Myocardial infarct size is reduced by nitrite and nitrate administration: a systematic review and meta-analysis of animal studies.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide and can be complicated by myocardial infarction (MI), leading to cardiac failure. Inorganic nitrite and nitrate, which release nitric oxide (NO), can protect the heart against myocardial injury. This animal systematic review and meta-analysis aims to assess whether the administration of nitrite/nitrate decreases myocardial infarct size. We systematically searched PubMed, Scopus, and Web of Science databases until October 2023; 15 eligible animal studies (35 study arms for in-vivo and 10 for in-vitro studies) published between 1989 and 2023 were included. In-vivo studies were conducted on rats, mice, cats, and dogs, and in-vitro studies on rats and mice with an overall exposure of 0.03 to 12713 mg/kg to nitrate/nitrite administrated before, after, or during ischemia mainly by intravenous single bolus or by oral over 270 days. All in-vitro studies used nitrite/nitrate before ischemia, with the concentration ranging between 0.34 to 201 μM. MI was induced by occlusion of the left anterior diagonal or left circumflex arteries in in-vitro studies and by isoproterenol in in-vivo studies. Infarct size was measured by direct staining of the sliced heart sections. In in-vivo studies, nitrite (overall effect size (ES)=-17.0 %, 95 % confidence interval (CI)=-21.3, -12.8, P<0.001) and nitrate (overall ES= -9.6 %, 95 % CI=-15.7, -3.4, P=0.002) reduced myocardial infarct size. In in-vitro studies, nitrite (overall ES=-15.8 %, 95 % CI=-25.5, -6.2, P=0.001) reduced the infarct size. Sensitivity analysis showed that the overall effect of nitrite on myocardial infarct size was unaffected by doses or health conditions in in-vivo and in-vitro studies. In conclusion, our meta-analysis showed that nitrite/nitrate administration can effectively reduce myocardial infarct size. However, these results should be approached with caution because of the limitations of animal studies and the existing high heterogeneity.