Daily Cardiology Research Analysis

OBJECTIVE: Traditional rejection surveillance after heart transplantation (HTx) is based on endomyocardial biopsies (EMBs), which are invasive, expensive, and associated with complications. Monitoring using cell-free DNA (cfDNA) is promising, but most studies report only on the donor fraction (DF) as the percentage of donor-derived cfDNA (dd-cfDNA) relative to total cfDNA. We evaluated the performance of dd-cfDNA to detect rejection. METHODS: HTx patients were prospectively enrolled in a multicenter study, and blood samples were collected concurrently with EMB. Dd-cfDNA was quantified using droplet digital PCR (ddPCR). Rejection was defined by EMB results and compared to nonrejection EMB. Patients with symptomatic rejection were studied as a subgroup, and test performance was determined using receiver operation characteristic analysis. RESULTS: We included 94 patients (70 adults and 24 children), which resulted in 1007 EMB and blood samples. In 19 patients, there were 32 rejection episodes >14 days past HTx, with 15 of them being symptomatic. In receiver operation characteristic analysis, dd-cfDNA and DF could discriminate quiescence from rejection with an area under the curve (AUC) of 0.68 and 0.65, respectively. Dd-cDNA at a threshold of 25 copies/ml showed an AUC of 0.87 to detect symptomatic rejection, significantly better than DF (AUC of 0.75). CONCLUSIONS: dd-cfDNA found good discrimination between cardiac recipients with and without rejection. Absolute quantification of dd-cfDNA with ddPCR is a fast and effective method to monitor graft health. Analyzing absolute dd-cfDNA levels helps identify other factors, besides rejection, that may influence cfDNA levels, potentially reducing the need for EMB.

Targeting the balance of mitochondrial fission and fusion can effectively alleviate the cardiac energy supply efficiency, to restore cardiac systolic dysfunction and reduce mortality. We previously found that Klf7 is closely related to cardiac energy metabolism. Here we generated cardiomyocyte-specific Klf7 knockout and overexpression mice that underwent myocardial infarction (MI) surgery. Klf7 expression increased in the ischemic myocardium of mice, and cardiomyocyte-specific knockout Klf7 significantly lowered the mortality of MI-inflicted mice and improved ATP insufficiency in MI. Subsequently, Klf7 overexpression aggravated adverse cardiac remodeling and mitochondrial fission and fusion imbalance after MI. Our results also demonstrated that Klf7 inhibited mitochondrial fusion and promoted mitochondrial fission by targeting prohibitin 2 (Phb2) and mitofusin 2 (Mfn2). Our study revealed a crucial role in upholding the overall balance of mitochondrial fission and fusion during MI. Furthermore, our findings indicated that the Klf7/Mfn2/Phb2 axis holds promise as a potential target for therapeutic interventions of MI.

BACKGROUND: Clinical trials have established the prognostic benefits of sodium‒glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) with preserved ejection fraction (HFpEF), although the underlying mechanisms are not clearly understood. The purpose of this study was to determine the effects of the SGLT2 inhibitor empagliflozin on functional capacity, left ventricular (LV) diastolic function/filling pressure, and cardiac reserves in patients with HFpEF and T2DM. METHODS: In the present prospective single-center trial, we enrolled 70 diabetic patients with stable HF according to the New York Heart Association functional class II-III criteria, an LV ejection fraction ≥ 50%, and increased LV filling pressure at rest and/or during exercise (determined by echocardiography). The patients were randomly assigned in an open-label fashion to the empagliflozin group (10 mg a day, n = 35) or the control group (n = 35) for 6 months. Echocardiography (at rest and during exercise), the 6-min walk test distance (6MWD), blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the profibrotic biomarker sST2 were analysed at baseline and 6 months after randomization. The primary endpoint was the change in the 6MWD, and the secondary endpoints included the change in the left atrial (LA) volume index, early mitral inflow to mitral annulus relaxation velocity (E/e') ratio both at rest and during exercise, key cardiac reserves and biomarkers in the blood from baseline to 6 months. RESULTS: After 6 months of empagliflozin therapy, the 6MWTD significantly increased, whereas the LA volume index and the E/e' ratio both at rest and during exercise decreased compared with those of the control group (P < 0.05 for all). LV diastolic, LA reservoir and contractile, and chronotropic reserves also improved in the empagliflozin group compared with those in the control group (P < 0.05 for all). Furthermore, treatment with empagliflozin led to improvements in NT-proBNP and ST2 blood levels compared with those in the control group (P < 0.05 for both). CONCLUSIONS: In diabetic patients with HFpEF, empagliflozin treatment improved exercise capacity, which appeared to be the result of favourable effects on LV diastolic dysfunction and key cardiac reserves: LV diastolic, LA reservoir and contractile, and chronotropic. These haemodynamic mechanisms may underline the benefits of SGLT2 inhibitors in large-scale HFpEF trials. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique Identifier NCT03753087.