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The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.2 (Cx30.2, also known as Gjd3) gene, which encodes a gap junction protein required for normal atrioventricular (AV) delay in mice, is necessary and sufficient to direct expression to the developing AV conduction system (AVCS). Moreover, we show that this enhancer requires Tbx5 and Gata4 for proper expression in the conduction system, and Gata4+/- mice have short PR intervals indicative of accelerated AV conduction. Thus, our results implicate Gata4 in conduction system function and provide a clearer understanding of the transcriptional pathways that impact normal AV delay.

Background— Recent reports demonstrate that multiple forms of cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury, provoke an increase in autophagic activity in cardiomyocytes. However, nothing is known regarding molecular events that stimulate autophagic activity in stressed myocardium. Because autophagy is a highly conserved process through which damaged proteins and organelles can be degraded, we hypothesized that stress-induced protein aggregation is a proximal trigger of cardiomyocyte autophagy. Methods and Results— Here, we report that pressure overload promotes accumulation of ubiquitinated protein aggregates in the left ventricle, development of aggresome-like structures, and a corresponding induction of autophagy. To test for causal links, we induced protein accumulation in cultured cardiomyocytes by inhibiting proteasome activity, finding that aggregation of polyubiquitinated proteins was sufficient to induce cardiomyocyte autophagy. Furthermore, attenuation of autophagic activity dramatically enhanced both aggresome size and abundance, consistent with a role for autophagic activity in protein aggregate clearance. Conclusions— We conclude that protein aggregation is a proximal trigger of cardiomyocyte autophagy and that autophagic activity functions to attenuate aggregate/aggresome formation in heart. Findings reported here are the first to demonstrate that protein aggregation occurs in response to hemodynamic stress, situating pressure-overload heart disease in the category of proteinopathies.

Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. Studies in preclinical models suggest that inhibition of histone deacetylase (HDAC) activity - using compounds that show promise in ongoing oncology trials - blunts pathologic growth of cardiac myocytes. Indeed, small-molecule inhibitors of HDACs are members of an evolving class of pharmacologic agents in development for the treatment of several diseases. If proved effective in the treatment of heart disease, HDAC inhibitors could have a significant impact on public health, as cardiovascular disease remains the leading cause of death in the US. This paper reviews understanding of the mechanisms of action of HDAC inhibitors in the heart and summarizes emerging data regarding their effects on disease-related cardiac remodeling and function.

The prevalence of heart failure is increasing rapidly worldwide, and yet effective treatments remain elusive. Pathological remodeling of the ventricle – and associated hypertrophic growth, fibrotic change, cavity dilatation and electrophysiological remodeling – is a significant contributor to the pathogenesis of this prevalent disorder. As a consequence, there is great interest in developing new therapies to target pathological remodeling of the heart with the intent to prevent, arrest, or possibly reverse the otherwise inexorable progression of disease. To tackle this problem, numerous models of disease have been developed, both in vivo and in vitro. Here, we review models of cardiac hypertrophy and failure, compare and contrast their strengths and limitations, and on occasion cite recent works where the use of these models has contributed to significant scientific advances.

Cardiac resynchronization therapy (CRT) has evolved as an effective therapy for patients with congestive heart failure (CHF) and ventricular dyssynchrony, currently defined as a wide QRS on the electrocardiogram. While multiple randomized controlled trials have confirmed the favorable effects of CRT on mortality and heart failure symptoms for patients in sinus rhythm, only recently observational studies have begun to suggest a similar benefit for patients with atrial fibrillation (AF) and dyssynchrony. Yet, implementing effective biventricular pacing in patients with AF can be problematic due to competing intrinsic AV conduction. For patients with depressed ejection fractions needing AV node (AVN) ablation to control fast ventricular rates, biventricular pacing has been shown to be superior to right ventricular pacing alone. When consistent pacing (over 90% of the time) cannot be achieved in AF patients due to a rapid ventricular response despite pharmacological therapy, AVN ablation should be considered. The additional benefit of performing AVN ablation to promote biventricular pacing in patients without rapid ventricular rates remains uncertain. A randomized controlled trial is needed to test the incremental benefit of AVN ablation to promote biventricular pacing in heart failure patients with AF and wide QRS.

Rationale: Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. Objective: We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Methods and Results: Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions: Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.

We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.Multiple cellular events that occur during pathological remodeling of the failing ventricle are implicated in the genesis of ventricular tachycardia (VT), including interstitial fibrosis. Recent studies suggest that ventricular fibrosis is reversible, and current anti-remodeling therapies attenuate ventricular fibrosis. However, the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium is currently not well defined.Class II histone deacetylases (HDACs) have been implicated in promoting collagen biosynthesis. As these enzymes are inhibited by protein kinase D1 (PKD1), we studied mice with cardiomyocyte-specific transgenic over-expression of a constitutively active mutant of PKD1 (caPKD). caPKD mice were compared with animals in which cardiomyopathy was induced by severe thoracic aortic banding (sTAB). Hearts were analyzed by echocardiographic and electrocardiographic means. Interstitial fibrosis was assessed by histology and quantified biochemically. Ventricular arrhythmias were induced by closed-chest, intracardiac pacing.Similar degrees of hypertrophic growth, systolic dysfunction and mortality were observed in the two models. In sTAB mice, robust ventricular fibrosis was readily detected, but myocardial collagen content was significantly reduced in caPKD mice. As expected, VT was readily inducible by programmed stimulation in sTAB mice and VT was less inducible in caPKD mice. Surprisingly, episodes of VT manifested longer cycle lengths and longer duration in caPKD mice.Attenuated ventricular fibrosis is associated with reduced VT inducibility, increased VT duration, and significantly longer arrhythmia cycle length.

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

Background: Ventricular hypertrophy will sometimes reverse when the inciting stimulus (e.g. hypertension) is removed; at a certain point, however, pathological remodeling becomes irreversible. Further, recent studies have highlighted differences in disease pathogenesis triggered by signaling pathways activated in males (M) versus females (F). However, little is known regarding mechanisms of hypertrophy resolution, markers of irreversibility, or the effects of gender-specific mechanisms thereon. Methods: We engineered mice that express a constitutively active calcineurin mutant driven by a tet-off-αMHC promoter (tetCnA). During gestation, through weaning, and up to 5 wks of age, tetCnA mice were exposed to doxycycline (dox). Then, mice were randomized to dox (OFF) or dH2O (ON) for 16 wks. In the ON group, half received dH20 for 8 wks followed by dox for 8 wks (ON-OFF). Serial echocardiography was performed every 2 wks. Results: Systolic function declined significantly (p Conclusions: Calcineurin activation in adolescent male mice triggers pathological remodeling that is severe and irreversible after 2 months. In contrast, similar degrees of calcineurin-induced ventricular remodeling in adolescent female mice remain reversible at 2 months.