RESUMO
Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.
Assuntos
Células Endoteliais , Fator A de Crescimento do Endotélio Vascular , Animais , Proliferação de Células , Células Endoteliais/fisiologia , Coração/fisiologia , Humanos , Recém-Nascido , Camundongos , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: A diagnosis of Lamin proteins A and C cardiomyopathy (LMNA-CM) not only impacts disease prognosis, but also leads to specific guideline-recommended treatment options for these patients. This etiology is fundamentally different from other genetic causes of dilated CM. METHODS AND RESULTS: LMNA-CM often presents early in the third to fourth decades and there is an age-dependent penetrance of nearly 90% among those with a positive genotype for LMNA-CM. Oftentimes, electrical abnormalities with either conduction disturbances and/or either atrial or ventricular arrhythmias manifest before there is imaging evidence of left ventricular dysfunction. Given these subtle early findings, cardiac magnetic resonance provides helpful guidance regarding patterns of enhancement associated with LMNA-CM, often before there is significant left ventricular dilation and/or a decrease in the ejection fraction and could be used for further understanding of risk stratification and prognosis of asymptomatic genotype-positive individuals. Among symptomatic patients with LMNA-CM, approximately one-quarter of individuals progress to needing advanced heart failure therapies such as heart transplantation. CONCLUSIONS: In the era of precision medicine, increased recognition of clinical findings associated with LMNA-CM and increased detection by genetic testing among patients with idiopathic nonischemic CM is of increasing importance. Not only does a diagnosis of LMNA-CM have implications for management and risk stratification, but new gene-based therapies continue to be evaluated for this group. Clinicians must be aware not only of the general indications for genetic testing in arrhythmogenic and dilated cardiomyopathies and of when to suspect LMNA-CM, but also of the clinical trials underway targeted toward the different genetic cardiomyopathies.
Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Mutação , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatias/terapia , Arritmias Cardíacas , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Lamina Tipo A/genéticaRESUMO
PURPOSE OF REVIEW: Cardiac sarcoidosis (CS) is an important cause of non-ischemic cardiomyopathy and has specific diagnostic and therapeutic considerations. With advances in imaging techniques and treatment approaches, the approach to monitoring disease progression and management of CS continues to evolve. The purpose of this review is to highlight advances in CS diagnosis and treatment and present a center's multidisciplinary approach to CS care. RECENT FINDINGS: In this review, we highlight advances in granuloma biology along with contemporary diagnostic approaches. Moreover, we expand on current targets of immunosuppression focused on granuloma biology and concurrent advances in the cardiovascular care of CS in light of recent guideline recommendations. Here, we review advances in the understanding of the sarcoidosis granuloma along with contemporary diagnostic and therapeutic considerations for CS. Additionally, we highlight knowledge gaps and areas for future research in CS treatment.
RESUMO
PURPOSE OF REVIEW: The replenishment of lost or damaged myocardium has the potential to reverse heart failure, making heart regeneration a goal for cardiovascular medicine. Unlike adult mammals, injury to the zebrafish or neonatal mouse heart induces a robust regenerative program with minimal scarring. Recent insights into the cellular and molecular mechanisms of heart regeneration suggest that the machinery for regeneration is conserved from zebrafish to mammals. Here, we will review conserved mechanisms of heart regeneration and their translational implications. RECENT FINDINGS: Based on studies in zebrafish and neonatal mice, cardiomyocyte proliferation has emerged as a primary strategy for effecting regeneration in the adult mammalian heart. Recent work has revealed pathways for stimulating cardiomyocyte cell cycle reentry; potential developmental barriers for cardiomyocyte proliferation; and the critical role of additional cell types to support heart regeneration. Studies in zebrafish and neonatal mice have established a template for heart regeneration. Continued comparative work has the potential to inform the translation of regenerative biology into therapeutics.