hindlimb-suspended mice. Treatment of hindlimb-suspended mice with astemizole, a known Merg1a channel blocker, inhibits atrophy in these animals. Importantly, in vivo expression of Merg1a in mouse skeletal muscle activates the ubiquitin proteasome pathway that is responsible for the majority of protein degradation that causes muscle atrophy, yet expression of a dysfunctional Merg1a mutant decreases levels of ubiquitin-proteasome proteolysis. Thus, expression of Merg1a likely initiates atrophy by activating ubiquitin-proteasome proteolysis. This gene and its product are potential targets for prevention and treatment of muscle atrophy.

Animals↗
PubMed2006

Genetic susceptibility to atrial fibrillation in patients with congestive heart failure.

BACKGROUND: Previous reports demonstrate an association between atrial fibrillation (AF) and certain polymorphisms in genes controlling the production of angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS). OBJECTIVES: The purpose of this study was to examine the association between polymorphisms of ACE and eNOS gene complexes and AF in an unselected series of patients with congestive heart failure (CHF). METHODS: In each of the 340 unselected, unrelated patients with CHF, common polymorphisms in ACE (I/D) and eNOS (T786C, G894T, and intron 4b/a) gene complexes were evaluated. Associations between individual genotypes and the presence of AF were assayed. RESULTS: AF was present in 51 patients (15%) and was significantly associated with the ACE D/D (odds ratio 1.5) and eNOS 894 T/T genotypes (odds ratio 3.2). There were no significant associations between AF and eNOS 786 or eNOS intron 4 genotypes. CONCLUSION: In patients with CHF, the presence of AF was significantly associated with certain ACE and eNOS genotypes.

Atrial Fibrillation↗
PubMed2006

Renal insufficiency predicts the time to first appropriate defibrillator shock.

BACKGROUND: Indications for implantable cardioverter defibrillator (ICD) implantation are expanding, but many primary and secondary ICD trials have excluded patients with advanced renal insufficiency. We investigated the effect of renal function on the incidence and time to first appropriate ICD shock. METHOD: We analyzed data from all new ICD implantations at a tertiary care center from July 2001 to December 2002. RESULTS: During a mean follow-up time of 445 +/- 285 days, 29 (13%) of 230 patients (age 63 +/- 14 years, 79% men, 77% white, 75% coronary artery disease, left ventricular ejection fraction 0.28 +/- 0.14) received 41 appropriate shocks. Patients were divided into tertiles according to their serum creatinine level. The 1-year incidence of appropriate ICD shock was 3.8%, 10.8%, and 22.7% in the first, second, and third tertiles, respectively (P = .003). Using the same cut off values of serum creatinine, the 1-year incidence of appropriate ICD therapy (shock and antitachycardia pacing) was 8.8%, 20.8%, and 26.3% (P = .02). After correcting for age, sex, race, left ventricular ejection fraction, indication for ICD implantation, and use of beta-blockers in a Cox regression model, serum creatinine was still an independent predictor of the time to first appropriate ICD shock (hazard ratio 6.0 for the third compared with the first tertile, P = .001). CONCLUSION: Renal insufficiency is a strong predictor of appropriate ICD shocks. Defibrillator therapy should therefore not be withheld based on the presence of this comorbidity. The mechanisms underlying the relationship between renal function and ventricular arrhythmias deserve further investigation.

Aged↗
PubMed2005

Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha.

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.

Action Potentials↗
PubMed2005

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}.

Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.

Action Potentials↗
PubMed2004

Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.

OBJECTIVES: We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival. BACKGROUND: The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated. METHODS: We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 +/- 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose ( 50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype. RESULTS: The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38). CONCLUSIONS: Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2004

Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation.

BACKGROUND: Conduction system defects and slowed ventricular conduction are common in patients with systolic dysfunction and contribute to arrhythmias and sudden death. In animal models of heart failure, cardiac alpha1-adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of alpha1-adrenergic signaling on connexin phosphorylation and cardiac conduction. METHODS AND RESULTS: Transgenic mice were generated with cardiac-specific overexpression of the transcription factor RTEF-1 (transcription enhancer factor-1-related factor), which mediates alpha1-adrenergic signaling in cardiac myocytes. Surface and intracardiac ECGs revealed prolongation of the PR, QRS, and AH intervals and the appearance of progressive atrial arrhythmias in RTEF-1 mice. Optical mapping using voltage-sensitive dye revealed slower conduction velocities across the atrial and ventricular myocardium. Intercellular dye transfer between RTEF-1 transgenic cardiac myocytes confirmed impaired conduction at the cellular level. Conduction defects were correlated with dephosphorylation of connexin40 and connexin43 and upregulation of protein phosphatase 1beta (PP1beta). Overexpression of PP1beta in HeLa cells dephosphorylated cardiac connexin. Confocal microscopy revealed increased levels of dephosphorylated connexin43 at the cardiac gap junctions in RTEF-1 mice, suggesting that defective conduction is a result of impaired gap-junction conductance rather than assembly. CONCLUSIONS: Constitutive activation of alpha1-adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1beta expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.

Animals↗
PubMed2004

Utilization of implantable cardioverter-defibrillators in survivors of cardiac arrest in the United States from 1996 to 2001.

OBJECTIVES: We analyzed the incidence of implantable cardioverter-defibrillator (ICD) therapy in survivors of cardiac arrest (CA) in the U.S. from 1996 through 2001. BACKGROUND: Cardiac arrest is a class I indication for ICD therapy. The current patterns of ICD utilization in survivors of CA have not been fully examined. METHODS: We searched a representative sample of all hospital discharges for patients admitted with the primary diagnosis of CA who survived to hospital discharge. Patients with a concomitant diagnosis of acute myocardial infarction or previous ICD in situ were excluded. RESULTS: From 1996 to 2001, 113,262 patients were admitted for CA. Of those, 63,745 (56.3%) did not survive to hospital discharge. Of the remaining 49,517 patients, 30.7% received an ICD before discharge, with a gradual increase in implantation rates from 1996 (23.6%) to 2001 (46.3%). Using logistic regression for the years 2000 and 2001, patients who were discharged without an ICD were older (odds ratio [OR] 0.93 for every 10-year increase in age, p < 0.001), more likely to be African American (OR 0.19, p < 0.001), and more likely to be admitted to a smaller hospital (OR 2.24 for each additional 100 beds, p < 0.001). These predictors were independent of other co-morbid illnesses. CONCLUSIONS: Although they are increasing, the rates of ICD therapy after CA remain very low. There are gross discrepancies by race. At a time when newer indications for ICD implantation are emerging, efforts should be focused on identifying the causes of this underutilization and discrepancies in survivors of CA.

Aged↗
PubMed2004

Epidemiology and determinants of outcome of admissions for atrial fibrillation in the United States from 1996 to 2001.

Despite numerous epidemiologic studies, few data exist on recent trends in admissions to United States hospitals of patients with atrial fibrillation (AF) as a primary diagnosis and on the determinants of outcome of these hospitalizations. In the present study, we investigated recent trends in the incidence of AF admissions to United States hospitals from 1996 to 2001 using a representative sample of all acute-care hospital admissions in the United States provided by the Centers for Disease Control, with special attention to the importance of age, gender, race, and other determinants of outcome, namely, in-hospital mortality.

Adolescent↗