Daily Cardiology Research Analysis

BACKGROUND: Guided by long-term safety data for AAV5 (adeno-associated virus 5) in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieves therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. METHODS: AAV-mediated cardiac gene transfer in pigs was performed by percutaneous catheter-based retrograde intravenous vector delivery, and vector genome and transgene expression levels determined by reverse transcription-polymerase chain reaction and immunoblotting. Postmyocardial infarction (MI) cardiac dysfunction porcine and murine models were generated by coronary catheter-based occlusion and ligation, respectively. The study end points left ventricular ejection fraction and left ventricular MI size, were measured by cardiac magnetic resonance imaging and echocardiography. Bulk myocardial RNA-sequencing and weighted gene correlation network analysis were used to link study end points to molecular pathway mechanisms. Safety was assessed by clinical chemistry, blood count and ECG. RESULTS: In a first biodistribution study, AAV5 (1×10 CONCLUSIONS: Providing the clinically relevant proof of concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility, and low preexisting immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease such as chronic heart failure, using therapeutic genetic effectors such as

NLRX1 is the only NOD-like innate immune receptor that localises to mitochondria. We previously demonstrated that NLRX1 deletion increased infarct size in isolated mouse hearts subjected to ischemia-reperfusion injury (IRI); however, underlying mechanisms are yet to be identified. Given the crucial role played by mitochondria in cardiac IRI, we here hypothesise that NLRX1 affects key mechanisms of cardiac IRI. Cardiac IRI was evaluated in isolated C57BL/6J (WT) and NLRX1 knock out (KO) mouse hearts. The following known modulators of IRI were explored in isolated hearts, isolated mitochondria; or permeabilised cardiac fibres: 1) mTOR/RISK/autophagy regulation, 2) AMPK and mitochondrial energy production, and 3) mitochondrial permeability transition pore (mPTP) opening. NLRX1 deletion increased IRI, and cardiac NLRX1 was decreased after IRI in mouse and pig hearts. NLRX1 ablation caused decreased mTOR and RISK pathway (Akt, ERK, and S6K) activation following IR, without affecting autophagy/inflammation/oxidative stress markers. The RISK activator Urocortin dissipated NLRX1 effects on mTOR, RISK pathway and IRI, indicating that increased cardiac IRI with NLRX1 deletion is, at least partly, due to impaired RISK activation. The energy sensor AMPK was activated in NLRX1 KO hearts, possibly due to slowed mitochondrial respiratory responses (impaired mitochondrial permeability) towards palmitoylcarnitine in permeabilised cardiac fibres. NLRX1 deletion completely abolished calcium-induced mPTP opening, and cyclosporine A (CsA) effects on mPTP, both before and after IR, and was associated with increased mitochondrial calcium content after IR. Mitochondrial sub-fractionation studies localised NLRX1 to the inner mitochondrial membrane. NLRX1 deletion associated with decreased phosphorylation of mitochondrial Got2, Cx43, Myl2, Ndufb7 and MICOS10. The mPTP inhibitor CsA abolished IRI differences between KO and WT hearts, suggesting that the permanent closure of mPTP due to NLRX1 deletion contributed to the increased IR sensitivity of NLRX1 KO hearts. This is the first demonstration that the mitochondrial NLRX1 is a novel factor required for mPTP opening and contributes to cardioprotection against acute IRI through RISK pathway activation and prevention of permanent mPTP closure.

AIMS: The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing mitral valve transcatheter edge-to-edge repair (M-TEER) for primary mitral regurgitation (PMR) is unclear. This study assessed the association between NT-proBNP and outcomes and explored its additive value to the Mitral Regurgitation International Database (MIDA) score. METHODS AND RESULTS: PRIME-MR, a retrospective, international, multicentre registry, includes 3083 consecutive PMR patients treated with M-TEER. This analysis focused on 1382 patients (median age 81 years, 47% female, 82% New York Heart Association [NYHA] functional class III/IV, median EuroSCORE II 4.1%) with available NT-proBNP levels and follow-up. The primary endpoint was death or heart failure hospitalization within 3 years. Median NT-proBNP level was 1991 pg/ml (T1: 578, T3: 6285), and 384 patients reached the primary endpoint (Kaplan-Meier estimate: 48.5%). Log-transformed NT-proBNP levels independently predicted the primary endpoint (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.07-1.28; p < 0.001) after adjusting for NYHA class, haemoglobin, creatinine, and atrial fibrillation. In 1041 patients with a modified MIDA score (median 9), the score was initially associated with the primary endpoint (HR 1.10, 95% CI 1.04-1.17; p = 0.002), but lost significance when adjusting for NT-proBNP levels, which remained independently predictive (adjusted HR 1.20, 95% CI 1.07-1.34; p = 0.002). CONCLUSIONS: NT-proBNP, but not the MIDA score, was independently associated with death or heart failure hospitalizations within 3 years in M-TEER-treated PMR patients. Incorporating NT-proBNP levels into clinical assessment may improve risk stratification and potentially supports earlier intervention at lower NT-proBNP levels to optimize outcomes.