{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:05:11Z","timestamp":1791446711875,"version":"4.3.3"},"reference-count":67,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,2,21]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO\u2010based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a \u201c2\u2010hit\u201d murine model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Nine\u2010week\u2010old male C57BL\/6\u2009N mice (n=15 per group) were treated concurrently with high\u2010fat diet and N(\u03c9)\u2010nitro\u2010L\u2010arginine methyl ester (L\u2010NAME)\u00a0(0.5\u2009g\/L per day) via drinking water for 10\u2009weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75\u2009mg\/L in the drinking water) and hydralazine (2.0\u2009mg\/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E\/E', LVEDP, and Tau in mice treated with L\u2010NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of \u201ctwo\u2010hit\u201d HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our data demonstrate that nitrite, a well\u2010established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the \u201c2\u2010hit\u201d mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the \u201c2\u2010hit\u201d cardiometabolic HFpEF. These data suggest that supplementing NO\u2010based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.122.028480","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T06:56:52Z","timestamp":1675839412000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a \u201c2\u2010Hit\u201d Murine Model"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0470-0138","authenticated-orcid":false,"given":"Kyle B.","family":"LaPenna","sequence":"first","affiliation":[{"name":"Cardiovascular Center of Excellence Louisiana State University Health Sciences Center New Orleans LA"},{"name":"Department of Pharmacology 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