Jose F. Huizar

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.

Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetics

OBJECTIVES The aim of this study was to determine whether sulfonylureas attenuate ST-segment elevation in diabetics during acute myocardial infarction (AMI). BACKGROUND Sulfonylureas block adenosine triphosphate-sensitive potassium channels found in the pancreas and heart. Animal studies have demonstrated that opening of these cardiac channels results in ST-segment elevation during AMI, and pretreatment with sulfonylureas blunts these ST-segment changes. METHODS We performed a retrospective study of diabetic patients hospitalized with AMI over a four-year period in Framingham, Massachusetts. Electrocardiograms obtained on arrival were analyzed for standard ST-segment criteria for thrombolytic therapy (>1 mm in two or more contiguous leads). Results were compared between the study group (40 patients taking sulfonylureas) and control group (48 patients taking alternative hypoglycemic agent). RESULTS Demographics were similar for both groups apart from a female preponderance in the study group. A significantly higher percentage of patients in the study group did not meet ST-segment criteria for thrombolytic therapy as compared with the control group (53% vs. 29%, p = 0.02). This difference was most prominent in patients with peak creatinine phosphokinase levels between 500 and 1,000 mg/dl (86% vs. 22%, p = 0.04). The magnitude of ST-segment elevation and the frequency of thrombolytic therapy were significantly lower in the sulfonylurea group than in the control group (1.1 +/- 1.0 mm vs. 2.1 +/- 2.7 mm, p = 0.02 and 20% vs. 40%, p = 0.04, respectively). CONCLUSIONS Sulfonylurea therapy appears to attenuate the magnitude of ST-segment elevation during an AMI, resulting in failure to meet criteria for thrombolytic therapy and as a consequence leading to inappropriate withholding therapy in this subset of diabetic patients.

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.

Spatiotemporal Relationship Between Intracellular Ca2+ Dynamics and Wave Fragmentation During Ventricular Fibrillation in Isolated Blood-Perfused Pig Hearts

Normal “master–slave” relationship between the action potential (AP) and intracellular Ca2+ transient (CaiT) is sometimes altered during ventricular fibrillation (VF). The nature of AP/CaiT dissociation during VF and its role in inducing wavebreaks (WBs) remain unclear. We simultaneously mapped AP (RH237) and CaiT (Rhod-2) during VF in blood-perfused pig hearts. We computed AP and CaiT dominant frequency (DF) and CaiT delay in each AP cycle. We identified WBs as singularity points in AP phase movies and sites of conduction block (CB) as sites where an AP wavefront failed to propagate. We analyzed spatiotemporal relationship between abnormal AP/CaiT sequences and CB sites. We used a calcium chelator (BAPTA-AM) to abolish CaiT and test its involvement in WB formation. During VF, the DF difference between AP and CaiT was <10% of the respective values in 95% of pixels, and 80% of all CaiT upstrokes occurred during the initial 25% of the excitation cycle. Aberrant sequences of AP and CaiT occurred almost exclusively near CB sites but could be traced to normal wavefront sequences away from CB sites. Thus, apparent AP/CaiT dissociation was largely attributable to spatial uncertainty of the absolute position of block of each wave. BAPTA-AM reduced CaiT amplitude to 30.5±12.9% of control and the DF of AP from 12.2±1.6 to 10.4±1.3Hz (P<0.01), but did not significantly alter WB incidence (0.76±0.19 versus 0.72±0.19SP/mm2). These results do not support presence of spontaneous, non–voltage-gated CaiTs during VF and suggest that AP/CaiT dissociation is a consequence rather than a cause of wave fragmentation.

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.

Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.

Current American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines ([1][1]) recommend cardiac resynchronization therapy (CRT) to patients with symptomatic heart failure (HF) New York Heart Association (NYHA) class III and IV in patients with wide QRS (>120 ms) and

Recruitment of bundle branches with permanent His bundle pacing in a patient with advanced conduction system disease: What is the mechanism?

Case report The patient was a 69-year-old man with coronary artery disease who presented with syncope. His electrocardiogram showed sinus rhythm with a first-degree atrioventricular block, right bundle branch block (RBBB), and left anterior fascicular block (LAFB), and he was referred for an electrophysiology (EP) study. Baseline electrograms suggested intra-Hisian conduction disease, with split His potentials, H0 and H, and an intra-Hisian interval of 78 ms (Figure 1A). It was difficult to maintain His catheter stability during the EP study, and only the distal His signal (H) was consistent, with an His-ventricular (HV) interval of 70 ms (Figure 1A). Decremental atrial pacing demonstrated progressive raterelated HV prolongation up to 280 ms, beyond which HV Wenckebach block occurred (Figure 1B). No arrhythmias were induced with programmed atrial or ventricular stimulation. Given the evidence of infranodal AV conduction disease with probable intra-Hisian disease, we decided to implant a pacemaker. Pacing from the proximal His bundle (HB) position with the His catheter resulted in a wide QRS complex (duration 164 ms) with RBBB/LAFB and a long stimulus-QRS interval, whereas pacing at the distal HB resulted in a narrower QRS using a pacing output of 5 mA at 2 ms (threshold). Given narrowing of the QRS with distal

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.

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.