bims-hafaim 2022-03-06 papers

Issue of 2022–03–06
three papers selected by
Kyle McCommis, Saint Louis University

Circulation. 2022 Mar 02.

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

Lingfang Zhuang, Kangni Jia, Chen Chen, Zhigang Li, Jiaxin Zhao, Jian Hu, Hang Zhang, Qin Fan, Chunkai Huang, Hongyang Xie, Lin Lu, Weifeng Shen, Guang Ning, Jiqiu Wang, Ruiyan Zhang, Kang Chen, Xiaoxiang Yan.

Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Since kinases have been reported to modulate mitochondrial function, we investigated the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. Methods: We engineered DYRK1B transgenic and knock out mice and used transverse aortic constriction (TAC) to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis and mitochondrial functional analysis. Results: We found that DYRK1B expression was clearly upregulated in failing human myocardium as well as in hypertrophic murine hearts. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated TAC-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α. Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.055727

Nat Med. 2022 Feb 28.

The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

DOI: https://doi.org/10.1038/s41591-021-01659-1

Nat Med. 2022 Feb 28.

The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial.

John A Spertus, Mary C Birmingham, Michael Nassif, C V Damaraju, Antonio Abbate, Javed Butler, David E Lanfear, Ildiko Lingvay, Mikhail N Kosiborod, James L Januzzi.

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8-7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.

DOI: https://doi.org/10.1038/s41591-022-01703-8