• CT-scan
• Cardiomegaly
• Diagnosis
• MRI
• Radiology
• Surveillance
• X-rays

• Humans
• Heart Failure/physiopathology
• Heart Failure/therapy
• Heart Failure/diagnosis
• Cardiomegaly/physiopathology
• Cardiomegaly/diagnostic imaging
• Cardiomegaly/therapy
• Cardiomegaly/diagnosis
• Tomography, X-Ray Computed/methods
• Multimodal Imaging/methods
• Magnetic Resonance Imaging/methods
• Electrocardiography

• Cardiac compensatory mechanisms
• Cardiac remodeling
• Cardiomyocyte
• Cardiomyopathy animal model
• Common final pathway
• Failing heart
• Fetal gene program
• Inherited cardiomyopathy
• Mutation
• Pathogenic variant

• Animals
• Humans
• Cardiomyopathies/genetics
• Cardiomyopathies/pathology
• Cardiomyopathies/metabolism
• Disease Models, Animal
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Signal Transduction/genetics

• Animal models
• Arrhythmogenic cardiomyopathy
• Desmosomes
• Human-induced pluripotent stem cell-derived cardiomyocytes
• Pathophysiology

• Animals
• Humans
• Heart Ventricles
• Induced Pluripotent Stem Cells
• Myocardium
• Myocytes, Cardiac

• 17ZB0476 Foundation of the Education Department of Sichuan Province
• 2021-JYJ-70 the Foundation of Office of Science & Technology of Luzhou City
• 22NSFSC3053 Natural Science Foundation of Sichuan Province
• 82200361 National Nature Science Foundation of China
• 2021ZKMS035 Southwest Medical University Scientific Research Fund
• Ruprecht-Karls-Universität Heidelberg (1026)

Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation. Although optimized medical therapies have been developed for heart failure during the last few decades, some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies. Desmosome, which is a dynamic cell-to-cell junctional component, maintains the structural integrity of heart tissues. Genetic mutations in desmosomal genes cause arrhythmogenic cardiomyopathy (AC), a rare inheritable disease, and predispose patients to sudden cardiac death and heart failure. Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies. Among desmosomal genes, mutations in PKP2 (which encodes PKP2) are most frequently identified in patients with AC. PKP2 deficiency causes various pathological cardiac phenotypes. Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs) in combination with genome editing, which allows the precise arrangement of the targeted genome, are powerful experimental tools for studying disease. This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by PKP2 deficiency.

• Cardiomyopathy
• Advanced heart failure
• Induced pluripotent stem cell-derived cardiomyocytes
• Desmosome
• Genome editing
• Gene therapy

• arrhythmia
• arrhythmogenic cardiomyopathy
• circadian
• daily
• implantable cardioverter defibrillator
• seasonal
• sudden death
• ventricular tachycardia

• Humans
• Seasons
• Arrhythmias, Cardiac
• Tachycardia, Ventricular/epidemiology
• Tachycardia, Ventricular/therapy
• Defibrillators, Implantable
• Arrhythmogenic Right Ventricular Dysplasia/complications
• Arrhythmogenic Right Ventricular Dysplasia/therapy

• Department of Health

• dilated cardiomyopathy
• heart failure
• review
• rodent model

• Animals
• Humans
• Cardiomyopathy, Dilated
• Rodentia
• Heart Failure

• Curtis Joseph and Harold Groves Chair in Anesthesia and Pain Medicine SickKids Foundation
• Merit Award Department of Anesthesiology and Pain Medicine, University of Toronto

• HIF-2α
• SGLT2 inhibitor
• arrhythmogenic cardiomyopathy
• fibrosis
• inflammation

Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.

•

Generation of isogenic iPSC-CMs with a precise dose of plakophilin-2

• Arrhythmias, Cardiac/genetics
• Arrhythmias, Cardiac/pathology
• CRISPR-Cas Systems/genetics
• Cell Differentiation
• Desmosomes/physiology
• Female
• Gene Editing
• Genetic Vectors/genetics
• Genetic Vectors/metabolism
• Heterozygote
• Humans
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/metabolism
• Male
• Models, Biological
• Myocardial Contraction/physiology
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/metabolism
• Pedigree
• Plakophilins/genetics
• Plakophilins/metabolism

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology‐specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three‐dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR‐Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies.

• arrhythmogenic cardiomyopathy
• autoimmunity
• immune cells
• infectious agents
• inflammation
• inflammatory cytokines
• sudden cardiac death

• European Research Area Network on Cardiovascular Diseases
• ZonMw
• European Research Council

• cardiovascular system

• Arrhythmias, Cardiac
• Arrhythmogenic Right Ventricular Dysplasia
• Humans
• Lipoproteins, LDL
• Risk Factors

• arrhythmogenic right ventricular dysplasia
• cardiomyopathies
• fibrosis
• heart failure
• translational medical research

Arrhythmogenic right ventricular cardiomyopathy is a hereditary, rare disease with an increased risk for sudden cardiac death. The disease-causing mutations are located within the desmosomal complex and the highest incidence is found in plakophilin2. However, there are other factors playing a role for the disease progression unrelated to the genotype such as inflammation or exercise. Competitive sports have been identified as risk factor, but the type and extend of physical activity as cofactor for arrhythmogenesis remains under debate. We thus studied the effect of light voluntary exercise on cardiac health in a mouse model. Mice with a heterozygous PKP2 loss-of-function mutation were given the option to exercise in a running wheel which was monitored 24 h/d. We analyzed structural and functional development in vivo by echocardiography which revealed that neither the genotype nor the exercise caused any significant structural changes. Ejection fraction and fractional shortening were not influenced by the genotype itself, but exercise did cause a drop in both parameters after 8 weeks, which returned to normal after 16 weeks of training. The electrophysiological analysis revealed that the arrhythmogenic potential was slightly higher in heterozygous animals (50% vs 18% in wt littermates) and that an additional stressor (isoprenaline) did not lead to an increase of arrhythmogenic events pre run or after 8 weeks of running but the vulnerability was increased after 16 weeks. Exercise-induced alterations in Ca handling and contractility of isolated myocytes were mostly abolished in heterozygous animals. No fibrofatty replacements or rearrangement of gap junctions could be observed. Taken together we could show that light voluntary exercise can cause a transient aggravation of the mutation-induced phenotype which is abolished after long term exercise indicating a beneficial effect of long term light exercise.

• Animals
• Arrhythmias, Cardiac/metabolism
• Arrhythmias, Cardiac/pathology
• Calcium Signaling
• Connexin 43/metabolism
• Disease Models, Animal
• Echocardiography
• Electrophysiological Phenomena
• Gap Junctions/metabolism
• Genotype
• Heart Ventricles/pathology
• Heterozygote
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Myocardium/metabolism
• Myocardium/pathology
• Phenotype
• Physical Conditioning, Animal
• Plakophilins/deficiency
• Plakophilins/genetics
• Ventricular Function/physiology

• Deutsche Forschungsgemeinschaft
• European Metrology Programme for Innovation and Research
• Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
• Universitätsklinikum Regensburg

Arrhythmogenic Cardiomyopathy (AC) is a rare inherited heart disease, manifesting with progressive myocardium degeneration and dysfunction, and life-threatening arrhythmic events that lead to sudden cardiac death. Despite genetic determinants, most of AC patients admitted to hospital are athletes or very physically active people, implying the existence of other disease-causing factors. It is recognized that AC phenotypes are enhanced and triggered by strenuous physical activity, while excessive mechanical stretch and load, and repetitive adrenergic stimulation are mechanisms influencing disease penetrance. Different approaches have been undertaken to recapitulate and study both mechanotransduction and adrenergic signaling in AC, including the use of in vitro cellular and tissue models, and the development of in vivo models (particularly rodents but more recently also zebrafish). However, it remains challenging to reproduce mechanical load stimuli and physical activity in laboratory experimental settings. Thus, more work to drive the innovation of advanced AC models is needed to recapitulate these subtle physiological influences. Here, we review the state-of-the-art in this field both in clinical and laboratory-based modeling scenarios. Specific attention will be focused on highlighting gaps in the knowledge and how they may be resolved by utilizing novel research methodology.

• adrenergic signaling
• animal models
• arrhythmogenic cardiomyopathy
• cell models of disease
• mechanotransduction

Cardiomyopathies are a highly heterogeneous group of heart muscle disorders. More than 100 causative genes have been linked to various cardiomyopathies, which explain about half of familial cardiomyopathy cases. More than a dozen candidate therapeutic signaling pathways have been identified; however, precision medicine is not being used to treat the various types of cardiomyopathy because knowledge is lacking for how to tailor treatment plans for different genetic causes. Adult zebrafish (Danio rerio) have a higher throughout than rodents and are an emerging vertebrate model for studying cardiomyopathy. Herein, we review progress in the past decade that has proven the feasibility of this simple vertebrate for modeling inherited cardiomyopathies of distinct etiology, identifying effective therapeutic strategies for a particular type of cardiomyopathy, and discovering new cardiomyopathy genes or new therapeutic strategies via a forward genetic approach. On the basis of this progress, we discuss future research that would benefit from integrating this emerging model, including discovery of remaining causative genes and development of genotype-based therapies. Studies using this efficient vertebrate model are anticipated to significantly accelerate the implementation of precision medicine for inherited cardiomyopathies.

• adult zebrafish
• animal model
• cardiomyopathy
• causative gene
• precision medicine

• arrhythmogenic cardiomyopathy
• intercalated disc
• sorbin and SH3 domain‐containing 2
• susceptibility gene

• Adaptor Proteins, Signal Transducing/genetics
• Adult
• Aged
• Animals
• Arrhythmias, Cardiac/genetics
• Arrhythmias, Cardiac/physiopathology
• Arrhythmogenic Right Ventricular Dysplasia/genetics
• Arrhythmogenic Right Ventricular Dysplasia/physiopathology
• Cardiomyopathies/physiopathology
• Case-Control Studies
• Disease Models, Animal
• Female
• Genetic Predisposition to Disease/genetics
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Mutation
• Myocardium/metabolism
• Myocardium/pathology
• Phenotype
• RNA-Binding Proteins/genetics

• R01 HL081753 NHLBI NIH HHS
• R56 HL074180 NHLBI NIH HHS
• R01 HL107304 NHLBI NIH HHS
• R56 GM063904 NIGMS NIH HHS
• R01 HL074180 NHLBI NIH HHS
• R01 GM063904 NIGMS NIH HHS
• NIH
• Mayo Foundation
• American Diabetes Association

Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the detection of desmoglein 2 auto-antibodies in AC patients. Using two mouse strains producing either a mutant desmoglein 2 or lacking desmoglein 2 in cardiomyocytes, we test the hypothesis that inflammation is a major component of disease pathogenesis. We show that multifocal cardiomyocyte necrosis initiates a neutrophil-dominated inflammatory response, which also involves macrophages and T cells. Increased expression of Ccl2/Ccr2, Ccl3/Ccr5, and Cxcl5/Cxcr2 mRNA reflects the observed immune cell recruitment. During the ensuing acute disease phase, Mmp12⁺ and Spp1⁺ macrophages and T cells accumulate in scars, which mature from cell- to collagen-rich. The expression of Cx3cl1/Cx3cr1, Ccl2/Ccr2, and Cxcl10/Cxcr3 dominates this disease phase. We furthermore find that during chronic disease progression macrophages and T cells persist within mature scars and are present in expanding interstitial fibrosis. Ccl12 and Cx3cl1 are predominant chemokines in this disease phase. Together, our observations provide strong evidence that specific immune cell populations and chemokine expression profiles modulate inflammatory and repair processes throughout AC progression.

• Cardiomyopathy
• Chronic disease progression
• Desmoglein
• Desmosome
• Immune cells
• Inflammation

• Animals
• Arrhythmias, Cardiac/genetics
• Arrhythmias, Cardiac/immunology
• Arrhythmias, Cardiac/pathology
• Cardiomyopathies/genetics
• Cardiomyopathies/immunology
• Cardiomyopathies/pathology
• Desmoglein 2/genetics
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/pathology
• Mice
• Mice, Mutant Strains
• Mutation

• Arrhythmia
• Arrhythmogenic right ventricular cardiomyopathy
• Exercise
• Genetics
• TMEM43

• GSK3β
• TMEM43
• arrhythmogenic right ventricular
• calcineurin
• dysplasia
• therapy