2,561 research outputs found

    Left atrial trajectory impairment in hypertrophic cardiomyopathy disclosed by geometric morphometrics and parallel transport

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    The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction

    A review of the molecular mechanisms underlying the development and progression of cardiac remodeling

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    Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling

    Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine

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    Genetic cardiomyopathies have been studied for decades, and it has become increasingly clear that these progressive diseases are more complex than originally thought. These complexities can be seen both in the molecular etiologies of these disorders and in the clinical phenotypes observed in patients. While these disorders can be caused by mutations in cardiac genes, including ones encoding sarcomeric proteins, the disease presentation varies depending on the patient mutation, where mutations even within the same gene can cause divergent phenotypes. Moreover, it is challenging to connect the mutation-induced molecular insult that drives the disease pathogenesis with the various compensatory and maladaptive pathways that are activated during the course of the subsequent progressive, pathogenic cardiac remodeling. These inherent complexities have frustrated our ability to understand and develop broadly effective treatments for these disorders. It has been proposed that it might be possible to improve patient outcomes by adopting a precision medicine approach. Here, we lay out a practical framework for such an approach, where patient subpopulations are binned based on common underlying biophysical mechanisms that drive the molecular disease pathogenesis, and we propose that this function-based approach will enable the development of targeted therapeutics that ameliorate these effects. We highlight several mutations to illustrate the need for mechanistic molecular experiments that span organizational and temporal scales, and we describe recent advances in the development of novel therapeutics based on functional targets. Finally, we describe many of the outstanding questions for the field and how fundamental mechanistic studies, informed by our more nuanced understanding of the clinical disorders, will play a central role in realizing the potential of precision medicine for genetic cardiomyopathies

    Animal Models of Cardiomyopathies

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    Cardiomyopathies are a heterogeneous group of disorders of heart muscle that ultimately result in congestive heart failure (CHF). Rapid progress in genetics as well as in molecular and cellular biology over the past three decades has greatly improved the understanding of pathogenic signaling pathways in inherited cardiomyopathies. This chapter will focus on animal models of different clinical forms of human cardiomyopathies with their summaries of triggered key molecules, and signaling pathways will be described

    Toward Personalized Medicine: Does Genetic Diagnosis of Pediatric Cardiomyopathy Influence Patient Management?

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    A goal of personalized medicine is to provide increasingly sophisticated, individualized approaches to management and therapy for disease. Genetics is the engine that drives personalized medicine, holding the promise of therapeutics directed toward the unique needs of each patient. The 3(rd) International Conference on Cardiomyopathy in Children provided a forum to discuss the current status of personalized approaches to diagnosis, management, and therapy in the pediatric cardiomyopathy population. This review will focus on the importance of genetic diagnosis in this population as a necessary first step toward understanding the best approach to management and influencing disease outcome. The genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the ability to risk stratify based on genotype, and the impact on cascade screening in family members will be discussed

    Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

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    Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

    Genetics of paediatric cardiomyopathies

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    PURPOSE OF REVIEW: Paediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the paediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. RECENT FINDINGS: With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified at a rapid rate. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences in pathogenesis from adult cardiomyopathy. Therapy targeted towards the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. SUMMARY: Genetics is moving at a rapid pace in paediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. Although interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted towards the underlying genetic cause is beginning to be realized

    Novel perspectives in redox biology and pathophysiology of failing myocytes: modulation of the intramyocardial redox milieu for therapeutic interventions - A review article from the Working Group of Cardiac Cell Biology, Italian Society of Cardiology

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    The prevalence of heart failure (HF) is still increasing worldwide, with enormous human, social, and economic costs, in spite of huge efforts in understanding pathogeneticmechanisms and in developing effective therapies that have transformed this syndrome into a chronic disease. Myocardial redox imbalance is a hallmark of this syndrome, since excessive reactive oxygen and nitrogen species can behave as signaling molecules in the pathogenesis of hypertrophy and heart failure, leading to dysregulation of cellular calcium handling, of the contractile machinery, of myocardial energetics and metabolism, and of extracellular matrix deposition. Recently, following new interesting advances in understanding myocardial ROS and RNS signaling pathways, new promising therapeutical approaches with antioxidant properties are being developed, keeping in mind that scavenging ROS and RNS tout court is detrimental as well, since these molecules also play a role in physiological myocardial homeostasis
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