Melissa Byrne

Three-Dimensional Mapping of Optimal Left Ventricular Pacing Site for Cardiac Resynchronization

Background— The efficacy of cardiac resynchronization therapy (CRT) depends on placement of the left ventricular lead within the late-activated territory. The geographic extent and 3-dimensional distribution of left ventricular (LV) locations yielding optimal CRT remain unknown. Methods and Results— Normal or tachypacing-induced failing canine hearts made dyssynchronous by right ventricular free wall pacing or chronic left bundle-branch ablation were acutely instrumented with a nonconstraining epicardial elastic sock containing 128 electrodes interfaced with a computer-controlled stimulation/recording system. Biventricular CRT was performed using a fixed right ventricular site and randomly selected LV sites covering the entire free wall. For each LV site, global cardiac function (conductance catheter) and mechanical synchrony (magnetic resonance imaging tagging) were determined to yield 3-dimensional maps reflecting CRT impact. Optimal CRT was achieved from LV lateral wall sites, slightly more anterior than posterior and more apical than basal. LV sites yielding ≥70% of the maximal dP/dtmax increase covered ≈43% of the LV free wall. This distribution and size were similar in both normal and failing hearts. The region was similar for various systolic and diastolic parameters and correlated with 3-dimensional maps based on mechanical synchrony from magnetic resonance imaging strain analysis. Conclusions— In hearts with delayed lateral contraction, optimized CRT is achieved over a fairly broad area of LV lateral wall in both nonfailing and failing hearts, with modest anterior or posterior deviation still capable of providing effective CRT. Sites selected to achieve the most mechanical synchrony are generally similar to those that most improve global function, confirming a key assumption underlying the use of wall motion analysis to optimize CRT.

Feasibility and Short-Term Efficacy of Percutaneous Mitral Annular Reduction for the Therapy of Heart Failure-Induced Mitral Regurgitation

Background—Mitral regurgitation (MR) frequently accompanies congestive heart failure (CHF) and is associated with poorer prognosis and more significantly impaired symptomatic status. Although surgical mitral valve annuloplasty has the potential to offer benefit, concerns about the combined surgical risk and possible effects on ventricular performance have limited progress. We evaluated the feasibility and short-term efficacy of a novel device placed in the coronary sinus to reduce MR in the setting of CHF. Methods and Results—CHF and MR were induced in 9 adult sheep by rapid ventricular pacing for 5 to 8 weeks. A mitral annular constraint device was implanted percutaneously through the right internal jugular vein in the coronary sinus and great cardiac vein to create a short-term stable reduction (24.9±2.5%) in the mitral annular septal-lateral dimension as assessed echocardiographically. Right and left heart pressures and cardiac output were determined before and 15 minutes after device implantation. MR extent was examined echocardiographically and expressed as a ratio of left atrial area (MR/LAA). After device placement, MR was substantially reduced from an MR/LAA of 42+6% to 4±3% (P <0.01). In association, mean pulmonary wedge pressure was significantly reduced (26±3 to 18±3 mm Hg; P <0.01) and mean cardiac output significantly increased (3.4±0.3 to 4.3±0.4 L/min; P =0.01). Conclusions—In this model of CHF, percutaneous placement of a mitral annular constraint device in the coronary sinus resulted in the short-term elimination or minimization of MR and was accompanied in the short term by favorable hemodynamic effects.

Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization

Background— Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. Methods and Results— Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (−4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-&agr; increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1&agr;, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3&agr; and GSK3&bgr;) were more phosphorylated in DHF than CRT and thus less involved. Conclusions— CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

Percutaneous Mitral Annular Reduction Provides Continued Benefit in an Ovine Model of Dilated Cardiomyopathy

Background—Functional mitral valve regurgitation plays a key role in the symptomatic severity and progression of heart failure. In an ovine model of dilated cardiomyopathy, we examined the chronic functional consequences of mitral regurgitation reduction using a recently developed novel percutaneous mitral annular reduction (PMAR) device. Methods and Results—Fourteen adult sheep were paced right ventricularly at 180 to 190 bpm for 5 weeks, leading to the development of moderate mitral valve regurgitation. After echocardiographic, hemodynamic, and neurohormonal analysis, 9 animals underwent PMAR. All animals were subsequently paced for another 28 days, and a final echocardiographic and hemodynamic study was conducted. Animals that had undergone PMAR showed significantly increased negative and positive dP/dt, whereas pulmonary capillary wedge pressure and mitral valve regurgitation were significantly reduced compared with those at device implant despite continued pacing. In conjunction, significant improvements in plasma norepinephrine and brain natriuretic peptide were apparent. Conclusions—The application of PMAR in animals with pacing-induced dilated cardiomyopathy and functional mitral valve regurgitation resulted in continued improvements in hemodynamic and neurohormonal parameters.

Phased-Array intracardiac echocardiography to guide radiofrequency ablation in the left atrium and at the pulmonary vein ostium

Echocardiography and Pulmonary Vein Ablation. Introduction: We sought to evaluate the utility of a phased‐array intracardiac echocardiography (ICE) device to identify left atrial (LA) and pulmonary vein (PV) anatomy; accurately guide radiofrequency ablation (RFA) to the right or left PV ostium and LA appendage (LAA); and evaluate PV blood flow before and after RFA using Doppler parameters.

Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1-SERCA2a gene delivery in experimental heart failure.

Down‐regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF.

Ventricular constraint in severe heart failure halts decline in cardiovascular function associated with experimental dilated cardiomyopathy

BACKGROUND We have shown that passive ventricular constraint during moderate heart failure can halt progressive deterioration in cardiac function in an experimental model of ovine pacing induced heart failure (HF). We report on ventricular constraint in severe heart failure. METHODS Eighteen adult merino sheep were used. Severe heart failure was induced in two stages, ie, high rate ventricular pacing for 21 days to produce moderate HF and then for 42 days to induce severe HF. A custom-made polyester mesh cardiac support device ([CSD] Acorn Cardiovascular, St Paul, MN) was implanted snugly around both ventricles through a lower partial sternotomy in 9 sheep (group 1). Rapid ventricular pacing was continued for a further 28 days in all animals to induce advanced HF. Cardiovascular functional indicators were determined using echocardiography and a submaximal treadmill exercise protocol at base line, moderate, severe, and advanced stages. The 9 sheep in group 2 were used as controls. RESULTS Cardiovascular function was significantly depressed in all animals in advanced heart failure compared with base line, with left ventricular ejection fraction (LVEF) falling from 50% to 25% (p < 0.05) and LV +dp/dt((max)) declining from 1,777 to 1,243 (p < 0.05). However after CSD implantation cardiovascular function during exercise improved significantly despite ongoing rapid pacing, with LVEF increasing to 30% and LV +dp/dt to 1,499 (p < 0.05) in group 1. There were no significant changes in left ventricular long axis area (157 to 151 cm(2)) and short axis (6.8 to 6.1 cm) dimensions at the termination of pacing compared with those at time of CSD implant. Mitral regurgitation improved slightly from 2.5 to 2.19 after containment (p < 0.05) in group 1 but increased to 2.83 in group 2. CONCLUSIONS Ventricular constraint in advanced heart failure with a custom-made polyester mesh device halted the decline in cardiac function seen in untreated animals with this pacing-induced animal model of heart failure. These results indicate potential clinical implications for ventricular containment in the treatment of end-stage heart failure.

Irregular Rhythm Adversely Influences Calcium Handling in Ventricular Myocardium: Implications for the Interaction Between Heart Failure and Atrial Fibrillation

Background—Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation–contraction coupling which contributes to the progression of HF. Methods and Results—We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura-2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular samples obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca2+) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction (P<0.01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% (P<0.05) decrease in sarcoplasmic reticulum Ca2+ATPase protein expression and an 85% (P<0.01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm. Conclusions—Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation–contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF.Background— Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation–contraction coupling which contributes to the progression of HF. Methods and Results— We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura-2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular samples obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca2+) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction ( P <0.01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% ( P <0.05) decrease in sarcoplasmic reticulum Ca2+ATPase protein expression and an 85% ( P <0.01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm. Conclusions— Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation–contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF.

CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

Heart failure (HF) is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice) or type II diabetes (Israeli Sand-rats) and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow) to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

Abnormal Mitochondrial L-Arginine Transport Contributes to the Pathogenesis of Heart Failure and Rexoygenation Injury

Background Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to impact upon mitochondrial function. However, the mechanism responsible for arginine transport into mitochondria and the effect of HF on such a process is unknown. We therefore aimed to characterize mitochondrial L-arginine transport and to investigate the hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and myocardial injury. Methods and Results In mitochondria isolated from failing hearts (sheep rapid pacing model and mouse Mst1 transgenic model) we demonstrated a marked reduction in L-arginine uptake (p<0.05 and p<0.01 respectively) and expression of the principal L-arginine transporter, CAT-1 (p<0.001, p<0.01) compared to controls. This was accompanied by significantly lower NO production and higher 3-nitrotyrosine levels (both p<0.05). The role of mitochondrial L-arginine transport in modulating cardiac stress responses was examined in cardiomyocytes with mitochondrial specific overexpression of CAT-1 (mtCAT1) exposed to hypoxia-reoxygenation stress. mtCAT1 cardiomyocytes had significantly improved mitochondrial membrane potential, respiration and ATP turnover together with significantly decreased reactive oxygen species production and cell death following mitochondrial stress. Conclusion These data provide new insights into the role of L-arginine transport in mitochondrial biology and cardiovascular disease. Augmentation of mitochondrial L-arginine availability may be a novel therapeutic strategy for myocardial disorders involving mitochondrial stress such as heart failure and reperfusion injury.