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Heart Failure ( HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor ( MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells ( EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 ( ICAM-1). Recently, we reported that ICAM-1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction ( TAC). Whether MR specifically in endothelial cells ( EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs ( EC- MR−/−) and wild-type littermate controls ( EC- MR+/+). MR was specifically deleted in heart EC, and in EC-containing tissues, but not in leukocytes of TAC EC- MR−/− mice. While EC- MR−/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC- MR+/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM-1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC- MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the molecular mechanisms that underlie gender- and hormonal-related differences in susceptibility to cardiac arrhythmias has been hampered by the lack of a suitable animal model. We examined the effect of hormonal status on the electrophysiologic (EP) properties of the mouse heart in an in vivo, closed chest model. Methods and Results: Fifty-three female C57/J mice aged 10 to 12 weeks were studied. Thirty-six mice underwent bilateral ovariectomies; 18 received estrogen (OVX+E) and 18 received placebo (OVX). Seventeen female mice underwent only sham surgery. All animals underwent in vivo EP studies. Select EP parameters were measured after quinidine treatment. Data were analyzed by a blinded observer. Compared with the intact female mice, the PR and AH intervals were significantly shorter in the OVX mice, and these parameters normalized with estrogen replacement (PR = 45.9 ± 4.5 msec in the intact mice, 42.1 ± 4.3 msec in the OVX group, and 46.9 ± 3.5 msec in the OVX + E group, P < 0.005; AH = 36.5 ± 4.9 msec in the intact mice, 34.4 ± 4.7 msec in the OVX group, and 38.8 ± 2.7 msec in the OVX+E group, P = 0.03). The right ventricular effective refractory period was significantly shorter in the OVX mice versus the intact mice, and this also normalized with estrogen replacement. Hormonal status did not significantly affect any other EP variable, including QT interval. Conclusion: In female mice, estrogen prolongs AV nodal conduction and the right ventricular effective refractory period. Taken together, these data suggest that hormonal status affects aspects of cardiac EP function. Future application of this mouse model will be helpful in determining the molecular pathways that mediate hormonal differences in cardiac EP. [ABSTRACT FROM AUTHOR]

Microwave Ablation of Canine Ventricle. Introduction: Radiofrequency current delivered during cardiac ablation is limited by a rise in impedance secondary to coagulum formation on the ablation electrode. Microwave antennas continue to deliver energy despite the presence of coagulum; thus, temperature control of the ablation electrode may be even more important for microwave than for radiofrequency ablations to avoid thromboembolic risks. The purpose of this study was to test the safety and efficacy of an ablation system utilizing a feedback control system to maintain a fixed target temperature for creating lesions with multiple applications of microwave energy. [ABSTRACT FROM AUTHOR]

Introduction: A mouse strain lacking functional myotonic dystrophy protein kinase (DMPK) has recently been developed. DMPK-/- mice exhibit muscular and conduction abnormalities consistent with the disease; however, the site of abnormal cardiac conduction is unknown. Methods and Results: Nine homozygous DMPK-/- mice and seven age matched wild-type (WT) controls underwent in vivo electrophysiologic studies using an endocardial 2-French catheter. Baseline intervals as well as Wenckebach and 2:1 cycle lengths were measured to assess AV and ventriculoatrial (VA) conduction. Effective refractory periods (ERP) and functional refractory periods were determined during atrial and ventricular premature stimulation. His-bundle recordings were obtained on all the studied animals (16/16). DMPK-/- mice had significantly prolonged PR (48.1 ± 5.5 vs 40.9 ± 3.9 msec, P = 0.010) and AH (36.7 ± 4.0 vs 31.6 ± 4.8 msec, P = 0.037) Intervals compared to WT controls. HV intervals were very significantly prolonged as well (14.7 ± 2.0 vs 10.3 ± 0.8 msec; P < 0.0001). Three of 9 DMPK-/- and 1 of 7 WT mice exhibited VA block. Atrial ERP was reached before AV node ER) in 2 (22%) of 9 of the knockout mice and 5 (71 %) of 7 of the controls (P = 0.06). Only one mouse (DMPK-/-) exhibited infra-Hisian block on premature atrial stimulation. Conclusion: In this mouse model of myotonic dystrophy, AV conduction abnormalities were localized to the supra-Hisian and Infra-Hisian conduction tissues, with a higher predilection to the latter, a finding similar to the human form of the disease. [ABSTRACT FROM AUTHOR]

Background: Cyclic GMP (cGMP) signaling attenuates cardiac remodeling, but it is unclear which cGMP effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the cGMP downstream effector, cGMP-dependent protein kinase G Iα (PKGIα), attenuates pressure overload-induced remodeling in vivo., Methods and Results: The effect of transaortic constriction (TAC)-induced left ventricular (LV) pressure overload was examined in mice with selective mutations in the PKGIα leucine zipper interaction domain. Compared with wild-type littermate controls, in response to TAC, these Leucine Zipper Mutant (LZM) mice developed significant LV systolic and diastolic dysfunction by 48 hours (n=6 WT sham, 6 WT TAC, 5 LZM sham, 9 LZM TAC). In response to 7-day TAC, the LZM mice developed increased pathologic hypertrophy compared with controls (n=5 WT sham, 4 LZM sham, 8 WT TAC, 11 LZM TAC). In WT mice, but not in LZM mice, phosphodiesterase 5 (PDE5) inhibition with sildenafil (Sil) significantly inhibited TAC-induced cardiac hypertrophy and LV systolic dysfunction in WT mice, but this was abolished in the LZM mice (n=3 WT sham, 4 LZM sham, 3 WT TAC vehicle, 6 LZM TAC vehicle, 4 WT TAC Sil, 6 LZM TAC Sil). And in response to prolonged, 21-day TAC (n=8 WT sham, 7 LZM sham, 21 WT TAC, 15 LZM TAC), the LZM mice developed markedly accelerated mortality and congestive heart failure. TAC induced activation of JNK, which inhibits cardiac remodeling in vivo, in WT, but not in LZM, hearts, identifying a novel signaling pathway activated by PKGIα in the heart in response to LV pressure overload., Conclusions: These findings reveal direct roles for PKGIα in attenuating pressure overload-induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.