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Biomedical subjects

Bruce B Lerman

Publications and source records attributed to Bruce B Lerman.

At least 19 recordsLinked to original sources
PubMed2006

Newly detected atrial fibrillation following dual chamber pacemaker implantation.

INTRODUCTION: Pacemaker (PPM)-detected atrial high-rate episodes (AHREs) of even 5-minute duration may identify patients at increased risk for stroke and death. In this study, we sought to determine the incidence of newly detected atrial fibrillation (AF defined as an AHRE > or = 5 minutes) in patients following dual-chamber PPM implantation and to define the clinical predictors of developing AF. METHODS AND RESULTS: We evaluated 262 patients (142 male; age 74 +/- 12 years) without documented AF who underwent PPM implantation for sinus node dysfunction (n = 122) or atrioventricular block (n = 140). Information regarding patient demographics, cardiovascular diseases, and medication history was obtained. The cumulative percentages of ventricular pacing as well as the frequency, duration, and time to first episode of an AHRE were also determined. During follow-up of 596 +/- 344 days, an AHRE > or = 5 minutes was detected in 77 (29%) patients. Of these, 47 (61%) patients had an AHRE > or = 1 hour, 22 (29%) patients had an AHRE > or = 1 day, and 12 (16%) patients had an AHRE > or = 1 week. An AHRE > or = 5 minutes was seen in 24% and 34% of patients at 1 year and 2 years, respectively. Among patients with sinus node dysfunction, > or = 50% cumulative ventricular pacing was the only significant predictor of an AHRE > or = 5 minutes (HR 2.2; CI 1.0-4.7; P = 0.04). CONCLUSIONS: Within 1 year of PPM implantation, AF is detected in 24% of patients without history of AF. In patients with sinus node dysfunction, > or = 50% cumulative right ventricular pacing is associated with a 2-fold increase in risk of developing AF.

Aged↗
PubMed2006

Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A-->G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.

Adult↗
PubMed2006

Right and left ventricular outflow tract tachycardias: evidence for a common electrophysiologic mechanism.

INTRODUCTION: "Idiopathic" ventricular arrhythmias most often arise from the right ventricular outflow tract (RVOT), although arrhythmias from the left ventricular outflow tract (LVOT) are also observed. While previous work has elucidated the mechanism and electropharmacologic profile of RVOT arrhythmias, it is unclear whether those from the LVOT share these properties. The purpose of this study was to characterize the electropharmacologic properties of RVOT and LVOT arrhythmias. METHODS AND RESULTS: One hundred twenty-two consecutive patients (61 male; 50.9 +/- 15.2 years) with outflow tract arrhythmias comprise this series, 100 (82%) with an RVOT origin, and 22 (18%) with an LVOT origin. The index arrhythmia was similar: sustained ventricular tachycardia (VT) (RVOT = 28%, LVOT = 36%), nonsustained VT (RVOT = 40%, LVOT = 23%), and premature ventricular complexes (RVOT = 32%, LVOT = 41%) (P = 0.32). Cardiac magnetic resonance imaging and microvolt T-wave alternans results (normal/indeterminate) were also comparable. In addition, 41% with RVOT foci and 50% with LVOT foci were inducible for sustained VT (P = 0.48), and induction of VT was catecholamine dependent in a majority of patients in both groups (66% and 73%; RVOT and LVOT, respectively; P = 1.0). VT was sensitive to adenosine (88% and 78% in the RVOT and LVOT groups, respectively, P = 0.59) as well as blockade of the slow-inward calcium current (RVOT = 70%, LVOT = 80%; P = 1.00) in both groups. CONCLUSIONS: Electrophysiologic and pharmacologic properties, including sensitivity to adenosine, are similar for RVOT and LVOT arrhythmias. Despite disparate sites of origin, these data suggest a common arrhythmogenic mechanism, consistent with cyclic AMP-mediated triggered activity. Based on these similarities, these arrhythmias should be considered as a single entity, and classified together as "outflow tract arrhythmias."

Action Potentials↗
PubMed2006

Structural and functional genetic disorders of the great vessels and outflow tracts.

Development of the aorta and pulmonary artery is a complex process involving multiple molecular genetic pathways that modulate morphogenesis of the outflow tracts and the anastomosis of branch vessels. Recent genetic studies of the cardiovascular system demonstrate that congenital and adult onset progressive disorders of the great vessels such as aneurysms are components of generalized vascular, cardiac, and extracardiovascular syndromes. Current paradigms suggest that aortic disease is founded in patterning anomalies of the conotruncus that occur in utero. These aberrations can be consequences of genetic aberrations in transcriptional regulation of signal transduction both within and outside the developing great vessels.

Blood Vessels↗
PubMed2005

Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract.

BACKGROUND: Tachycardia-induced cardiomyopathy caused by ventricular tachycardia is a well-defined clinical entity. Less well appreciated is whether simple ventricular ectopy can result in cardiomyopathy. We sought to examine a potential causal relationship between repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract and cardiomyopathy and the role of ablation in reversing this process. METHODS AND RESULTS: The study consisted of 27 patients (11 men; age, 47+/-15 years) with repetitive monomorphic ventricular ectopy, including 8 patients (30%) with depressed ventricular function (ejection fraction < or =45%). All patients underwent assessment of cardiac structure and function. The burden of ectopy was quantified through 24-hour Holter monitoring. Patients then underwent ablation guided by 3D mapping. After ablation, patients underwent repeated Holter monitoring and reassessment of cardiac function. Patients with depressed ventricular function were more likely to be older than patients with normal function (58+/-14 versus 42+/-18 years; P=0.013). However, the burden of ventricular ectopy was similar in patients with (17,859+/-13,488 ectopic beats per 24 hours) and without (17,541+/-11,479 ectopic beats per 24 hours; P=0.800) preserved ventricular function. Successful ablation was performed in 23 patients (85%), including 7 of 8 patients with depressed ventricular function. In this latter group, ventricular function improved in all patients (from 39+/-6% to 62+/-6%; P=0.017). CONCLUSIONS: Repetitive monomorphic ventricular ectopy (in the absence of sustained ventricular tachycardia) originating from the right ventricular outflow tract is an underappreciated cause of unexplained cardiomyopathy. Successful ablation of the focal source of ventricular ectopy results in normalization of left ventricular function. Patients with ectopy-induced cardiomyopathy are significantly older than patients with preserved ventricular function, which suggests either that older patients are more susceptible to the development of a cardiomyopathy or that the cardiomyopathy has had a longer period of time in which to evolve.

Adult↗
PubMed2005

Usefulness of prolonged QRS duration to identify high-risk ischemic cardiomyopathy patients with syncope and inducible ventricular tachycardia.

We evaluated 61 consecutive patients who had coronary artery disease, decreased left ventricular function, and syncope and underwent implantation of a cardioverter-defibrillator because sustained ventricular tachycardia was inducible at electrophysiologic testing. During a follow-up of 3.0 +/- 1.8 years, 23 patients (38%) developed ventricular tachycardia. Prolonged QRS duration (>/=120 ms) was the only significant predictor of arrhythmia. The 1- and 2-year rates without ventricular arrhythmia were 82% and 77%, respectively, in patients whose QRS duration was <120 ms. In contrast, 1- and 2-year rates without ventricular arrhythmia were only 64% and 51%, respectively, in patients whose QRS duration was >/=120 ms (risk ratio 3.7, 95% confidence interval 1.4 to 9.8, p = 0.0092).

Aged↗
PubMed2005

Out-of-hospital cardiac arrest rectilinear biphasic to monophasic damped sine defibrillation waveforms with advanced life support intervention trial (ORBIT).

BACKGROUND: Although biphasic defibrillation waveforms appear to be superior to monophasic waveforms in terminating VF, their relative benefits in out-of-hospital resuscitation are incompletely understood. Prior comparisons of defibrillation waveform efficacy in out-of-hospital cardiac arrest (OHCA) are confined to patients presenting in a shockable rhythm and resuscitated by first responder (basic life support). This effectiveness study compared monophasic and biphasic defibrillation waveform for conversion of ventricular arrhythmias in all OHCA treated with advance life support (ALS). METHODS AND RESULTS: This prospective randomized controlled trial compared the rectilinear biphasic (RLB) waveform with the monophasic damped sine (MDS) waveform, using step-up energy levels. The study enrolled OHCA patients requiring at least one shock delivered by ALS providers, regardless of initial presenting rhythm. Shock success was defined as conversion at 5s to organized rhythm after one to three escalating shocks. We report efficacy results for the cohort of patients treated by ALS paramedics who presented with an initially shockable rhythm who had not received a shock from a first responder (MDS: n=83; RLB: n=86). Shock success within the first three ascending energy shocks for RLB (120, 150, 200J) was superior to MDS (200, 300, 360J) for patients initially presenting in a shockable rhythm (52% versus 34%, p=0.01). First shock conversion was 23% and12%, for RLB and MDS, respectively (p=0.07). There were no significant differences in return of spontaneous circulation (47% versus 47%), survival to 24h (31% versus 27%), and survival to discharge (9% versus 7%). Mean 24h survival rates of bystander witnessed events showed differences between waveforms in the early circulatory phase at 4-10 min post event (mean (S.D.) RLB 0.45 (0.07) versus MDS 0.31 (0.06), p=0.0002) and demonstrated decline as time to first shock increased to 20 min. CONCLUSION: Shock success to an organized rhythm comparing step-up protocol for energy settings demonstrated the RLB waveform was superior to MDS in ALS treatment of OHCA. Survival rates for both waveforms are consistent with current theories on the circulatory and metabolic phases of out-of-hospital cardiac arrest.

Adult↗
PubMed2005

Effect of transthoracic shocks on left ventricular function.

Although defibrillating shocks are thought to depress ventricular function transiently, the independent effects of high strength shocks (without the metabolic sequelae of pre-shock fibrillation) have not been assessed systematically in humans. Therefore, we delivered three consecutive synchronized monophasic transthoracic shocks (200, 200 and 360 J) at 60s intervals during sinus rhythm and evaluated the effect on left ventricular chamber size and function as determined by transesophageal echocardiography in 11 patients (mean age 67+/-8 years, 9M/2F) with depressed left ventricular function (left ventricular ejection fraction: 14-37%). The shocks did not alter hemodynamics consistently. On average, the shocks did not alter stroke volume, cardiac output, left ventricular ejection fraction or regional wall thickening (all p>0.05 versus baseline). This effect was highly variable and 36% of patients experienced a >25% reduction in cardiac output by the final shock. There was a tendency for regional wall thickening to worsen in the best baseline sextant with an offsetting significant increase in thickening in the worst baseline sextant (p=0.05). Thus, repetitive defibrillation strength transthoracic shocks do not impair left ventricular function consistently in patients with cardiomyopathy. However, the effect is widely variable and potentially important depression of left ventricular function does occur in some patients.

Aged↗
PubMed2005

Detection of repolarization alternans with an implantable cardioverter defibrillator lead in a porcine model.

Mechanistic links have been suggested between repolarization alternans (RPA) and the onset of ventricular tachycardia (VT) and/or fibrillation. Endocardial detection of RPA may, therefore, be an important step in future device-based treatments of arrhythmias. Here, we investigate if RPA could be detected during acute ischemia using an implantable cardioverter defibrillator (ICD) lead (tip to distal coil) located in the right ventricular apex. In 18 pigs, the right coronary (n = 10) or left anterior descending coronary (n = 8) artery was occluded for 10 min using a balloon catheter, followed by reperfusion for 30 min, and re-occlusion for 30 min. RPA magnitude, computed using the modified moving average (MMA) method, showed a sharp increase in all 18 animals, from a mean baseline level of 1.9 +/- 1.3 mV to 3.0 +/- 1.3 mV during first occlusion (p < 0.001). RPA magnitude showed a prominent increase in 10 animals during re-occlusion, from a mean baseline level of 1.7 +/- 1.0 mV to 3.3 +/- 1.5 mV (p < 0.001). The protocol was terminated during the first two stages of occlusion and reperfusion for the remaining 8 animals due to the occurrence of ventricular fibrillation (VF). These results confirm that RPA increases under ischemic conditions and that it is possible to detect and track RPA dynamics with an ICD lead that is positioned in a clinically realistic location. Such an approach may be useful in formulating improved arrhythmia detection and control algorithms.

Algorithms↗
PubMed2005

Calibrated current divider network for precision current delivery during high-voltage transthoracic defibrillation.

The design of a calibrated resistive-network current divider for precision current delivery during transthoracic defibrillation shocks is presented together with test results. The current divider presents a constant 50-ohm load to the defibrillator and thus maintains a constant pulse shape. Current is selected before the shock by setting three rheostats using a computer-generated calibration table. Following each shock, the data acquisition and display software updates the calibration table based on the measured value of transthoracic resistance. Over a range of 15-27 A, the root-mean-square (rms) error for delivered versus selected current was 0.48% for a 45-ohm resistive load, and 0.71% for a 100-ohm load. These test results were confirmed by animal experiments. Over 3 dogs, the rms error was 0.49% from 15-27 A and not greater than 1.5% over the entire 8-44 A range.

Calibration↗
PubMed2004

Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.

Adolescent↗
PubMed2004

Effect of beta-adrenergic blockade on dynamic electrical restitution in vivo.

The slope of the action potential duration (APD) restitution curve may be a significant determinant of the propensity to develop ventricular fibrillation, with steeper slopes associated with a more arrhythmogenic substrate. We hypothesized that one mechanism by which beta-blockers reduce sudden cardiac death is by flattening the APD restitution curve. Therefore, we investigated whether infusion of esmolol modulates the APD restitution curve in vivo. In 10 Yorkshire pigs, dynamic APD restitution curves were determined from measurements of APD at 90% repolarization with a monophasic action potential catheter positioned against the right ventricular septum during right ventricular apical pacing in the basal state and during infusion of esmolol. APD restitution curves were fitted to the three-parameter (a, b, c) exponential equation, APD = a.[1 - e((-b.DI))] + c, where DI is the diastolic interval. Esmolol decreased the maximal APD slope, 0.68 +/- 0.14 vs. 0.94 +/- 0.24 (baseline), P = 0.002, and flattened the APD restitution curve at shorter DIs, 75 and 100 ms (P < 0.05). To compare the slopes of the APD restitution curves at similar steady states, slopes were also computed at points of intersection between the restitution curve and the lines representing pacing at a fixed cycle length (CL) of 200, 225, 250, 275, and 300 ms using the relationship CL = APD + DI. Esmolol decreased APD restitution slopes at CLs 200-275 ms (P < 0.05). Esmolol flattens the cardiac APD restitution curve in vivo, particularly at shorter CLs and DIs. This may represent a novel mechanism by which beta-blockers prevent sudden cardiac death.

Action Potentials↗
PubMed2004

Significance of adenosine-induced atrioventricular block in patients with unexplained syncope.

OBJECTIVES: The purpose of this study was to test whether a prolonged (>/=6 seconds) period of AV block in response to adenosine triphosphate (ATP) identifies additional patients at risk for bradycardia who may benefit from pacemaker implantation. BACKGROUND: Bradycardia is a common etiology for syncope in patients without underlying structural heart disease. Conventional testing using electrophysiologic and tilt table studies often fail to identify patients prone to episodes of symptomatic bradycardia. METHODS: Adenosine testing was performed in 92 consecutive patients (64 women, age 55 +/- 21 years) with syncope of uncertain origin referred for tilt table testing. The adenosine test measured the maximal R-R interval after bolus administration of intravenous adenosine 150 mug/kg to upright patients. A positive adenosine AV block response was defined as a maximal R-R interval > or =6 seconds. RESULTS: A total of 21 patients (23%) had a positive response. During mean follow-up of 14.3 +/- 5.9 months, 14 patients (16%) had recurrent syncope. Among patients with a positive adenosine response, 3 patients (14%) had recurrent syncope. In comparison, 11 of 69 patients (16%) without adenosine-induced AV block had recurrent syncope (P = 1.00). CONCLUSIONS: Prolonged adenosine-induced AV block in patients with unexplained syncope failed to predict recurrent syncopal episodes. These data do not support therapeutic interventions (e.g., pacemaker implantation) based on a positive adenosine AV block response alone.

Adenosine Triphosphate↗