Karoly Kaszala

Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy.

Background— Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as a possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathologic abnormalities. Methods and Results— Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hour Holter monitoring corroborated ventricular bigeminy in the PVC group (PVC, 49.8% versus control, <0.01%; P<0.0001). After 12 weeks, only the PVC group had cardiomyopathy, with a significant reduction in left ventricular ejection fraction (PVC, 39.7±5.4% versus control, 60.7±3.8%; P<0.0001) and an increase in left ventricular end-systolic dimension (PVC, 33.3±3.5 mm versus control, 23.7±3.6 mm; P<0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2 to 4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. Conclusions— This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced cardiomyopathy lacks gross histopathologic and mitochondrial abnormalities seen in other canine models of cardiomyopathy.Background— Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as a possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathologic abnormalities. Methods and Results— Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hour Holter monitoring corroborated ventricular bigeminy in the PVC group (PVC, 49.8% versus control, <0.01%; P <0.0001). After 12 weeks, only the PVC group had cardiomyopathy, with a significant reduction in left ventricular ejection fraction (PVC, 39.7±5.4% versus control, 60.7±3.8%; P <0.0001) and an increase in left ventricular end-systolic dimension (PVC, 33.3±3.5 mm versus control, 23.7±3.6 mm; P <0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2 to 4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. Conclusions— This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced cardiomyopathy lacks gross histopathologic and mitochondrial abnormalities seen in other canine models of cardiomyopathy.

Left Ventricular Systolic Dysfunction Induced by Ventricular Ectopy: a Novel Model for PVC-induced Cardiomyopathy

Background— Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as a possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathologic abnormalities. Methods and Results— Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hour Holter monitoring corroborated ventricular bigeminy in the PVC group (PVC, 49.8% versus control, <0.01%; P<0.0001). After 12 weeks, only the PVC group had cardiomyopathy, with a significant reduction in left ventricular ejection fraction (PVC, 39.7±5.4% versus control, 60.7±3.8%; P<0.0001) and an increase in left ventricular end-systolic dimension (PVC, 33.3±3.5 mm versus control, 23.7±3.6 mm; P<0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2 to 4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. Conclusions— This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced cardiomyopathy lacks gross histopathologic and mitochondrial abnormalities seen in other canine models of cardiomyopathy.Background— Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as a possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathologic abnormalities. Methods and Results— Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n=7) or no PVCs (control, n=6). Continuous 24-hour Holter monitoring corroborated ventricular bigeminy in the PVC group (PVC, 49.8% versus control, <0.01%; P <0.0001). After 12 weeks, only the PVC group had cardiomyopathy, with a significant reduction in left ventricular ejection fraction (PVC, 39.7±5.4% versus control, 60.7±3.8%; P <0.0001) and an increase in left ventricular end-systolic dimension (PVC, 33.3±3.5 mm versus control, 23.7±3.6 mm; P <0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2 to 4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. Conclusions— This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced cardiomyopathy lacks gross histopathologic and mitochondrial abnormalities seen in other canine models of cardiomyopathy.

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

BACKGROUND Frequent premature ventricular contractions (PVCs) are associated with increased risk of sudden cardiac death and can cause secondary cardiomyopathy. OBJECTIVE We sought to determine the mechanism(s) responsible for prolonged refractory period and left ventricular (LV) dysfunction demonstrated in our canine model of PVC-induced cardiomyopathy. METHODS Single myocytes were isolated from LV free wall of PVC and control canines and used for patch-clamp recording, intracellular Ca(2+) measurements, and immunocytochemistry/confocal microscopy. LV tissues adjacent to the area of myocyte isolation were used for the immunoblot quantification of protein expression. RESULTS In the PVC group, LV ejection fraction decreased from 57.6% ± 1.5% to 30.4% ± 3.1% after ≥4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had decreased densities of both outward (transient outward current [Ito] and inward rectifier current [IK1]) and inward (L-type Ca current [ICaL]) currents, but no consistent changes in rapid or slow delayed rectifier currents. The reduction in Ito, IK1, and ICaL was accompanied by decreased protein levels of their channel subunits. The extent of reduction in Ito, IK1, and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from the sarcoplasmic reticulum (SR), without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (ryanodine receptor 2). CONCLUSION PVCs increase dispersion of action potential configuration/duration, a risk factor for sudden cardiac death, because of the heterogeneous reduction in Ito, IK1, and ICaL. The excitation-contraction coupling is impaired because of the decrease in ICaL and Cav1.2 misalignment with respect to ryanodine receptor 2.

When Right May Not Be Right: Right Bundle-Branch Block and Response to Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) in appropriately selected patients has been shown to improve cardiac function, heart failure symptoms, and survival. 1,2 On the basis of results of large, randomized trials, current American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines recommend consideration of CRT in patients with cardiomyopathy on optimal medical therapy with left ventricular ejection fraction 35%, New York Heart Association class III or IV symptoms, and QRS duration 120 ms. 3 The idea of resynchronization therapy was derived from the seminal observations that intraventricular conduction abnormalities, extensively characterized in patients with left bundle-branch block (LBBB), adversely affect left ventricular mechanics. LBBB produces predictable changes in the left ventricular activation sequence.4,5 Abnormal activation of the interventricular septum and markedly delayed activation of the lateral left ventricle are typically seen in patients with LBBB. However, left ventricular activation patterns may be highly variable and more complex in patients with underlying cardiomyopathy.6 Delayed, dyssynchronous electromechanical activation in these segments leads to increased cardiac work, less efficient cardiac contraction, and lower cardiac output. 7 Electric (and mechanical) preactivation of the late-activating left ventricular region with CRT has been accepted to be prerequisite for successful clinical response. 8 Although remarkable symptomatic improvement is seen in many patients, up to 30% of subjects who participated in CRT trials failed to respond to therapy or may have worsened.2 Several clinical features have been identified that carry adverse clinical prognosis and predict less response to CRT therapy (Table). Despite extensive efforts, preimplant identification of nonresponders remains a significant problem and erodes the overall clinical (and cost) effectiveness of CRT therapy.

Contemporary Pacemakers: What the Primary Care Physician Needs to Know

Pacemaker therapy is most commonly initiated because of symptomatic bradycardia, usually resulting from sinus node disease. Randomized multicenter trials assessing the relative benefits of different pacing modes have made possible an evidence-based approach to the treatment of bradyarrhythmias. During the past several decades, major advances in technology and in our understanding of cardiac pathophysiology have led to the development of new pacing techniques for the treatment of heart failure in the absence of bradycardia. Left ventricular or biventricular pacing may improve symptoms of heart failure and objective measurements of left ventricular systolic dysfunction by resynchronizing cardiac contraction. However, emerging clinical data suggest that long-term right ventricular apical pacing may have harmful effects. As the complexity of cardiac pacing devices continues to grow, physicians need to have a basic understanding of device indications, device function, and common problems encountered by patients with devices in the medical and home environment.

Abnormal Left Ventricular Mechanics of Ventricular Ectopic Beats: Insights into Origin and Coupling Interval in Premature Ventricular Contraction-Induced Cardiomyopathy

Background—Left ventricular (LV) dyssynchrony caused by premature ventricular contractions (PVCs) has been proposed as a mechanism of PVC-induced cardiomyopathy. We sought to understand the impact of different PVC locations and coupling intervals (prematurity) on LV regional mechanics and global function of the PVC beat itself. Methods and Results—Using our premature pacing algorithm, pentageminal PVCs at coupling intervals of 200 to 375 ms were delivered from the epicardial right ventricular apex, RV outflow tract, and LV free wall, as well as premature atrial contractions, from the left atrial appendage at a coupling interval of 200 ms in 7 healthy canines. LV short-axis echocardiographic images, LV stroke volume, and dP/dtmax were obtained during all ectopic beats and ventricular pacing. LV dyssynchrony was assessed by dispersion of QRS-to-peak strain (earliest—last QRS-to-peak strain) between 6 different LV segments during each of the aforementioned beats (GE, EchoPac). LV dyssynchrony was greater during long-coupled rather than short-coupled PVCs and PVCs at 375 ms compared with rapid ventricular pacing at 400 ms (P<0.0001), whereas no difference was found between PVC locations. Longer PVC coupling intervals were associated with greater stroke volume and dP/dtmax despite more pronounced dyssynchrony (P<0.001). Conclusions—PVCs with longer coupling intervals demonstrate more pronounced LV dyssynchrony, whereas PVC location has minimal impact. LV dyssynchrony cannot be attributed to prematurity or abnormal ventricular activation alone, but rather to a combination of both. This study suggests that late-coupled PVCs may cause a more severe cardiomyopathy if dyssynchrony is the leading mechanism responsible for PVC-induced cardiomyopathy.

Impact of ventricular ectopic burden in a premature ventricular contraction–induced cardiomyopathy animal model

BACKGROUND Frequent premature ventricular contractions (PVCs) have been associated with PVC-induced cardiomyopathy (CM) in some patients. OBJECTIVE The purpose of this study was to understand the cardiac consequences of different PVC burdens and the minimum burden required to induce left ventricular (LV) dysfunction. METHODS Right ventricular apical PVCs at a coupling interval of 240 ms were introduced at different PVC burdens in 9 mongrel canines. A stepwise increase in PVC burden was implemented every 8 weeks from 0% (baseline), 7%, 14%, 25%, 33% to 50% using our premature pacing algorithm. Echocardiogram and 24-hour Holter were obtained at 4- and 8-week period for each PVC burden with a single blinded reader assessing all echocardiographic parameters including those assessed by speckle tracking imaging (EchoPAC workstation, General Electric). CM was defined as left ventricular ejection fraction (LVEF) <50% or LVEF drop >10% points. Interleukin-6 and pro-brain natriuretic peptide levels were obtained at the end of each PVC burden. RESULTS The mean LVEF (mean heart rate) at 8 weeks for each PVC burden (0%, 7%, 14%, 33%, and 50%) were 57% ± 2.9% (85 ± 13 beats/min), 54.4% ± 3% (81 ± 10 beats/min), 53.3% ± 5% (77 ± 12 beats/min), 51.1% ± 4.2% (79 ± 14 beats/min), 47.7% ± 3.8% (80 ± 14 beats/min), and 44.7% ± 1.9% (157 ± 43 beats/min). PVC-induced CM was present in 11.1%, 44.4%, and 100% of animals with 25%, 33%, and 50% PVC burden, respectively. E/A ratio and radial strain decreased while left atrial size increased beyond 33% PVC burden. No changes in pro-brain natriuretic peptide and interleukin-6 levels were noted at any PVC burden. CONCLUSION LV systolic function (LVEF and radial strain) declined linearly as PVC burden increased. PVC-induced CM developed in some canines with 25% and 33% PVC burden, but developed in all animals with 50% PVC burden.

Spectrum of issues detected by an ICD diagnostic alert that utilizes far-field electrograms: Clinical implications

BACKGROUND Implantable cardioverter-defibrillator (ICD) lead failure is one of the major causes of inappropriate shocks. Algorithms have been developed by manufacturers to identify ICD lead failure and avoid inappropriate shocks. The SecureSense RV Lead Noise Discrimination (St Jude Medical, St Paul, MN) algorithm is designed to differentiate oversensing due to lead failure from ventricular arrhythmias and withhold inappropriate therapies. Several non-lead failure-related issues can trigger the SecureSense automated algorithm. OBJECTIVE Our objective was to explain the SecureSense algorithm in a detailed fashion, highlighting examples of SecureSense alerts triggered by non-lead failure-related issues. METHODS This is a nonrandomized observational case series. SecureSense-triggered alerts from 3 ICD device clinics were analyzed, and representative examples of SecureSense triggers due to non-lead failure-related issues were chosen to explain the function and malfunction of this algorithm. RESULTS The series includes 8 cases of SecureSense alerts triggered by non-lead failure-related issues---myopotential oversensing (1), P-wave oversensing (1), T-wave oversensing (1), loss of capture (1), R-wave undersensing (1), timing cycle issues (2), and cross talk (1)---and 1 case of failure of the algorithm to appropriately identify lead failure and prevent ICD shocks. CONCLUSION Lead failure detection algorithms such as the one assessed in this study have an inherent risk of false-positive and false-negative detections. The latter might have fatal consequences. The true accuracy of these algorithms needs to be evaluated in large-scale real-life prospective clinical studies.

Comparison of Different Pacing Strategies to Minimize Phrenic Nerve Stimulation in Cardiac Resynchronization Therapy

Phrenic nerve (PN) stimulation (PNS) frequently limits cardiac resynchronization therapy (CRT). Yet, pacing strategies to minimize PNS have not been systematically compared. We propose to: (1) compare different pacing strategies to minimize PNS in CRT and (2) evaluate differences between PN and left ventricular (LV) capture thresholds among LV pacing configurations.

Repetitive nonreentrant ventriculoatrial synchrony: An underrecognized cause of pacemaker-related arrhythmia

Similar to endless loop tachycardia (ELT), repetitive nonreentrant ventriculoatrial synchrony (RNRVAS) is a ventriculoatrial (VA) synchrony pacemaker-mediated arrhythmia. RNRVAS was first described in 1990 and can only occur in the presence of retrograde VA conduction and dual-chamber or cardiac resynchronization devices with tracking (P-synchronous ventricular pacing such as DDD, DDDR) or nontracking pacing modes that allow AV-sequential pacing (DDI, DDIR). RNRVAS is promoted by (1) high lower rate limit or any feature that allows rapid pacing, (2) long AV intervals, or (3) long postventricular atrial refractory period (PVARP). In contrast to ELT, RNRVAS is a less well-recognized form of pacemaker-mediated arrhythmia; thus, unlike ELT, there are no specific device algorithms to prevent, recognize, and terminate RNRVAS. However, RNRVAS has been recently shown to occur frequently. We present a series of cases, some of which were found fortuitously. Owing to its clinical implications, we propose that algorithms should be developed to prevent, identify, and terminate RNRVAS.