An hiPSC-CM approach for electrophysiological phenotyping of a patient-specific case of short-coupled TdP.

Introduction: A healthy young woman, age 26 without prior cardiac complications, experienced an out-of-hospital cardiac arrest caused by ventricular fibrillation (VF), which coincided with a fever. Comprehensive diagnostics including echo, CMR, exercise testing, and genetic sequencing, did not identify any potential cause. This led to the diagnosis of idiopathic VF and installment of an implantable cardioverter defibrillator, which six months later appropriately intervened another VF episode under conditions comparable to the first event.

Maturation and Function of the Intercalated Disc: Report of Two Pediatric Cases Focusing on Cardiac Development and Myocardial Hyperplasia.

The development of the normal human heart, ranging from gestational age to the mature adult heart, relies on a very delicate and timely orchestrated order of processes. One of the most striking alterations in time is the gradual extinction of the ability for cardiomyocytes to proliferate. Once passing this event, cardiomyocytes grow and increase in contractile strength by means of physiological hypertrophy.

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization.

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis.

Circulating Biomarkers of Fibrosis Formation in Patients with Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis patterns is challenging using clinically applied cardiac imaging modalities (e.g.

Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved.

PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM.

The intercalated disc: a unique organelle for electromechanical synchrony in cardiomyocytes.

The intercalated disc (ID) is a highly specialized structure that connects cardiomyocytes via mechanical and electrical junctions. Although described in some detail by light microscopy in the 19th century, it was in 1966 that electron microscopy images showed that the ID represented apposing cell borders and provided detailed insight into the complex ID nanostructure. Since then, much has been learned about the ID and its molecular composition, and it has become evident that a large number of proteins, not all of them involved in direct cell-to-cell coupling via mechanical or gap junctions, reside at the ID.

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700-800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS.

Clinical Phenotypes of Heart Failure With Preserved Ejection Fraction to Select Preclinical Animal Models.

At least one-half of the growing heart failure population consists of heart failure with preserved ejection fraction (HFpEF). The limited therapeutic options, the complexity of the syndrome, and many related comorbidities emphasize the need for adequate experimental animal models to study the etiology of HFpEF, as well as its comorbidities and pathophysiological changes. The strengths and weaknesses of available animal models have been reviewed extensively with the general consensus that a "1-size-fits-all" model does not exist, because no uniform HFpEF patient exists.

Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients.

Pathogenic variants in (, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in p.

Buccal Mucosa Cells as a Potential Diagnostic Tool to Study Onset and Progression of Arrhythmogenic Cardiomyopathy.

In arrhythmogenic cardiomyopathy (ACM) pathogenic variants are found in genes encoding desmosomal proteins and in non-desmosomal genes, such as (, p.Arg14del variant). Previous research showed that plakoglobin protein levels and localization in the cardiac tissue of ACM patients, and p.

Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice.

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this.

Identification of Disrupted Myocardial Calcium Homeostasis as Proarrhythmic Trigger in Arrhythmogenic Cardiomyopathy.

Patients with arrhythmogenic cardiomyopathy may suffer from lethal ventricular arrhythmias. Arrhythmogenic cardiomyopathy is predominantly triggered by mutations in plakophilin-2, a key component of cell-to-cell adhesion and calcium cycling regulation in cardiomyocytes. Calcium dysregulation due to plakophilin-2 mutations may lead to arrhythmias but the underlying pro-arrhythmic mechanisms remain unclear.

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice.

Aims: SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms.

Arrhythmogenic cardiomyopathy: pathogenesis, pro-arrhythmic remodelling, and novel approaches for risk stratification and therapy.

Arrhythmogenic cardiomyopathy (ACM) is a life-threatening cardiac disease caused by mutations in genes predominantly encoding for desmosomal proteins that lead to alterations in the molecular composition of the intercalated disc. ACM is characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ventricular dilatation, cardiac dysfunction, and heart failure but mostly dominated by the occurrence of life-threatening arrhythmias and sudden cardiac death (SCD). As SCD appears mostly in apparently healthy young individuals, there is a demand for better risk stratification of suspected ACM mutation carriers.

Required G to Suppress Automaticity of iPSC-CMs Depends Strongly on I Model Structure.

Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depolarized resting membrane potential (RMP) because of lack of I. Such immaturity hampers their application in assessing drug safety. The electronic overexpression of I (e.

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.

Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy.

Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease.

Background: Cardiovascular diseases (CVDs) culminating into heart failure (HF) are major causes of death in men and women. Prevalence and manifestation, however, differ between sexes, since men mainly present with coronary artery disease (CAD) and myocardial infarction (MI), and post-menopausal women predominantly present with hypertension. These discrepancies are probably influenced by underlying genetic and molecular differences in structural remodeling pathways involved in hypertrophy, inflammation, fibrosis, and apoptosis.