Sarcoidosis is a systemic infiltrative disease characterized by non-caseating granuloma formation, and its cardiac phenotype is an important prognostic factor.1 Sarcoidosis affecting the heart without extracardiac involvement is termed isolated cardiac sarcoidosis (CS). Isolated CS was once thought to be a rare manifestation of sarcoidosis because of the diagnostic challenge arising from the low sensitivity of endomyocardial biopsy (EMB).2 Considering that the importance of early diagnosis and treatment are critical in managing CS,3 the Japanese Circulation Society (JCS) updated its guidelines to allow a clinical diagnosis of CS using multimodal imaging techniques, such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), even in the absence of histological evidence of non-caseating granulomas.4 Under the situation in which isolated CS can be clinically diagnosed without histological findings, we should pay more attention to differentiating isolated CS from other cardiomyopathies. Here, we describe a 50-year-old male who was clinically diagnosed with isolated CS and prescribed with prednisolone without much effect, and subsequent genetic analysis revealed pathogenic variants in LMNA and TNNT2, representative genes for cardiomyopathy. A 48-year-old man with hypertension and dyslipidaemia presented to a hospital with advanced atrioventricular block (AVB) pointed out during his annual health check-up. He had no family history of heart disease or sudden death, and his electrocardiogram (ECG) 2 years earlier showed a first-degree AVB and left axis deviation (Figure 1A). ECG in the first hospital presentation shows high-degree AVB and multiple morphologically distinct premature ventricular contractions (Figure 1B), and ambulatory ECG monitoring revealed advanced AVB with the longest pause being 1.57 seconds accompanied by escape rhythms. Transthoracic echocardiography (TTE) demonstrated normal cardiac chamber size and function without any regional wall motion abnormalities. He remained asymptomatic and declined further investigation or regular outpatient follow-up. At the age of 50, he complained of mild dyspnoea on exertion, categorized as New York Heart Association Class II, and was diagnosed with atrial fibrillation and complete AVB and referred to our hospital (Figure 1C). He started receiving edoxaban 60 mg/day. Blood test revealed elevated levels of B-type natriuretic peptide at 290.5 pg/mL and high-sensitivity cardiac troponin I at 30.9 pg/mL. Soluble interleukin-2 receptor and angiotensin-converting enzyme levels were within normal ranges. His chest X-ray indicated cardiomegaly. TTE showed a reduced left ventricular ejection fraction of 38% and hypokinesis of the septal and posterior walls of the left ventricle, without regional wall thinning or ventricular aneurysms (Figure 2A and Video S1). Non-contrast computed tomography did not depict any enlarged lymph nodes, pulmonary nodules or other organ abnormalities, and ophthalmologic and dermatologic examinations were unremarkable. Ambulatory ECG detected non-sustained ventricular tachycardia (NSVT). Coronary computed tomographic angiography showed intact coronary arteries. Cardiac magnetic resonance imaging demonstrated a linear pattern of late gadolinium enhancement (LGE) in the mid-wall of the septum, with a reduced ejection fraction and a dilated left ventricle (Figure 2B and Videos S2 and S3). T2-weighted imaging revealed a high signal in the mid-wall of the septum, corresponding to the region of LGE, indicative of myocardial inflammation (Figure S1). Subsequently, a whole-body FDG-PET scan after 18 h of fasting showed a focal FDG uptake in the ventricular septum, typical pattern for CS, but no uptake in other organs (Figure 2C). The multimodal imaging findings and the presence of arrhythmia such as AVB and NSVT were typical for CS, and we clinically diagnosed the patient with isolated CS without performing EMB, as the patient met criteria (a), (c), (d) and (e) in the JCS guideline4 (Table 1). Following his admission, we initiated prednisolone 30 mg (0.5 mg/kg)/day, but continuous ECG monitoring showed frequent NSVTs with multiple morphologies (Figure 2D). The heart team concluded that semi-urgent defibrillator implantation was necessary, and he received a cardiac resynchronization therapy device with defibrillator (CRT-D) while taking prednisolone 25 mg daily and was discharged 7 days after the implantation. However, 10 days after discharge, the wound was partly detached and bleeding, forcing the patient to be readmitted to the hospital. He was treated with prophylactic antibiotics and surgical site compression for 7 days and was discharged with prednisolone 15 mg/day. Despite the initiation of prednisolone therapy, his symptoms and cardiac dysfunction did not improve much, and NSVTs continued to occur. We performed whole-exome sequencing analysis to evaluate the risk of inherited cardiomyopathies and identified two missense variants in TNNT2 (chr1:201364335(hg38), NM_001001430.3, c.422G>A, p.Arg141Gln) and LMNA (chr1:156136096(hg38), NM_170707.4, c.1132A>C, p.Lys378Gln) (Figure 3). The TNNT2 variant has been previously reported as pathogenic in multiple patients with idiopathic cardiomyopathies (ClinVar accession number: VCV000043637.14). In contrast, the LMNA variant is novel and located in exon 6, a known hot-spot region. This region corresponds to part of the coil 2 domain within the central rod domain of lamin A/C and is related to multiple pathogenic missense variants.5 This variant has not been identified in the general population according to the gnomAD and Tohoku Medical Megabank databases and was predicted to be pathogenic by multiple in silico analyses with a Combined Annotation Dependent Depletion score of 26.6 and a Polymorphism Phenotyping v2 score of 0.999. According to the American College of Medical Genetics and Genomics guidelines,6 LMNA p.Lys378Gln was classified as likely pathogenic (PM1, PM2, PP2 and PP3). Therefore, we hypothesized that these variants were involved in the progressive conduction defects and worsened cardiac function. We describe a patient initially diagnosed with isolated CS using a multimodality imaging approach and treated with prednisolone. He had not improved with steroid therapy and was later found to have two likely pathogenic variants in cardiomyopathy-causing LMNA and TNNT2 genes. Although the possibility of an overlap of CS and genetic cardiomyopathy cannot be excluded, this case underscores the importance of early genetic analysis to reconsider an optimal therapeutic strategy for treatment-resistant patients. As patients with CS are at high risk of malignant arrhythmias,7 delays in diagnosis and intervention might worsen the patient's prognosis.3 Despite this, the diagnosis of isolated CS, characterized by the absence of extracardiac involvement,8 is basically challenging due to the low sensitivity of EMB, which is only up to 20%.2 This difficulty had been hindering early and appropriate management of isolated CS. To address this issue, the JCS guidelines proposed clinical diagnostic criteria for isolated CS without histological evidence,4 which enables timely diagnosis and treatment. Since then, clinical data based on the guideline-recommended diagnostic criteria have been accumulated.9 However, like the present case, there are patients fulfilling the clinical criteria for isolated CS, but the presence of pathogenic variants in cardiomyopathy-related genes might actually cause cardiac dysfunction or be a risk factor for exacerbation of the clinical condition. We clinically diagnosed this case as isolated CS without performing EMB because of concerns about possible procedural complications and the fact that a negative biopsy result would not change the management strategy. His clinical course and multimodal imaging findings, including FDG-PET, were strongly suggestive of isolated CS. However, previous studies have shown that cardiomyopathies, such as arrhythmogenic cardiomyopathy, can exhibit FDG uptake in the heart.10 Lal et al. reported that cardiomyopathy-related genetic variants can be identified in patients previously diagnosed with CS.11 Considering the steroid-unresponsiveness and the fact that cardiomyopathy caused by pathogenic LMNA variant can also produce a variety of abnormalities,12 the appropriate diagnosis for this case was dilated cardiomyopathy rather than CS. The CS diagnostic criteria in JCS guidelines4 contribute to improved sensitivity in the diagnosis; however, recent reports, including this case, have highlighted that the criteria might sacrifice diagnostic specificity. To prevent overdiagnosis of CS with improved diagnostic accuracy, genetic analysis could bridge the gap. In this case, high disease activity estimated from high FDG uptake and frequent NSVTs led to early implantation of CRT-D while taking high-dose prednisolone. Unfortunately, this patient suffered from the surgical site complication. He was at high risk of postoperative pocket haematoma due to the need for both CRT-D implantation and anticoagulant.13 Additionally, haematoma and steroid administration are significant risk factors for device infection, which could lead to serious adverse events.14 Although he recovered with conservative management, he remained exposed to a high risk of device infection. Early genetic assessment prior to the strategic decision-making might have provided a rationale for precision medicine, potentially preventing surgical complications. Furthermore, as laminopathy caused by pathogenic LMNA variants has high penetrance, genetic cascade screening can profoundly contribute to high-quality management of family members. TNNT2 encodes the cardiac isoform of troponin T, and LMNA encodes lamin A/C, which provides structural support with the nucleus. Both genes are strongly associated with genetic cardiomyopathy. Because his cardiac phenotypes such as progressive conduction disturbance and atrial fibrillation are often observed in laminopathy,12 his cardiac abnormalities might be caused by the LMNA variant. FDG uptake has also been reported in some cases of LMNA-related cardiomyopathy,11, 15 but not in those with TNNT2 variants. The mechanism of FDG uptake in laminopathy still remains elusive but is possibly explained by (1) myocardial inflammation and associated apoptosis reflecting rapid disease progression and/or (2) activated glucose metabolism in failing myocardium, which warrants further clarification. In conclusion, caution should be exercised when diagnosing isolated CS clinically without a myocardial biopsy, and genetic analysis might be useful for achieving an accurate diagnosis. We thank R. Nakanishi, I. Sakamoto, N. Matsuzaki, T. Miyoshi, Y. Kaneko, Y. Yokota, Y. Chiba, K. Akiba, A. Okamoto and M. Yoshitake for providing support with analysis. None declared. This work was supported by grants from the SENSHIN Medical Research Foundation (to S.N.), the Japan Foundation for Applied Enzymology (to S.N. and Z.D.), the Kanae Foundation for the Promotion of Medical Science (to S.N.), the MSD Life Science Foundation, Public Interest Incorporated Foundation (to S.N.), the Tokyo Biomedical Research Foundation (to S.N.), the Astellas Foundation for Research on Metabolic Disorders (to S.N.), the NOVARTIS Foundation (Japan) for the Promotion of Science (to S.N.), the Japanese Circulation Society (to S.N.), the Takeda Science Foundation (to S.N.), the Cell Science Research Foundation (to S.N.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to S.N.) and the Daiichi Sankyo Foundation of Life Science (to S.N.); a Grant-in-Aid for Scientific Research (A) (to S.N.); a Grant-in-Aid for Scientific Research (S) (to I.K.); the UTEC-UTokyo FSI Research Grant Program (to S.N.); the JST FOREST Program (Grant JPMJFR210U) (to S.N.); a Japan Society for the Promotion of Science Grant-in-Aid for Japan Society for the Promotion of Science fellow (23KJ0434) (to Z.D.); and the Japan Agency for Medical Research and Development (AMED) (JP20ek0109487, JP18km0405209, JP19ek0109406, JP21ek0109543, JP21ek0109569, JP21tm0724601, JP22ama121016, JP22ek0210172, JP22ek0210167, JP22bm1123011, JP23tm0724607, JP23gm4010020, JP23tm0524004, JP23tm0524009, JP23jf0126003, JP24ek0109755 and JP24ek0210205) (to S.N. and I.K.). Figure S1. T2-weighted imaging of cardiac magnetic resonance imaging. The mid-wall of the septum shows high signal intensity, corresponding to the region of late gadolinium enhancement (red arrows). Video S1. Transthoracic echocardiogram. Video S2. Cardiac magnetic resonance imaging. Video S3. Late gadolinium enhancement in short-axis and long-axis four-chamber views. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

Heart failure (HF) is one of the most common causes of death, and the number of HF patients is increasing worldwide due to population ageing. The pathogenesis of HF has been extensively studied by many researchers with a focus on cardiomyocytes, but its complex pathophysiology has yet to be elucidated. Non-cardiomyocytes account for >70% of the cells that comprise the heart, and there is close communication between non-cardiomyocytes and cardiomyocytes, suggesting that non-cardiomyocytes might play a pivotal role in the development of HF. Neurohumoral factors, such as the autonomic nerves and hormones, regulate the heart’s function. Conversely, the heart affects many other organs through blood perfusion, underscoring the importance of interorgan communication. This review discusses the role of non-cardiomyocytes and interorgan communication between the heart and other organs in the development of HF, a topic that has not been extensively explored.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.

BACKGROUND:Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. OBJECTIVES:In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. METHODS:The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants." RESULTS:Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). CONCLUSIONS:Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

BACKGROUND:The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS:Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS:Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS:Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Background: Skeletal muscle atrophy is frequently caused by the disuse of muscles. It impacts quality of life, especially in aging populations and those with chronic diseases. Understanding the molecular mechanisms underlying muscle atrophy is crucial for developing effective therapies. Objective: To investigate the roles of vascular endothelial growth factor (VEGF) and various microRNAs (miRNAs) in muscle atrophy using a mouse model of denervation (DEN)-induced disuse, and to elucidate their interactions and regulatory functions through comprehensive network analysis. Methods: The right sciatic nerve of C57BL/6J mice (n=6) was excised to simulate DEN, with the left serving as a sham surgery control (Sham). Following a two-week period, wet muscle weight was measured. Total RNA was extracted from the tibialis anterior muscle for microarray analysis. Significant expression changes were analyzed via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and miRNet for miRNAs. Results: Denervated limbs showed a significant reduction in muscle weight. Over 1,000 genes displayed increased expression, while 527 showed reductions to less than half of control levels. VEGF, along with specific miRNAs such as miR-106a-5p, miR-mir20a-5p, mir93-5p and mir17-5p, occupied central regulatory nodes within the gene network. Functional analysis revealed that these molecules are involved in key biological processes including regulation of cell migration, vasculature development, and regulation of endothelial cell proliferation. The increased miRNAs were subjected to further network analysis that revealed significant regulatory interactions with target mRNAs. Conclusion: VEGF and miRNAs play crucial roles in the progression of skeletal muscle atrophy, offering potential targets for therapeutic interventions aimed at reducing atrophy and enhancing muscle regeneration.

Introduction: Dilated cardiomyopathy (DCM) is one of the causative diseases of heart failure, caused by genetic mutations. Cases with mutations in the LMNA gene, which encodes lamin A/C protein and constitutes the nuclear lamina, are known to have a poor prognosis. We have previously shown that the DNA damage accumulation and the consequent activation of DDR in cardiomyocytes are the cause of cardiac function impairment. However, the method to reduce DNA damage in the heart has not been elucidated. Therefore, we decided to explore the compounds that could reduce it in the cardiomyocytes. Methods and Results: We generated iPS cells from DCM patients with a LMNA mutation (p.Q353R) and differentiated them into cardiomyocytes. The mutant cardiomyocytes showed severe deformation of nuclear morphology as well as reduced contractility. In addition, the number of positive foci for γH2AX, a DNA double-strand break marker, was increased in the nuclei of the mutant strain. These results indicate that in vitro disease modeling using iPS cell-derived cardiomyocytes was successfully achieved. We administered a library of 175 compounds to the mutant cardiomyocytes to search for compounds that reduce the positive foci of γH2AX. We found that vitamin D2 (VD2) significantly reduced DNA damage in the mutant strains. RNA-seq analysis revealed that VD2 restored the expression of DNA repair enzymes that were downregulated in the mutant strains. We then screened binding molecules of the mutant LMNA p.Q353R protein and wild-type LMNA protein using a protein array. The screening results showed that the binding to the vitamin D receptor (VDR) was significantly enhanced in the mutant protein compared to the wild-type protein. In the mutant cardiomyocytes, VDR was localized to the periphery of the nuclear membrane, and reporter assays showed decreased transcriptional activity of VDR. Finally, we examined the effects of VD2 on DNA damage accumulation and cardiac function in vivo. VD2 analog reduced DNA damage accumulation and improved cardiac function in two mouse models: a pressure-loaded heart failure model and a Lmna nonsense mutant cardiomyopathy model. Conclusion: Using patient-derived iPS cells, we could recapitulate various pathological processes in diseased cardiomyocytes, as well as identify therapeutic candidates through compound screening. One of the existing drugs, VD2, was a hit in this screening, and clinical trials for drug repositioning are expected.

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R -LMNA– related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA -related DCM.

HomeCirculation: Genomic and Precision MedicineAhead of PrintCompound Heterozygous Truncating Variants in the BAG5 Gene As a Cause of Early-Onset Dilated Cardiomyopathy No AccessLetterRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessLetterRequest AccessCompound Heterozygous Truncating Variants in the BAG5 Gene As a Cause of Early-Onset Dilated Cardiomyopathy Shunsuke Inoue, Toshiyuki Ko, Seitaro Nomura, Takanobu Yamada, Bo Zhang, Zhehao Dai, Takahiro Jimba, Manami Kato, Junichi Ishida, Eisuke Amiya, Masaru Hatano, Norifumi Takeda, Hiroyuki Morita, Minoru Ono and Issei Komuro Shunsuke InoueShunsuke Inoue https://orcid.org/0009-0007-9902-4086 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Toshiyuki KoToshiyuki Ko https://orcid.org/0000-0002-9043-064X Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Seitaro NomuraSeitaro Nomura Seitaro Nomura, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan, Email E-mail Address: [email protected] Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Takanobu YamadaTakanobu Yamada https://orcid.org/0000-0002-8258-4219 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Bo ZhangBo Zhang https://orcid.org/0000-0002-0086-6985 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Zhehao DaiZhehao Dai https://orcid.org/0000-0002-0363-7563 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Takahiro JimbaTakahiro Jimba https://orcid.org/0000-0002-3757-3959 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Manami KatoManami Kato https://orcid.org/0000-0001-5634-9170 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Junichi IshidaJunichi Ishida Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Eisuke AmiyaEisuke Amiya https://orcid.org/0000-0003-2810-8040 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Masaru HatanoMasaru Hatano https://orcid.org/0000-0003-2135-3625 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Norifumi TakedaNorifumi Takeda https://orcid.org/0000-0003-4818-3347 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Hiroyuki MoritaHiroyuki Morita https://orcid.org/0000-0003-0879-5576 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). Search for more papers by this author , Minoru OnoMinoru Ono Department of Cardiovascular Surgery, Graduate School of Medicine, The University of Tokyo, Japan (M.O.). Search for more papers by this author and Issei KomuroIssei Komuro Correspondence to: Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan, Email E-mail Address: [email protected] https://orcid.org/0000-0002-0714-7182 Department of Cardiovascular Medicine, Graduate School of Medicine (S.I., T.K., S.N., T.Y., B.Z., Z.D., T.J., M.K., J.I., E.A., M.H., N.T., H.M., I.K.). International University of Health and Welfare, Tokyo, Japan (I.K.). Search for more papers by this author Originally published24 Oct 2023https://doi.org/10.1161/CIRCGEN.123.004282Circulation: Genomic and Precision Medicine. 2023;0:e004282FootnotesFor Sources of Funding and Disclosures, see page XXX.Correspondence to: Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan, Email komuro-tky@umin.ac.jpSeitaro Nomura, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan, Email senomura-cib@umin.ac.jp eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.123.004282PMID: 37873655 Originally publishedOctober 24, 2023 Keywordscardiomyopathyenalaprilheat shock proteinheart failurespironolactonePDF download Advertisement Subjects Genetics Precision Medicine

BACKGROUND:Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure. OBJECTIVES:The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure. METHODS:The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation. RESULTS:Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001). CONCLUSIONS:DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

Dilated cardiomyopathy (DCM) is a major cause of advanced heart failure requiring a left ventricular assist device (LVAD) or heart transplantation. Although implantation of an LVAD ameliorates end-organ dysfunction and improves exercise tolerance, right heart failure (RHF) after LVAD implantation remains a major unsolved problem. 1 Teuteberg JJ Cleveland Jr, JC Cowger J Higgins RS Goldstein DJ Keebler M et al. The Society of Thoracic Surgeons Intermacs 2019 Annual Report: the changing landscape of devices and indications. Ann Thorac Surg. 2020; 109: 649-660 Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar The incidence of RHF in the late phase after LVAD implantation has been reported to be 8%–11% and is associated with poor prognoses. 2 Rich JD Gosev I Patel CB Joseph S Katz JN Eckman PM et al. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. J Heart Lung Transplant. 2017; 36: 50-58 Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Therefore, it is important to predict the development of late RHF after LVAD implantation. We hypothesized that genetic factors are involved in the development of late RHF after LVAD implantation and examined whether Lamin A/C (LMNA) mutations, which cause DCM with a severe phenotype, 3 Hasselberg NE Haland TF Saberniak J Brekke PH Berge KE Leren TP et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation. Eur Heart J. 2018; 39: 853-860 Crossref PubMed Scopus (162) Google Scholar are associated with late RHF and poor prognosis after LVAD implantation.

Heart failure is caused by a variety of factors, and although many new drug and non-drug therapies have been developed for its treatment in the past decades, the number of patients with heart failure continues to increase and its prognosis is still poor. In this era, it is necessary to continue to develop new therapies. For that purpose, basic research aimed at a deeper understanding of the pathogenesis of heart failure is essential. To that end, an investigation of the ischaemia-mediated molecular mechanisms of various processes, from adaptive cardiac hypertrophy to contractile failure and DNA damage, as a cause of heart failure, has been undertaken. A novel stratification of heart failure based on comprehensive mutation and gene expression analyses has also been carried out. This article reviews the recent advances in basic heart failure research and treatment. In the future, understanding of the diversity of this disease at the molecular level is expected to lead to the development of optimal therapies that are tailored to the individual patient.

Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell–specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α–mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.

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.

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 ( Nrg4 ) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.