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Background: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood., Methods: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31 P nuclear magnetic resonance (NMR) spectroscopy and substrate oxidation profile was assessed by 13 C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes., Results: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes., Conclusions: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation., Competing Interests: None.

Background: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding., Methods: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point., Results: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point., Conclusions: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502., Competing Interests: Disclosures Dr Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr Morimoto reports lecturer’s fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; article fees from Bristol Myers Squibb and Pfizer; and membership on advisory boards for Novartis and Teijin. Dr Nishimoto received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo. Dr Ogihara received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Bayer Healthcare and Daiichi Sankyo. Dr Dohi received lecture fees from Bayer Healthcare, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Daiichi Sankyo. Dr N. Ikeda received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. Dr Tsubata received lecture fees from AstraZeneca, Chugai Pharmaceutical, Bristol Myers Squibb, Kyowa Kirin, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and Daiichi Sankyo, and grant support from Daiichi Sankyo, AstraZeneca, and Ono Pharmaceutical. Dr S. Ikeda received lecture fees from Bayer Healthcare, Bristol Myers Squibb, and Daiichi Sankyo. Dr Mo received lecture fees from Bayer Healthcare. The other authors report no conflicts.

Rationale: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro., Objective: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation., Methods and Results: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into α-myosin heavy chain (αMHC)-GFP transgenic mouse hearts induced the expression of αMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric α-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes., Conclusions: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts.