{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:28:09Z","timestamp":1792099689776,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"School of Medicine Library Open Article Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca2+) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor to RHF pathogenesis by suppressing the cardioprotective cGMP\u2013PKG signaling pathway\u2014a conclusion largely extrapolated from left-sided heart failure models. This review examines existing evidence regarding PDE9A\u2019s role in RHF, focusing on its effects on intracellular calcium cycling, fibrosis, hypertrophy, and contractile dysfunction. Data from preclinical models demonstrate that pathological stress upregulates PDE9A expression in cardiomyocytes, leading to diminished PKG activation, impaired SERCA2a function, RyR2 instability, and increased arrhythmogenic Ca2+ leak. Pharmacological or genetic inhibition of PDE9A restores cGMP signaling, improves calcium handling, attenuates hypertrophic and fibrotic remodeling, and enhances ventricular compliance. Early-phase clinical studies in heart failure populations suggest that PDE9A inhibitors are well tolerated and effectively augment cGMP levels, although dedicated trials in RHF are still needed. Overall, these findings indicate that targeting PDE9A may represent a promising therapeutic strategy to improve outcomes in RHF by directly addressing the molecular mechanisms underlying calcium mishandling and myocardial remodeling.<\/jats:p>","DOI":"10.3390\/ijms26136361","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T04:11:04Z","timestamp":1751429464000},"page":"6361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["PDE9A Promotes Calcium-Handling Dysfunction in Right Heart Failure via cGMP\u2013PKG Pathway Suppression: A Mechanistic and Therapeutic Review"],"prefix":"10.3390","volume":"26","author":[{"given":"Spencer","family":"Thatcher","sequence":"first","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arbab","family":"Khalid","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0844-9357","authenticated-orcid":false,"given":"Abu-Bakr","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randeep","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Kia","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"},{"name":"Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1161\/CIRCRESAHA.113.301129","article-title":"The right ventricle in pulmonary arterial hypertension: Disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure","volume":"115","author":"Ryan","year":"2014","journal-title":"Circ. 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