6 research outputs found
The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy
Acute endothelinA receptor antagonism improves coronary artery compliance in coronary artery disease patients
Sustained improvement in peripheral immune response by biventricular pacing and its association with exercise tolerance and quality of life
Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human
In human disease and experimental animal models, depressed Ca(2+) handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy
Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine
In 2020, SARS-COV-2 put health systems under unprecedented resource and
manpower pressure leading to significant number of deaths. Expectedly,
researchers sought to shed light on the pathophysiologic background of
this novel disease (COVID-19) as well as to facilitate the design of
effective therapeutic modalities. Indeed, early enough the pivotal role
of inflammatory and thrombotic pathways in SARS-COV-2 infection has been
illustrated. The purpose of this article is to briefly present the
epidemiologic and clinical features of COVID-19, analyze the
pathophysiologic importance of immunologic dysregulation and
hypercoagulability in developing disease complications and finally to
present an up-to-date systematic review of colchicine's immunomodulating
capacity in view of hindering coronavirus complications
Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy
International audienceA number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhyth-mias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca 2 þ handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies