Background: Currently, standard medical therapies have limited effects on heart failure with preserved ejection fraction (HFpEF), which impacts on the life quality and survival of patients. This study aimed to evaluate the safety and efficacy of the percutaneous radiofrequency ablation–based interatrial shunting for HFpEF with a novel atrial septostomy device. Methods: A preclinical study in 11 normal domestic pigs and the first-in-man study in 10 patients with HFpEF were performed. The major safety events and interatrial shunt performance were evaluated at baseline, 1 month, 3 months, and 6 months post-procedure in both animals and human patients. The clinical functional status was also assessed in the first-in-man study. Results: Percutaneous radiofrequency ablation–based interatrial shunting therapy was performed successfully both in animals and patients. In the animal study, a left-to-right interatrial shunt was created with a mean defect size of 5.5±2.2 mm without procedure-related safety events. Seven pigs showed the continuous shunting with a mean defect size of 4.1±1.5 mm at 6 months. In the first-in-man study, a median interatrial defect diameter of 5.0 (4.0–6.0) mm was measured immediately. No major safety events including death and thromboembolism were observed. The continuous shunting with the defect size of 4.0 (3.0–4.0) mm could still be observed in 7 patients at 6 months. The clinical status was significantly improved with NT-proBNP (N-terminal pro-B-type natriuretic peptide) reduced by 2149 pg/mL ([95% CI, 204–3301] P =0.028), with 6-minute walk distance increased by 88 m ([95% CI, 50–249] P =0.008) and with New York Heart Association class improved in 8 patients at 6 months. Conclusions: The present results showed that percutaneous radiofrequency ablation–based interatrial shunting was a safe and potentially effective therapy for HFpEF, providing a nonpharmacological and nonimplanted option for HFpEF management. Registration: URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR1900027664.

Background Myocardial infarction (MI) is a cardiovascular disease with high morbidity and mortality. PI16 (peptidase inhibitor 16), as a secreted protein, is highly expressed in heart diseases such as heart failure. However, the functional role of PI16 in MI is unknown. This study aimed to investigate the role of PI16 after MI and its underlying mechanisms. Methods and Results PI16 levels after MI were measured by enzyme‐linked immunosorbent assay and immunofluorescence staining, which showed that PI16 was upregulated in the plasma of patients with acute MI and in the infarct zone of murine hearts. PI16 gain‐ and loss‐of‐function experiments were used to investigate the potential role of PI16 after MI. In vitro, PI16 overexpression inhibited oxygen–glucose deprivation–induced apoptosis in neonatal rat cardiomyocytes, whereas knockdown of PI16 exacerbated neonatal rat cardiomyocyte apoptosis. In vivo, left anterior descending coronary artery ligation was performed on PI16 transgenic mice, PI16 knockout mice, and their littermates. PI16 transgenic mice showed decreased cardiomyocyte apoptosis at 24 hours after MI and improved left ventricular remodeling at 28 days after MI. Conversely, PI16 knockout mice showed aggravated infract size and remodeling. Mechanistically, PI16 downregulated Wnt3a (wingless‐type MMTV integration site family, member 3a)/β‐catenin pathways, and the antiapoptotic role of PI16 was reversed by recombinant Wnt3a in oxygen–glucose deprivation–induced neonatal rat cardiomyocytes. PI16 also inhibited HDAC1 (class I histone deacetylase) expression, and overexpression HDAC1 abolished the inhibition of apoptosis and Wnt signaling of PI16. Conclusions In summary, PI16 protects against cardiomyocyte apoptosis and left ventricular remodeling after MI through the HDAC1‐Wnt3a‐β‐catenin axis.

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