Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and ...clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
Aim: Previous studies on peripheral artery disease (PAD) only enrolled patients with atherosclerotic lesion limited to any one of isolated locations (aortoiliac AI, femoropopliteal FP, and below the ...knee BTK). However, the interventions for PAD in a real-world clinical setting are often simultaneously performed for several different locations. Methods: We conducted a prospective multicenter study that included 2,230 patients with PAD who received intervention for lower extremity lesions in each area and across different areas. Patients were divided into 7 groups according to the combination of treatment locations. Overall survival (OS), major adverse limb events (MALEs), and risk factors for OS and MALEs were statistically analyzed. Results: After adjustment for confounding factors, the attributable risk for OS was similar among isolated AI, FP, and BTK treatments. MALEs increased in correlation with the number of treatment locations. Dialysis and critical limb ischemia were the common risk factors for OS and MALEs. However, the contribution of other factors such as type of drug usage was different according to treatment locations. Conclusions: In patients with PAD, OS was largely defined by comorbidities but not by lesion location. The background risk factors, underlying comorbidities, and event rates were different according to PAD location, suggesting that stratified treatment should be established for different patient populations.
Pathological heart injuries such as myocardial infarction induce adverse ventricular remodeling and progression to heart failure owing to widespread cardiomyocyte death. The adult mammalian heart is ...terminally differentiated unlike those of lower vertebrates. Therefore, the proliferative capacity of adult cardiomyocytes is limited and insufficient to restore an injured heart. Although current therapeutic approaches can delay progressive remodeling and heart failure, difficulties with the direct replenishment of lost cardiomyocytes results in a poor long-term prognosis for patients with heart failure. However, it has been revealed that cardiac function can be improved by regulating the cell cycle or changing the cell state of cardiomyocytes by delivering specific genes or small molecules. Therefore, manipulation of cardiomyocyte plasticity can be an effective treatment for heart disease. This review summarizes the recent studies that control heart regeneration by manipulating cardiomyocyte plasticity with various approaches including differentiating pluripotent stem cells into cardiomyocytes, reprogramming cardiac fibroblasts into cardiomyocytes, and reactivating the proliferation of cardiomyocytes.
Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through ...single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but ...little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants.
Abstract
Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart ...failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia.
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