Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. Methods and Results-Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin ϩ/Ϫ ) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all PϽ0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin ϩ/Ϫ hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin ϩ/Ϫ mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. Conclusions-Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.

Atrial natriuretic peptide (ANP), via its vasodilating and diuretic effects, has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance of this is controversial. To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination. Notably, despite full preservation of the direct vasodilating effects of ANP, mice with endothelium-restricted deletion of the GC-A gene (EC GC-A KO) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations together with the Evan's blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11-13%, even under conditions of normal dietary salt intake. Infusion of ANP caused immediate increases in hematocrit in control but not in EC GC-A KO mice, which indicated that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume produced by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice. We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.

Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model.G-CSF/SCF improved cardiac output after myocardial infarction. Although G-CSF/SCF led to a twofold increased, potentially proarrhythmic homing of bone marrow (BM)-derived cells to the area of infarction, <1% of these cells adopted a cardial phenotype. Inducibility of ventricular tachycardias during programmed stimulation was reduced 5 wk after G-CSF/SCF treatment. G-CSF/SCF increased cardiomyocyte diameter, arteriogenesis, and expression of connexin43 in the border zone of the infarction. An enhanced expression of the G-CSF receptor demonstrated in cardiomyocytes and other cell types of the infarcted myocardium indicates a sensitization of the heart to direct influences of this cytokine. In addition to paracrine effects potentially caused by the increased homing of BM-derived cells, these might contribute to the therapeutic effects of G-CSF.

Background— Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na + /H + exchanger NHE-1 to cardiac remodeling in GC-A–deficient (GC-A −/− ) mice. Methods and Results— Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A −/− mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca 2+ levels. Chronic treatment of GC-A −/− mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca 2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A −/− mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca 2+ /calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A −/− mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy. Conclusions— On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca 2+ , and CaMKII as well as Akt activity.