Staying connected without connexin43: can you hear me now?
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Animals↗
Biomedical subjects
Barry London
Publications and source records attributed to Barry London.
Effect of the TNF-alpha-promoter polymorphism on cardiac allograft rejection.
BACKGROUND: A polymorphism exists in the tumor necrosis factor alpha (TNF-alpha) promoter (position -308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-alpha production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. METHODS: We prospectively analyzed 57 subjects (aged 54 +/- 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 +/- 605 days) and the frequency of allograft rejection (biopsy Grade > or =2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. RESULTS: The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 +/- 11 days; Group B, 20 +/- 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). CONCLUSION: The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.
Adult↗
Interaction of implantable defibrillator therapy with angiotensin-converting enzyme deletion/insertion polymorphism.
INTRODUCTION: The angiotensin-converting enzyme deletion allele (ACE D) decreases survival in patients with advanced heart failure. Whether the adverse impact on survival reflects an increased risk of pump failure or arrhythmic sudden death remains uncertain. If the ACE D genotype increases the risk of sudden death, implantable cardioverter defibrillator (ICD) therapy should diminish its negative impact. We sought to evaluate the effect of ICD therapy on ACE D genetic risk. METHODS AND RESULTS: The Genetic Risk Assessment of Cardiac Events (GRACE) study enrolled 479 patients at the University of Pittsburgh between 1996 and 2001. Blood was genotyped for the ACE D/I (deletion/insertion) polymorphism. Of the 479 patients, 82 (77% male, 84% Caucasian, age 56 +/- 11 years, 60% ischemic, left ventricular ejection fraction 0.23 +/- 0.08) received an ICD and were selected for outcomes analysis (mean follow-up 871 +/- 538 days). Transplant-free survival and survival alone were compared in ACE DD patients (n = 24, 29%) versus ACE DI/II patients (n = 58, 71%). Survival was significantly improved in ACE DI/II patients compared to those without an ICD (1 year: 93% vs 87%; 2 year: 89% vs 77%; P = 0.02) but not in ACE DD patients. Transplant-free survival among patients with an ICD was significantly worse in ACE DD versus ACE DI/II (1 year: 67% vs 88%, 2 year: 55% vs 80%, P = 0.03). Analysis of survival as a single endpoint revealed a similar result (1 year = 78% vs 94%; 2 year: 72% vs 88%; P = 0.05). ICD telemetry data showed a nonsignificant trend toward fewer individuals with arrhythmias in the ACE-DD group (46% vs 65%, P = 0.22) CONCLUSION: ICDs do not diminish the adverse influence of the ACE DD genotype on survival. This finding suggests that mortality in this high-risk genetic subset of patients is due to progression of heart failure rather than arrhythmic sudden death.
Alleles↗
Fatty acid metabolism and arrhythmias.
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Arrhythmias, Cardiac↗
Cardiac autonomic modulation by estrogen in female mice undergoing ambulatory monitoring and in vivo electrophysiologic testing.
INTRODUCTION: Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice. METHODS: Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring. RESULTS: With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups). CONCLUSION: Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women.
Animals↗
Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype.
Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of caveolin-3 expression is fundamental for normal muscle functions. Since caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of caveolin-3 on cardiac structure and function by characterizing caveolin-3 transgenic mice. Our results indicate that overexpression of caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of caveolin-3 in the heart. Taken together, these results indicate that overexpression of caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.
Animals↗
Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure.
BACKGROUND: Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. METHODS AND RESULTS: Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56+/-12 years) with systolic dysfunction (left ventricular ejection fraction < or =0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp298 variant. Event-free survival was significantly poorer in patients with the Asp298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P=0.03). In subset analysis, the adverse impact of the Asp298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P=0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P=0.71). CONCLUSIONS: For patients with heart failure caused by systolic function, the Asp298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.
Adult↗
Detecting instabilities of cardiac rhythm.
Diminished beat-to-beat variations in cardiac cycle lengths (CLs) are associated with poor prognosis after acute myocardial infarction and in patients with heart failure. Short-long-short sequences of cardiac cycles, or ultra-short rhythm instabilities, precede initiation of ventricular tachyarrhythmias in some patients. However, little is known about clinical or prognostic significance of abrupt short-term instabilities in CL (AICL) that occur minutes to hours before the event, in part because appropriate analytical methods are lacking. Although various techniques have been used to analyze CL changes, methods for analysis of AICL are limited. We compared performance of time domain, spectral, nonlinear, and pattern recognition techniques with respect to the detection and quantification of AICL. Because of high intra- and inter-subject variability of CL, pattern recognition techniques compared favorably to other studied methods. In continuous ambulatory ECG recordings, AICL occurred hours before spontaneous initiation of sustained atrial and ventricular arrhythmias in different patient populations. AICL were also found prior to the onset of spontaneous ventricular arrhythmias in a mouse model of congestive heart failure. To quantify AICL, we used the number of unstable orthogonal projection coefficients; this number gradually increased hours before the event. Removal of ectopic beats reduced but did not eliminate AICL. To illustrate potential physiological effects and temporal evolution of AICL, we used a simple, continuous, two-dimensional model of cardiac tissue governed by the Morris-Lecar equations. Computer simulations in this model showed that AICL may lead to gradual accumulation of spatial irregularities of the propagation wavefront giving rise to the initiation of reentry. Time-frequency analysis of the most significant eigenvectors of cardiac rhythm in subjects undergoing head-up tilt showed that AICL could indicate instabilities and unsuccessful adaptation of autonomic nervous system activity to physiological stimuli.
Animals↗
A second ACE of hearts.
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Angiotensin-Converting Enzyme 2↗
Autonomic blockade unmasks maturational differences in rate-dependent atrioventricular nodal conduction and facilitation in the mouse.
INTRODUCTION: In large animals, rate-dependent AV nodal (AVN) properties of conduction are modulated by autonomic inputs. In this study, we investigated whether the properties of AVN conduction and facilitation are altered by autonomic blockade in the mouse and whether this effect is age dependent. METHODS AND RESULTS: Young (age 4-6 weeks; n = 11) and adult (age 8-9 months; n = 11) female mice underwent in vivo electrophysiologic testing, before and after autonomic blockade. After autonomic blockade, the adult mice had significantly longer AVN effective refractory period (AVNERP; 67 +/- 14 msec vs 56 +/- 4 msec, P = 0.05) and functional refractory period (AVNFRP; 81 +/- 10 msec vs 72 +/- 4 msec, P = 0.05). With autonomic blockade, the increase from baseline of AVN Wenckebach cycle length (deltaAVW; 1.8 +/- 8.1 msec vs 8.8 +/- 3.3 msec, P = 0.04), as well as of AVNERP (deltaAVNERP; 3.5 +/- 3.5 msec vs 21.4 +/- 12.6 msec, P = 0.002) and AVNFRP (deltaAVNFRP; 2.3 +/- 3.2 msec vs 12.8 +/- 9.0 msec, P = 0.008), was significantly larger in adult than in young mice. Compared with young mice, adult mice were less likely to exhibit AVN facilitation (44% vs 90%, P = 0.03) and had smaller maximal shortening of AVN conduction times after the "test beat" for any coupling of the "facilitating beat" (4 +/- 4 msec vs 7 +/- 3 msec, P = 0.05). CONCLUSION: Complete autonomic blockade significantly increases AVN conduction times and refractory periods in adult but not in young mice. Adult mice also exhibit less AVN facilitation. Our results confirm that, like in larger animals, rate-dependent murine AVN properties of conduction are under autonomic regulation. Adult mice have higher sympathetic AVN inputs at baseline, leading to slower conduction after autonomic blockade.
Adaptation, Physiological↗
Calcium-dependent arrhythmias in transgenic mice with heart failure.
Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.
Action Potentials↗
Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3.
BACKGROUND: Brugada syndrome is a form of idiopathic ventricular fibrillation characterized by a right bundle-branch block pattern and ST elevation (STE) in the right precordial leads of the ECG. Sodium channel blockers increase STE. Mutations of the cardiac sodium channel SCN5A cause the disorder, and an implantable cardioverter-defibrillator is often recommended for affected individuals. Mutations in other genes have not been identified, and it is not known if the efficacy of drug testing or the malignancy of arrhythmias correlates to the gene defect. METHODS AND RESULTS: We performed histories, physical examinations, ECGs, and drug testing on a large multigenerational family with Brugada syndrome. DNA isolated from blood samples, polymorphic genomic markers, and polymorphisms within candidate sodium channels were used for a genome-wide screen, fine mapping, and linkage analysis. We identified 12 affected individuals (right bundle-branch block, > or =1-mm STE) with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. Four affected individuals had syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death. Procainamide infusions did not identify additional affected individuals. Linkage was present to an approximately equal 15-cM region on chromosome 3p22-25 (maximum LOD score=4.00). The sodium channel genes SCN5A, SCN10A, and SCN12A on chromosome 3 were excluded as candidates (LOD scores < or =-2). CONCLUSIONS: A Brugada syndrome locus distinct from SCN5A is associated with progressive conduction disease, a low sensitivity to procainamide testing, and a relatively good prognosis in a single large pedigree.
Adult↗
Presynaptic factors in the regulation of DSI expression in hippocampus.
We studied the mechanisms by which GABA release is reduced in the retrograde signaling process called depolarization-induced suppression of inhibition (DSI). DSI is mediated by endocannabinoids in acute and cultured organotypic hippocampal slices. We examined a variety of K(+) channel antagonists to determine the nature of the K(+) channel that, when blocked, reduces DSI. Among 4-AP, TEA, dendrotoxin, Cs, margatoxin, and charybdotoxin, only 4-AP was highly effective in blocking DSI, suggesting that a K(+) channel composed in part of K(V1.4,) K(V1.5) or K(V1.7) subunits can readily regulate DSI. The inhibition of DSI by 4-AP is largely overcome by reducing [Ca(2+)](o), however, suggesting that DSI expression can be prevented by saturation of the release process when a K(V1.X) channel is inhibited. DSI of agatoxin- and TTX-insensitive mIPSCs was unaffected by 4-AP, but was largely occluded by omega-conotoxin GVIA, indicating that block of presynaptic N-type Ca(2+) channels is probably a major mechanism of DSI expression. Significant DSI of mIPSCs remained in omega-conotoxin, hence we infer that block of N-channels does not fully explain hippocampal DSI expression.
2-Amino-5-phosphonovalerate↗
Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice.
Transgenic mice are widely used to study cardiac function, but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. We compared 1) short-term pharmacological responses of cardiac rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2) long-term physiological dynamics of cardiac rhythm and survival in tumor necrosis factor (TNF)-alpha transgenic mice with heart failure (TNF-alpha mice) on defined backgrounds. Ambulatory telemetry electrocardiographic recordings and response to saline, adrenergic, and cholinergic agents were examined in FVB and C57Black6/SV129 mice. In FVB mice, baseline heart rate (HR) was higher and did not change after injection of isoproterenol or atropine but decreased with propranolol. In C57Black6/SV129 mice, HR did not change with propranolol but increased with isoproterenol or atropine. Mean HR, but not indexes of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF-alpha mice on an FVB background than on a mixed FVB/C57Black6 background. The homeostatic states of ANSA are strain specific, which can explain the interstrain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments.
Adrenergic alpha-Antagonists↗
Clinical importance of beta-adrenoceptor polymorphisms in cardiovascular disease.
beta-Adrenoceptor antagonists play an important role in the treatment of cardiovascular disease and have been used for three decades in the treatment of hypertension and ischemic heart disease. More recently they have been demonstrated to improve survival in patients with mild to moderate congestive heart failure. The beneficial effects of beta-adrenoceptor antagonists stems from their ability to limit the deleterious effects of adrenergic stimulation, which in the cardiovascular system is primarily transmitted through two subclasses of receptor, beta(1) and beta(2). The advances of the Human Genome Project have led to an increased appreciation that variations in genetic background may underlie a substantial portion of the clinical heterogeneity apparent in cardiovascular disease. This review examines the molecular, functional, and clinical significance of the most common polymorphisms of the beta(1 and beta(2)-adrenoceptors. Initial research in adrenoceptor variation focused on the beta(2)-adrenoceptor. Three common polymorphisms appear to influence receptor function: Arg16-->Gly, Glu(27)-->Gln, and Thr(164)-->Ile. In in vitro studies of agonist stimulation, Gly(16) receptors demonstrate enhanced downregulation, while Glu(27) variants are resistant to downregulation. There is much controversy and conflict among various clinical studies regarding the effect of these variants on vasoreactivity and hypertensive risk. The Ile(164) variant demonstrates decreased responsiveness to agonist activity both in vitro and in animal models. In studies of patients with congestive heart failure, this variant has been associated with poor functional capacity and decreased survival. More recent investigations have focused on the two common polymorphisms of the beta(1)-adrenoceptor: Ser(49)-->Gly, and Arg(389)-->Gly. In vitro studies of Arg(389) receptors demonstrate a gain of function, as agonist stimulation results in significantly higher intracellular levels of cyclic adenosine monophosphate when compared with the Gly(389) variant. Consistent with the in vitro data, clinical studies demonstrate increased responsiveness to beta-agonist stimulation, and an increased risk of hypertension among Arg(389) homozygotes. Further investigation of the clinical implications of these common variants of beta(1)- and beta2)-adrenoceptors are needed. Importantly, the pharmacogenetic impact of these variants on the effectiveness of beta-adrenergic blockade remains unknown.
Animals↗
Heel spur syndrome: a retrospective report on the percutaneous plantar transverse incisional approach.
The purpose of this retrospective study was to investigate patient satisfaction and pain relief of chronic heel spur syndrome via a percutaneous plantar transverse incisional surgical approach. Forty-five patients underwent the procedure between June 1995 and August 1997; 29 responded to a questionnaire. Of the 29 respondents, a 96% success rate was obtained (the procedure met or exceeded patient expectations) at an average of 21 months postoperatively. Based on a 10-point visual analog scale, pain improved from an average of 8.4 +/- 0.3 preoperatively to 1.2 +/- 0.3 at the time of the survey. The surgical technique is also described.
Adult↗