Improved left atrial catheterization efficiency and consistency using a novel steerable transseptal puncture sheath.

BACKGROUND: While steerable sheaths are widely used to improve catheter stability and contact force during radiofrequency (RF) catheter ablation in patients with atrial fibrillation (AF), steerable sheaths are less commonly used during transseptal puncture. This study evaluated whether left atrial catheterization efficiency can be improved using the VersaCross combined steerable sheath and transseptal system compared to previous standard workflow. METHODS: This study retrospectively analyzed AF ablation performed using the VersaCross Workflow consisting of VersaCross steerable sheath and RF wire for transseptal puncture and catheter ablation (VCW) to the standard workflow using a fixed curve sheath with RF needle followed by exchange for an Agilis steerable sheath for catheter ablation (STW). RESULTS: Thirty patients underwent RF ablation for paroxysmal or persistent AF, 15 using the VCW and 15 using the STW. Transseptal puncture time was 10.8 mins faster with the VCW compared to the standard workflow (20.9 ± 5.9 min vs. 31.7 ± 15.1 min; p = 0.024). Time to left atrial catheterization was 40% faster with the VCW compared to the STW (21.3 ± 5.8 min vs. 35.2 ± 14.4 min; p = 0.003). Overall procedure time was 14.2 min faster in the VCW compared to the STW (86.3 ± 16.1 min vs. 100.5 ± 19.3 min; p = 0.044). CONCLUSIONS: Use of the VersaCross steerable system significantly reduced time to transseptal puncture, time to left atrial catheterization, and overall RF ablation time.

Electromechanical cardioplasty using a wrapped elasto-conductive epicardial mesh.

Heart failure remains a major public health concern with a 5-year mortality rate higher than that of most cancers. Myocardial disease in heart failure is frequently accompanied by impairment of the specialized electrical conduction system and myocardium. We introduce an epicardial mesh made of electrically conductive and mechanically elastic material, to resemble the innate cardiac tissue and confer cardiac conduction system function, to enable electromechanical cardioplasty. Our epicardium-like substrate mechanically integrated with the heart and acted as a structural element of cardiac chambers. The epicardial device was designed with elastic properties nearly identical to the epicardial tissue itself and was able to detect electrical signals reliably on the moving rat heart without impeding diastolic function 8 weeks after induced myocardial infarction. Synchronized electrical stimulation over the ventricles by the epicardial mesh with the high conductivity of 11,210 S/cm shortened total ventricular activation time, reduced inherent wall stress, and improved several measures of systolic function including increases of 51% in fractional shortening, ~90% in radial strain, and 42% in contractility. The epicardial mesh was also capable of delivering an electrical shock to terminate a ventricular tachyarrhythmia in rodents. Electromechanical cardioplasty using an epicardial mesh is a new pathway toward reconstruction of the cardiac tissue and its specialized functions.

Prolonged atrial refractoriness predicts the onset of atrial fibrillation: A 12-year follow-up study.

BACKGROUND: Tissue refractoriness to conduction is a crucial electrophysiological factor in determining susceptibility to fibrillation. The relationship between atrial refractoriness and future onset of atrial fibrillation (AF) has not been well studied. OBJECTIVES: We investigated whether atrial effective refractory period (AERP) was associated with AF occurrence in a relatively healthy population. METHODS: A total of 1308 patients with no overt structural heart diseases and no evidence of congestive heart failure who underwent electrophysiology studies for paroxysmal supraventricular tachycardia from January 1986 to January 2011 were included in the study (626 male, mean age 44 ± 16 years). RESULTS: AERP increased with increasing age. Over a mean follow-up of 12 years, 51 of 1308 subjects (3.9%) developed AF. In univariate analysis, baseline AERP ≥280 ms (hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.27-5.07, P = .008) was strongly associated with new-onset AF. In multivariate Cox regression analysis, age (adjusted HR 1.40 per 10 years, 95% CI 1.15-1.70, P = .001) and AERP ≥280 ms (adjusted HR 2.08, 95% CI 1.03-4.21, P = .041) were associated with new-onset AF. Kaplan-Meier AF-free survival curves demonstrated that subjects with an AERP of ≥280 ms had significantly lower AF-free survival compared those with AERP of <280 ms. CONCLUSIONS: AERP increases with age and AERP of ≥280 ms was predictive of patients at significantly increased future risk of developing AF.

Rotors in patients with persistent atrial fibrillation: case report of a left atrial appendage rotor identified by a novel computational mapping algorithm integrated into 3-dimensional mapping and termination of atrial fibrillation with ablation.

Recent clinical trials using panoramic mapping techniques have shown success in targeting rotors and focal impulses in atrial fibrillation (AF). Ablations directed toward these organized sources improve outcomes in AF. The left atrial appendage (LAA) has been suspected as a possible extrapulmonary source of AF, and ablation within the LAA or electrical isolation of the LAA improves outcomes in certain cases. This case highlights a unique example of panoramic imaging created with a computational mapping algorithm integrated in 3-dimensional mapping, which identified rotors within the LAA. Furthermore, ablations performed near an identified rotor core within the LAA terminated AF.

Fragmented QRS as a candidate marker for high-risk assessment in hypertrophic cardiomyopathy.

BACKGROUND: The relationship between a fragmented QRS complex (fQRS) on 12-lead ECG and fatal arrhythmic events in hypertrophic cardiomyopathy (HCM) remains unclear. OBJECTIVE: The purpose of this study was to investigate whether fQRS is associated with ventricular arrhythmic events (VAEs) in HCM patients. METHODS: Of an initial cohort of 273 patients (57% male, mean age 55 years) diagnosed with HCM, 167 patients were included and divided into 2 groups: those with fQRS (n = 67) and those without fQRS (n = 100). fQRS was defined as notching of the R or S wave in 2 contiguous leads. VAEs were defined as nonsustained or sustained ventricular tachycardia (VT) or sudden cardiac death (SCD). Major arrhythmic events (MAEs) were sustained VT or SCD. RESULTS: During mean follow-up of 6.3 years, univariate analysis showed that fQRS was significantly associated with increased VAEs (unadjusted hazard ratio [HR] 6.17, 95% confidence interval [CI] 2.46-15.49, P < .001) and MAEs (unadjusted HR 5.12, 95% CI 1.38-19.01, P = .014). Multivariate analysis revealed that fQRS was a strong independent predictor of VAEs (adjusted HR 6.28, 95% CI 2.49-15.84, P < .001) and MAEs (adjusted HR 6.04, 95% CI 1.49-24.39, P = .011). fQRS in the inferior leads was most closely related to MAEs compared to fQRS in other myocardial territories, and its inclusion in a risk calculator for mortality in HCM patients increased the positive predictive value from 8% to 25% in low-risk patients. CONCLUSION: Presence of an fQRS may be a good candidate marker for prediction of VAE in patients with HCM.

Paced QT interval is a better predictor of mortality than the intrinsic QT interval: long-term follow-up study.

BACKGROUND: Prolongation of the corrected QT (QTc) interval on 12-lead electrocardiogram is related to total mortality and sudden cardiac death. The value of the paced QTc interval in predicting mortality has not been investigated. OBJECTIVE: To evaluate the relationship between the paced QTc interval and mortality. METHODS: Of 1440 patients who underwent pacemaker implantation from January 1990 to March 2010, 766 had a recorded intrinsic and ventricular paced rhythm and were included in this study. The intrinsic and paced QTc intervals were measured on 12-lead electrocardiogram before and 1-month after implantation. RESULTS: During a mean follow-up period of 7 ± 5 years, 189 (24.4%) patients died, of which 63 (8.1%) were cardiac deaths. Compared with patients in the first tertile of the paced QTc interval (<484 ms), patients in the third tertile (>511 ms) were significantly more likely to die (19% vs 29%; P < .05). A comparison of the third and first tertiles of the QTc interval showed that a prolonged paced QTc interval was a significant independent predictor of all-cause mortality (adjusted hazard ratio 2.08; 95% confidence interval 1.44-3.01; P < .001) and cardiac mortality (adjusted hazard ratio 2.53; 95% confidence interval 1.29-4.95; P = .007) and a better predictor than was a prolonged intrinsic QTc interval. When treated as a continuous variable, a prolonged paced QTc interval predicted increased total mortality and cardiac mortality. CONCLUSION: The paced QTc interval appears to be a more useful marker in predicting bad prognosis than does the intrinsic QTc interval in patients with indications for a permanent pacemaker.

Multistage electrotherapy delivered through chronically-implanted leads terminates atrial fibrillation with lower energy than a single biphasic shock.

OBJECTIVES: The goal of this study was to develop a low-energy, implantable device-based multistage electrotherapy (MSE) to terminate atrial fibrillation (AF). BACKGROUND: Previous attempts to perform cardioversion of AF by using an implantable device were limited by the pain caused by use of a high-energy single biphasic shock (BPS). METHODS: Transvenous leads were implanted into the right atrium (RA), coronary sinus, and left pulmonary artery of 14 dogs. Self-sustaining AF was induced by 6 ± 2 weeks of high-rate RA pacing. Atrial defibrillation thresholds of standard versus experimental electrotherapies were measured in vivo and studied by using optical imaging in vitro. RESULTS: The mean AF cycle length (CL) in vivo was 112 ± 21 ms (534 beats/min). The impedances of the RA-left pulmonary artery and RA-coronary sinus shock vectors were similar (121 ± 11 Ω vs. 126 ± 9 Ω; p = 0.27). BPS required 1.48 ± 0.91 J (165 ± 34 V) to terminate AF. In contrast, MSE terminated AF with significantly less energy (0.16 ± 0.16 J; p < 0.001) and significantly lower peak voltage (31.1 ± 19.3 V; p < 0.001). In vitro optical imaging studies found that AF was maintained by localized foci originating from pulmonary vein-left atrium interfaces. MSE Stage 1 shocks temporarily disrupted localized foci; MSE Stage 2 entrainment shocks continued to silence the localized foci driving AF; and MSE Stage 3 pacing stimuli enabled consistent RA-left atrium activation until sinus rhythm was restored. CONCLUSIONS: Low-energy MSE significantly reduced the atrial defibrillation thresholds compared with BPS in a canine model of AF. MSE may enable painless, device-based AF therapy.

A novel low-energy electrotherapy that terminates ventricular tachycardia with lower energy than a biphasic shock when antitachycardia pacing fails.

OBJECTIVES: The authors sought to develop a low-energy electrotherapy that terminates ventricular tachycardia (VT) when antitachycardia pacing (ATP) fails. BACKGROUND: High-energy implantable cardioverter-defibrillator (ICD) shocks are associated with device failure, significant morbidity, and increased mortality. A low-energy alternative to ICD shocks is desirable. METHODS: Myocardial infarction was created in 25 dogs. Sustained, monomorphic VT was induced by programmed stimulation. Defibrillation electrodes were placed in the right ventricular apex, and coronary sinus and left ventricular epicardium. If ATP failed to terminate sustained VT, the defibrillation thresholds (DFTs) of standard versus experimental electrotherapies were measured. RESULTS: Sustained VT ranged from 276 to 438 beats/min (mean 339 beats/min). The right ventricular-coronary sinus shock vector had lower impedance than the right ventricular-left ventricular patch (54.4 ± 18.1 Ω versus 109.8 ± 16.9 Ω; p < 0.001). A single shock required between 0.3 ± 0.2 J to 5.9 ± 2.5 J (mean 2.64 ± 3.22 J; p = 0.008) to terminate VT, and varied depending upon the phase of the VT cycle in which it was delivered. By contrast, multiple shocks delivered within 1 VT cycle length were not phase dependent and achieved lower DFT compared with a single shock (0.13 ± 0.09 J for 3 shocks, 0.08 ± 0.04 J for 5 shocks, and 0.09 ± 0.07 J for 7 shocks; p < 0.001). Finally, a multistage electrotherapy (MSE) achieved significantly lower DFT compared with a single biphasic shock (0.03 ± 0.05 J versus 2.37 ± 1.20 J; respectively, p < 0.001). At a peak shock amplitude of 20 V, MSE achieved 91.3% of terminations versus 10.5% for a biphasic shock (p < 0.001). CONCLUSIONS: MSE achieved a major reduction in DFT compared with a single biphasic shock for ATP-refractory monomorphic VT, and represents a novel electrotherapy to reduce high-energy ICD shocks.

Remodeling of calcium handling in human heart failure.

Heart failure (HF) is an increasing public health problem accelerated by a rapidly aging global population. Despite considerable progress in managing the disease, the development of new therapies for effective treatment of HF remains a challenge. To identify targets for early diagnosis and therapeutic intervention, it is essential to understand the molecular and cellular basis of calcium handling and the signaling pathways governing the functional remodeling associated with HF in humans. Calcium (Ca(2+)) cycling is an essential mediator of cardiac contractile function, and remodeling of calcium handling is thought to be one of the major factors contributing to the mechanical and electrical dysfunction observed in HF. Active research in this field aims to bridge the gap between basic research and effective clinical treatments of HF. This chapter reviews the most relevant studies of calcium remodeling in failing human hearts and discusses their connections to current and emerging clinical therapies for HF patients.

Altered systemic ketone body metabolism in advanced heart failure.

Heart failure is a systemic disease in which both myocardium and skeletal muscle exhibit alterations of energy metabolism. Failing myocardium exhibits impaired utilization of free fatty acids and glucose, which are major substrates for myocardial energy production. Ketone bodies normally provide a modest contribution to energy balance, but serum concentrations of ketone bodies are elevated in heart failure. To profile ketone body metabolism in advanced heart failure, we directly measured ketone body utilization by heart and skeletal muscle.Metabolite concentrations in arterial, coronary sinus, and central venous beds were measured to derive myocardial and skeletal-muscle ketone body utilization in 11 patients with advanced heart failure and 10 healthy control subjects who were undergoing electrophysiologic procedures. As expected, the mean myocardial arteriovenous oxygen difference was significantly increased in the heart-failure patients (8.3 ± 0.4 mL/dL, vs 7 ± 0.5 mL/dL in the control subjects; P = 0.05). Although the mean myocardial ketone body extraction ratio was relatively unchanged (0.49 ± 0.05 in heart-failure patients vs 0.54 ± 0.06 in control subjects, P = 0.53), skeletal-muscle ketone body utilization was markedly lower in the heart-failure patients (0.18 ± 0.06, vs 0.4 ± 0.04 in control subjects; P = 0.01).In this preliminary study, heart failure was associated with tissue-specific alteration of ketone body metabolism. In advanced heart failure, skeletal-muscle ketone body utilization was impaired, whereas myocardial ketone body utilization was preserved. Future studies are needed to determine whether ketone body metabolism serves as a dynamic quantitative biomarker of skeletal myopathy and fatigue in heart failure.

Low-energy multistage atrial defibrillation therapy terminates atrial fibrillation with less energy than a single shock.

BACKGROUND: Implantable device therapy of atrial fibrillation (AF) is limited by pain from high-energy shocks. We developed a low-energy multistage defibrillation therapy and tested it in a canine model of AF. METHODS AND RESULTS: AF was induced by burst pacing during vagus nerve stimulation. Our novel defibrillation therapy consisted of 3 stages: stage (ST) 1 (1-4 low-energy biphasic [BP] shocks), ST2 (6-10 ultralow-energy monophasic [MP] shocks), and ST3 (antitachycardia pacing). First, ST1 testing compared single or multiple MP and BP shocks. Second, several multistage therapies were tested: ST1 versus ST1+ST3 versus ST1+ST2+ST3. Third, 3 shock vectors were compared: superior vena cava to distal coronary sinus, proximal coronary sinus to left atrial appendage, and right atrial appendage to left atrial appendage. The atrial defibrillation threshold (DFT) of 1 BP shock was <1 MP shock (0.55 ± 0.1 versus 1.38 ± 0.31 J, P=0.003). Two to 3 BP shocks terminated AF with lower peak voltage than 1 BP or 1 MP shock and with lower atrial DFT than 4 BP shocks. Compared with ST1 therapy alone, ST1+ST3 lowered the atrial DFT moderately (0.51 ± 0.46 versus 0.95 ± 0.32 J, P=0.036), whereas 3-stage therapy (ST1+ST2+ST3) dramatically lowered the atrial DFT (0.19 ± 0.12 versus 0.95 ± 0.32 J for ST1 alone, P=0.0012). Finally, the 3-stage therapy was equally effective for all studied vectors. CONCLUSIONS: Three-stage electrotherapy significantly reduces the AF DFT and opens the door to low-energy atrial defibrillation at or below the pain threshold.

HIV-1 Nef binds the DOCK2-ELMO1 complex to activate rac and inhibit lymphocyte chemotaxis.

The infectious cycle of primate lentiviruses is intimately linked to interactions between cells of the immune system. Nef, a potent virulence factor, alters cellular environments to increase lentiviral replication in the host, yet the mechanisms underlying these effects have remained elusive. Since Nef likely functions as an adaptor protein, we exploited a proteomic approach to directly identify molecules that Nef targets to subvert the signaling machinery in T cells. We purified to near homogeneity a major Nef-associated protein complex from T cells and identified by mass spectroscopy its subunits as DOCK2-ELMO1, a key activator of Rac in antigen- and chemokine-initiated signaling pathways, and Rac. We show that Nef activates Rac in T cell lines and in primary T cells following infection with HIV-1 in the absence of antigenic stimuli. Nef activates Rac by binding the DOCK2-ELMO1 complex, and this interaction is linked to the abilities of Nef to inhibit chemotaxis and promote T cell activation. Our data indicate that Nef targets a critical switch that regulates Rac GTPases downstream of chemokine- and antigen-initiated signaling pathways. This interaction enables Nef to influence multiple aspects of T cell function and thus provides an important mechanism by which Nef impacts pathogenesis by primate lentiviruses.

T-cell receptor:CD3 down-regulation is a selected in vivo function of simian immunodeficiency virus Nef but is not sufficient for effective viral replication in rhesus macaques.

We investigated the function of severely truncated simian immunodeficiency virus (SIV) Nef proteins (tNef) in vitro and in vivo. These variants emerged in rhesus monkeys infected with SIVmac239 containing a 152-bp deletion in the nef-unique region and have been suggested to enhance SIV virulence (E. T. Sawai, M. S. Hamza, M. Ye, K. E. Shaw, and P. A. Luciw, J. Virol. 74:2038-2045, 2000). We found that the tNef proteins were unable to down-regulate the cell surface expression of major histocompatibility complex class I proteins, CD4, and CD28 and neither stimulated SIV replication nor enhanced virion infectivity. The tNef proteins did efficiently down-regulate T-cell receptor (TCR):CD3 cell surface expression. Nevertheless, the SIVmac239 tnef variants were strongly attenuated in six infected juvenile rhesus macaques. Thus, while the ability of SIV Nef to down-modulate TCR:CD3 cell surface expression apparently confers a selective advantage in vivo, it is insufficient for efficient viral replication in infected macaques. Additional mutations elsewhere in SIVmac239 tnef genomes are required for a virulent phenotype.