Body surface mapping using an ECG belt to characterize electrical heterogeneity for different left ventricular pacing sites during cardiac resynchronization: Relationship with acute hemodynamic improvement.

BACKGROUND: Electrical heterogeneity (EH) during cardiac resynchronization therapy may vary with different left ventricular (LV) pacing sites. OBJECTIVE: The purpose of this study was to evaluate the relationship between such changes and acute hemodynamic response (AHR). METHODS: Two EH metrics-standard deviation of activation times and mean left thorax activation times-were computed from isochronal maps based on 53-electrode body surface mapping during baseline AAI pacing and biventricular (BiV) pacing from different pacing sites in coronary veins in 40 cardiac resynchronization therapy-indicated patients. AHR at different sites was evaluated by invasive measurement of LV-dp/dtmax at baseline and BiV pacing, along with right ventricular (RV)-LV sensing delays and QRS duration. RESULTS: The site with the greatest combined reduction in standard deviation of activation times and left thorax activation times from baseline to BiV pacing was hemodynamically optimal (defined by AHR equal to, or within 5% of, the largest dp/dt response) in 35 of 40 patients (88%). Sites with the longest RV-LV and narrowest paced QRS were hemodynamically optimal in 26 of 40 patients (65%) and 28 of 40 patients (70%), respectively. EH metrics from isochronal maps had much better accuracy (sensitivity 90%, specificity 80%) for identifying hemodynamically responsive sites (∆LV dp/dtmax ≥10%) compared with RV-LV delay (69%, 85%) or paced QRS reduction (52%, 76%). Multivariate prediction model based on EH metrics showed significant correlation (R2 = 0.53, P <.001) between predicted and measured AHR. CONCLUSION: Changes in EH from baseline to BiV pacing more accurately identified hemodynamically optimal sites than RV-LV delays or paced QRS shortening. Optimization of LV lead location by minimizing EH during BiV pacing, based on body surface mapping, may improve CRT response.

Prevalence and predictors of complications of radiofrequency catheter ablation for atrial fibrillation.

INTRODUCTION: Up to 6% of patients experience complications after radiofrequency catheter ablation (RFA) of atrial fibrillation (AF). The purpose of this study is to determine the prevalence and predictors of periprocedural complications after RFA for AF. METHODS AND RESULTS: The subjects were 1,295 consecutive patients (age = 60 ± 10 years) who underwent RFA (n = 1,642) for paroxysmal (53%) or persistent AF (47%) from January 2007 to January 2010. A complication occurred in 57 patients (3.5%); a vascular access complication in 31 (1.9%); pericardial tamponade in 20 (1.2%); a thromboembolic event in 4 (0.2%); deep venous thrombosis in 1 (<0.01%); and pulmonary vein stenosis in 1 patient (<0.01%). There were no procedure-related deaths. On multivariate analysis, female gender (OR = 2.27; ±95% CI: 1.31-2.57, P < 0.01) and procedures performed in July or August (OR = 2.10; ±95% CI: 1.16-3.80, P = 0.01) were independent predictors of any complication. For vascular complications, treatment with clopidogrel (OR = 4.40; ±95% CI: 1.43-13.53, P = 0.01), female gender (OR = 3.65; ±95% CI: 1.72-7.75, P < 0.01) and performing RFA in July or August (OR = 2.71; ±95% CI: 1.25-5.87, P = 0.01) were independent predictors. The only predictor of cardiac tamponade was prior RFA (OR = 3.32; ±95% CI: 0.95-11.61; P < 0.05). CONCLUSION: Prevalence of perioperative complications for RFA of AF is 3.5% and vascular access complications constitute the majority. The need for clopidogrel therapy should be carefully considered prior to RFA. At teaching institutions close supervision should be exercised during vascular access early in the year. Improvements in ablation technology and elimination of the need for repeat procedures may decrease the risk of pericardial tamponade.

Identification of Nogo as a novel indicator of heart failure.

Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant beta-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gbetagamma inhibitory carboxy-terminus of the beta-adrenergic receptor kinase (betaARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their betaARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP-/-), which closely parallels human dilated cardiomyopathy disease progression and aberrant beta-adrenergic signaling, and their betaARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP-/- subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.

Novel pharmacological therapies for atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is a common yet difficult cardiac rhythm to treat. Limitations of the currently available medications, increasing complexity of atrial fibrillation patient populations and the prevalence of the condition have made new drug development crucial. Our understanding of the pathophysiology of atrial fibrillation has increased tremendously over the years. The importance of electrical remodeling and structural remodeling has been widely appreciated and has opened new avenues for pharmacological research. RECENT FINDINGS: Novel ion channel blockers have targeted atrial-specific ion channels or a combination of ion channels in order to maximize efficacy and minimize proarrhythmic risk. Understanding of atrial fibrillation as a metabolically complex condition with activation of multiple signaling cascades has fuelled drug development in a new direction. Exciting new drugs inhibiting fibrosis, cellular hypertrophy and improving cell-cell communication may help treat chronic atrial fibrillation in the future. SUMMARY: Continuing progress in our knowledge of the ionic and structural remodeling in atrial fibrillation will only accelerate the search for a safe antidote. In the future focal pharmacological modulation may help target specific targets in diverse populations. The potential of many of these pharmacotherapies, however, will need to be tested in large randomized trials before our faith in them is realized.

A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications.

The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin.

Altered right atrial excitation and propagation in connexin40 knockout mice.

BACKGROUND: Intercellular coupling via connexin40 (Cx40) gap junction channels is an important determinant of impulse propagation in the atria. METHODS AND RESULTS: We studied the role of Cx40 in intra-atrial excitation and propagation in wild-type (Cx40(+/+)) and knockout (Cx40(-/-)) mice using high-resolution, dual-wavelength optical mapping. On ECG, the P wave was significantly prolonged in Cx40(-/-) mice (13.4+/-0.5 versus 11.4+/-0.3 ms in Cx40(+/+)). In Cx40(+/+) hearts, spontaneous right atrial (RA) activation showed a focal breakthrough at the junction of the right superior vena cava, sulcus terminalis, and RA free wall, corresponding to the location of the sinoatrial node. In contrast, Cx40(-/-) hearts displayed ectopic breakthrough sites at the base of the sulcus terminalis, RA free wall, and right superior vena cava. Progressive ablation of such sites in 4 Cx40(-/-) mice resulted in ectopic focus migration and cycle length prolongation. In all Cx40(-/-) hearts the focus ultimately shifted to the sinoatrial node at a very prolonged cycle length (initial ectopic cycle length, 182+/-20 ms; postablation sinus cycle length, 387+/-44 ms). In a second group of experiments, epicardial pacing at 10 Hz revealed slower conduction in the RA free wall of 5 Cx40(-/-) hearts than in 5 Cx40(+/+) hearts (0.61+/-0.07 versus 0.94+/-0.07 m/s; P<0.05). Dominant frequency analysis in Cx40(-/-) RA demonstrated significant reduction in the area of 1:1 conduction at 16 Hz (40+/-10% versus 69+/-5% in Cx40(+/+)) and 25 Hz (36+/-11% versus 65+/-9% in Cx40(+/+)). CONCLUSIONS: This is the first demonstration of intra-atrial block, ectopic rhythms, and altered atrial propagation in the RA of Cx40(-/-) mice.

Unique Kir2.x properties determine regional and species differences in the cardiac inward rectifier K+ current.

The inwardly rectifying potassium (Kir) 2.x channels mediate the cardiac inward rectifier potassium current (I(K1)). In addition to differences in current density, atrial and ventricular I(K1) have differences in outward current profiles and in extracellular potassium ([K+]o) dependence. The whole-cell patch-clamp technique was used to study these properties in heterologously expressed Kir2.x channels and atrial and ventricular I(K1) in guinea pig and sheep hearts. Kir2.x channels showed distinct rectification profiles: Kir2.1 and Kir2.2 rectified completely at potentials more depolarized than -30 mV (I approximately 0 pA). In contrast, rectification was incomplete for Kir2.3 channels. In guinea pig atria, which expressed mainly Kir2.1, I(K1) rectified completely. In sheep atria, which predominantly expressed Kir2.3 channels, I(K1) did not rectify completely. Single-channel analysis of sheep Kir2.3 channels showed a mean unitary conductance of 13.1+/-0.1 pS in 15 cells, which corresponded with I(K1) in sheep atria (9.9+/-0.1 pS in 32 cells). Outward Kir2.1 currents were increased in 10 mmol/L [K+]o, whereas Kir2.3 currents did not increase. Correspondingly, guinea pig (but not sheep) atrial I(K1) showed an increase in outward currents in 10 mmol/L [K+]o. Although the ventricles of both species expressed Kir2.1 and Kir2.3, outward I(K1) currents rectified completely and increased in high [K+]o-displaying Kir2.1-like properties. Likewise, outward current properties of heterologously expressed Kir2.1-Kir2.3 complexes in normal and 10 mmol/L [K+]o were similar to Kir2.1 but not Kir2.3. Thus, unique properties of individual Kir2.x isoforms, as well as heteromeric Kir2.x complexes, determine regional and species differences of I(K1) in the heart.

Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) commonly associates with atrial dilatation by poorly understood mechanisms. We hypothesized that elevation of intra-atrial pressure elicits high-frequency and spatio-temporally organized left atrial (LA) sources emanating from the superior pulmonary veins. METHODS AND RESULTS: We used a stretch-related AF model in the sheep heart to induce stable episodes of AF (>40 minutes) in 9 animals. Video movies of the LA free wall (LAFW) and LA superior pulmonary vein junction (JPV) were obtained by using di-4-ANEPPS. Electrograms from the right atrium were recorded. At intra-atrial pressures >10 cm H2O, the maximum dominant frequency (DFMax) was significantly higher in the JPV than in the LAFW (12.0+/-0.2 and 10.5+/-0.2 Hz, respectively [mean+/-SEM]; P<0.001). Below 10 cm H2O, DFMax was similar in the JPV and LAFW (10.8+/-0.3 versus 10.2+/-0.3 Hz; P=0.6); DFMax in both JPV and LAFW was significantly higher than in the right atrium (7.8+/-0.3 Hz; P<0.001). Analysis of excitation direction in JPV showed positive correlation between intra-atrial pressure and the number of waves emanating from the left superior pulmonary vein (r=0.79, P=0.02) but not from the LAFW (r=0.54, P=0.09). The number of spatio-temporally periodic waves in the JPV correlated with pressure (r=0.92, P=0.002). In 3 cases, JPV rotors were identified with a cycle length equal to 1/DFMax. CONCLUSIONS: We demonstrate for the first time that an increase in intra-atrial pressure increases the rate and organization of waves emanating from the superior pulmonary veins underlying stretch-related AF.

Blockade of the inward rectifying potassium current terminates ventricular fibrillation in the guinea pig heart.

INTRODUCTION: Stable high-frequency rotors sustain ventricular fibrillation (VF) in the guinea pig heart. We surmised that rotor stabilization in the left ventricle (LV) and fibrillatory conduction toward the right ventricle (RV) result from chamber-specific differences in functional expression of inward rectifier (Kir2.x) channels and unequal IK1 rectification in LV and RV myocytes. Accordingly, selective blockade of IK1 during VF should terminate VF. METHODS AND RESULTS: Relative mRNA levels of Kir2.x channels were measured in LV and RV. In addition, LV (n = 21) and RV (n = 20) myocytes were superfused with BaCl2 (5-50 micromol/L) to study the effects on IK1. Potentiometric dye-fluorescence movies of VF were obtained in the presence of Ba2+ (0-50 micromol/L) in 23 Langendorff-perfused hearts. Dominant frequencies (DFs) were determined by spectral analysis, and singularity points were counted in phase maps to assess VF organization. mRNA levels for Kir2.1 and Kir2.3 were significantly larger in LV than RV. Concurrently, outward IK1 was significantly larger in LV than RV myocytes. Ba2+ decreased IK1 in a dose-dependent manner (LV change > RV change). In baseline control VF, the fastest DF domain (28-40 Hz) was located on the anterior LV wall and a sharp LV-to-RV frequency gradient of 21.2 +/- 4.3 Hz was present. Ba2+ significantly decreased both LV frequency and gradient, and it terminated VF in a dose-dependent manner. At 50 micromol/L, Ba2+ decreased the average number of wavebreaks (1.7 +/- 0.9 to 0.8 +/- 0.6 SP/sec x pixel, P < 0.05) and then terminated VF. CONCLUSION: The results strongly support the hypothesis that IK1 plays an important role in rotor stabilization and VF dynamics.