Elad Anter

Atrial Fibrillation and Heart Failure Treatment Considerations for a Dual Epidemic

Atrial fibrillation (AF) and heart failure have emerged as new cardiovascular epidemics over the last decade.1 Heart failure affects ≈5 million patients in the United States, and >550 000 patients are diagnosed with new heart failure each year.2 Although the incidence of heart failure remained stable over the past 50 years, the prevalence of heart failure in the United States has steadily increased. Heart failure is the primary reason for 12 to 15 million office visits and 6.5 million hospital days yearly.3 From 1990 to 1999, the annual number of hospitalizations increased from ≈800 000 to >1 million for heart failure as a primary diagnosis and from 2.4 to 3.6 million for heart failure as a primary or secondary diagnosis.4 The steadily increasing number of patients with heart failure is due partially to better treatment and “salvage” of patients with acute myocardial infarctions earlier in life.2 As a consequence, heart failure carries a significant economic burden on our society because it is the most common discharge diagnosis and because more Medicare dollars are spent for the diagnosis and treatment of heart failure than for any other diagnosis.5 In 2007, the American Heart Association estimated that

Acute EGCG Supplementation Reverses Endothelial Dysfunction in Patients with Coronary Artery Disease

33 billion was spent on heart failure alone.6 AF is the most common arrhythmia in clinical practice, accounting for approximately one third of admissions resulting from cardiac rhythm disturbances. An estimated 2.3 million people in North America have AF. During the last 20 years, hospital admissions for AF have increased by 66% for a number of reasons, including the aging of the population, the rising prevalence of chronic heart disease, and more frequent diagnosis as a result of increased monitoring.7 The recent Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study projected that the prevalence of AF …

Oxidative stress, antioxidants, and endothelial function.

Background: Epidemiological studies demonstrate an inverse relation between dietary flavonoid intake and cardiovascular risk. Recent studies with flavonoid-containing beverages suggest that the benefits of these nutrients may relate, in part, to improved endothelial function. Objective: We hypothesized that dietary supplementation with epigallocatechin gallate (EGCG), a major catechin in tea, would improve endothelial function in humans. Design: We examined the effects of EGCG on endothelial function in a double blind, placebo-controlled, crossover design study. We measured brachial artery flow-mediated dilation by vascular ultrasound at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments. Results: A total of 42 subjects completed the study, and brachial artery flow-mediated dilation improved from 7.1 ± 4.1 to 8.6 ± 4.7% two hours after the first dose of 300 mg of EGCG (P = 0.01), but was similar to baseline (7.8 ± 4.2%, P = 0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, which increased from 2.6 ± 10.9 to 92.8 ± 78.7 ng/ml after acute EGCG (P < 0.001), but were unchanged from baseline after two weeks of treatment (3.4 ± 13.1 ng/ml). Conclusion: EGCG acutely improves endothelial function in humans with coronary artery disease, and may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function.

Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase

Endothelial dysfunction, characterized by a loss in nitric oxide bioactivity, is an early event in the development of atherosclerosis and determines future vascular complications. Emerging evidence suggests a causal role for oxidative stress in this process. Reactive oxygen species can directly inactivate nitric oxide, modulate protein function and act as cellular signaling molecules. These events contribute to the initiation and progression of endothelial dysfunction. Considerable data also indicates that antioxidant compounds limit oxidative damage and restore endothelial function. The purpose of this review is to discuss these data and suggest novel approaches for lowering the oxidative stress in the vasculature.

p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor α-Dependent Pathway in Response to Black Tea Polyphenols

Background—Estradiol activates endothelial nitric oxide synthase (eNOS) by mechanisms that involve estrogen receptor-α (ERα), protein kinase B/Akt, mitogen-activated protein kinases, and heat shock protein 90 (HSP90). Recently, AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in cellular adaptation to metabolic stress, has been implicated in physiological eNOS activation by the hormones adiponectin and insulin. We therefore investigated whether AMPK is activated by estradiol in endothelial cells and plays a role in estradiol-induced eNOS activation. Methods and Results—Porcine aortic endothelial cells exhibited time- and concentration-dependent AMPK activation as determined by phosphorylation of AMPK and its downstream target acetyl coenzyme A carboxylase in response to estradiol (1 nmol/L to 10 &mgr;mol/L, 1 to 30 minutes). AMPK activation by estradiol was independent of both AMP levels and ERα but required estradiol conversion to its catechol metabolites. Estradiol treatment increased eNOS catalytic activity, an effect that was largely reversed when endothelial cells were infected with an AMPK dominant-negative adenovirus. However, inhibition of AMPK did not alter estradiol-induced eNOS phosphorylation at serine 1177 or threonine 495 but decreased eNOS interaction with HSP90. Consistent with this observation, blood vessels from α1-AMPK-null mice exhibited defective eNOS-mediated NO production in response to estradiol. Conclusions—Taken together, these data indicate that AMPK activity is essential for estradiol-induced eNOS activation via the promotion of eNOS interaction with HSP90. These data point to a novel role for AMPK in modulating endothelial cell NO bioactivity and HSP90 function.

High-Resolution Mapping of Scar-Related Atrial Arrhythmias Using Smaller Electrodes with Closer Interelectrode Spacing

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERα on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERα on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38α MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERα phosphorylation and downstream activation of Akt, and eNOS. The key role of ERα Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERα subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERα with p38 MAPK as ERα with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERα and these data uncover a new mechanism of ERα activation that has broad implications for NO bioactivity and endothelial cell phenotype.

Noninvasive Programmed Ventricular Stimulation Early After Ventricular Tachycardia Ablation to Predict Risk of Late Recurrence

Background—The resolution of mapping is influenced by electrode size and interelectrode spacing. Smaller electrodes with closer interelectrode spacing may improve mapping resolution, particularly in scar. The aims of this study were to establish normal electrogram criteria in the atria for both 3.5-mm electrode tip linear catheters (Thermocool) and 1-mm multielectrode-mapping catheters (Pentaray) and to compare their mapping resolution in scar-related atrial arrhythmias. Methods and Results—Normal voltage amplitude cutoffs for both catheters were validated in 10 patients with structurally normal atria. In 20 additional patients with scar-related atrial arrhythmias, similar sequential mapping with both catheters was performed. Normal bipolar voltage amplitude was similar between 3.5- and 1-mm electrode catheters with a fifth percentile of 0.48 and 0.52 mV, respectively (P=0.65). In patients with scar-related atrial arrhythmias, the total area of bipolar voltage <0.5 mV measured using 1-mm electrode catheters was smaller than that measured using 3.5-mm catheter (14.7 versus 20.4 cm2; P=0.02). The mean bipolar voltage amplitude in this area of low voltage was significantly higher with 1-mm electrode catheters (0.28 and 0.17 mV; P=0.01). Importantly, 54.4% of all low voltage data points recorded with 1-mm electrode catheter had distinct electrograms that allowed annotation of local activation time compared with only 21.4% with 3.5-mm electrode tip catheters (P=0.01). Overdrive pacing with capture of the tachycardia from within the area of low voltage was more frequent with 1-mm electrode catheters (66.7 versus 33.4; P=0.01). Conclusions—Mapping with small closely spaced electrode catheters can improve mapping resolution within areas of low voltage.

Surgical Ablation of Refractory Ventricular Tachycardia in Patients With Nonischemic Cardiomyopathy

OBJECTIVES The goal of this study was to evaluate the ability of noninvasive programmed stimulation (NIPS) after ventricular tachycardia (VT) ablation to identify patients at high risk of recurrence. BACKGROUND Optimal endpoints for VT ablation are not well defined. METHODS Of 200 consecutive patients with VT and structural heart disease undergoing ablation, 11 had clinical VT inducible at the end of ablation and 11 recurred spontaneously. Of the remaining 178 patients, 132 underwent NIPS through their implantable cardioverter-defibrillator 3.1 ± 2.1 days after ablation. At 2 drive cycle lengths, single, double, and triple right ventricular extrastimuli were delivered to refractoriness. Clinical VT was defined by comparison with 12-lead electrocardiograms and stored implantable cardioverter-defibrillator electrograms from spontaneous VT episodes. Patients were followed for 1 year. RESULTS Fifty-nine patients (44.7%) had no VT inducible at NIPS; 49 (37.1%) had inducible nonclinical VT only; and 24 (18.2%) had inducible clinical VT. Patients with inducible clinical VT at NIPS had markedly decreased 1-year VT-free survival compared to those in whom no VT was inducible (<30% vs. >80%; p = 0.001), including 33% recurring with VT storm. Patients with inducible nonclinical VT only, had intermediate 1-year VT-free survival (65%). CONCLUSIONS When patients with VT and structural heart disease have no VT or nonclinical VT only inducible at the end of ablation or their condition is too unstable to undergo final programmed stimulation, NIPS should be considered in the following days to further define risk of recurrence. If clinical VT is inducible at NIPS, repeat ablation may be considered because recurrence over the following year is high.

High-Resolution Mapping of Postinfarction Reentrant Ventricular Tachycardia: Electrophysiological Characterization of the Circuit.

Background— The surgical approach for the treatment of ventricular tachycardia (VT) has been largely replaced by percutaneous, catheter-based techniques. However, some VT circuits, particularly in patients with nonischemic cardiomyopathy, remain inaccessible to percutaneous ablation. Surgical therapy of these VTs is an alternative approach; however, its methodology has not been well defined. The purpose of this study was to evaluate the efficacy of preoperative electroanatomic and electrophysiological characterization of the VT substrate and circuit to guide surgical ablation. Methods and Results— Eight patients with recurrent sustained VT refractory to antiarrhythmic drugs underwent endocardial and/or epicardial ablation procedures. Electroanatomic mapping was performed, and the VT substrate and circuit(s) were defined using voltage, activation, entrainment, and pace mapping. All 8 patients underwent detailed endocardial mapping; 6 patients also underwent epicardial mapping. Radiofrequency ablation was performed with the use of an open-irrigation catheter. After the unsuccessful percutaneous approach, surgical cryoablation was applied to the sites previously identified and targeted during the percutaneous procedure. There were no significant perioperative complications. During a mean follow-up period of 23±6 months (range, 15 to 34 months), 6 patients had significant reduction in VT burden as evident by a reduced number of implantable cardioverter-defibrillator shocks after ablation (6.6 to 0.6 shocks per patient; P=0.026). Two patients died, one of progressive heart failure and one of sepsis. Conclusions— VT circuits inaccessible to percutaneous ablation techniques are rare but can be encountered in patients with nonischemic cardiomyopathy. These VTs can be successfully targeted by surgical cryoablation guided by preoperative electroanatomic and electrophysiological mapping.

Coronary Artery Bypass Grafting in Patients with Severe Left Ventricular Dysfunction—Early and Mid-Term Outcomes

Background: In vivo description of ventricular tachycardia (VT) circuits is limited by insufficient spatiotemporal resolution. We used a novel high-resolution mapping technology to characterize the electrophysiological properties of the postinfarction reentrant VT circuit. Methods: In 15 swine, myocardial infarction was induced by left anterior descending artery balloon occlusion. Animals were studied 6 to 8 weeks after myocardial infarction. Activation mapping of VTs was performed by using the Rhythmia mapping system. Activation time was based on a combination of bipolar and unipolar electrograms. The response to overdrive pacing from different zones of the circuit was examined. Results: A total of 56 monomorphic VTs were induced (3.8±2.1 per animal). Among these, 21 (37.5%) were hemodynamically stable and allowed mapping of the circuit. Isthmuses were 16.4±7.2 mm long and 7.4±2.8 mm wide. Conduction velocities were slowest at the inward curvature into the isthmus entrance (0.28±0.2 m/s), slightly faster at the outward curvature exit (0.40±0.3 m/s) and nearly normal at the central isthmus (0.62±0.2 m/s). In 3 animals, 2 VT morphologies with opposite axes sharing the same isthmus were mapped. Conduction velocities within the shared isthmus were dependent on the activation vector, consistently slower at the proximal curvature. Overdrive pacing from isthmus sites determined by activation mapping was consistent with entrainment criteria for isthmus. However, dimensions of the isthmus defined by entrainment exceeded dimensions of the isthmus measured by activation mapping by 32±18%. Conclusions: In postinfarction reentrant VT, conduction velocities are slowest at the proximal and distal curvatures. Entrainment mapping overestimates the true size of the isthmus. High-resolution activation mapping of VT may better guide ablation therapy. # Clinical Perspective {#article-title-25}Background: In vivo description of ventricular tachycardia (VT) circuits is limited by insufficient spatiotemporal resolution. We used a novel high-resolution mapping technology to characterize the electrophysiological properties of the postinfarction reentrant VT circuit. Methods: In 15 swine, myocardial infarction was induced by left anterior descending artery balloon occlusion. Animals were studied 6 to 8 weeks after myocardial infarction. Activation mapping of VTs was performed by using the Rhythmia mapping system. Activation time was based on a combination of bipolar and unipolar electrograms. The response to overdrive pacing from different zones of the circuit was examined. Results: A total of 56 monomorphic VTs were induced (3.8±2.1 per animal). Among these, 21 (37.5%) were hemodynamically stable and allowed mapping of the circuit. Isthmuses were 16.4±7.2 mm long and 7.4±2.8 mm wide. Conduction velocities were slowest at the inward curvature into the isthmus entrance (0.28±0.2 m/s), slightly faster at the outward curvature exit (0.40±0.3 m/s) and nearly normal at the central isthmus (0.62±0.2 m/s). In 3 animals, 2 VT morphologies with opposite axes sharing the same isthmus were mapped. Conduction velocities within the shared isthmus were dependent on the activation vector, consistently slower at the proximal curvature. Overdrive pacing from isthmus sites determined by activation mapping was consistent with entrainment criteria for isthmus. However, dimensions of the isthmus defined by entrainment exceeded dimensions of the isthmus measured by activation mapping by 32±18%. Conclusions: In postinfarction reentrant VT, conduction velocities are slowest at the proximal and distal curvatures. Entrainment mapping overestimates the true size of the isthmus. High-resolution activation mapping of VT may better guide ablation therapy.