Inhaled HYdrogen for myocardial preservation in patients with ST-Elevation Myocardial Infarction admitted in the emergency room – HY-STEMI trial

Background. Early, successful restoration of myocardial perfusion after a ST-segment elevation myocardial infarction (STEMI) is the most effective way to reduce final infarct size and improve clinical outcome. However, experimental and clinical data have shown that reperfusion per se may have harmful effects, the “myocardial reperfusion injury” is identified as a target for cardioprotection. Molecular hydrogen (H2) is the most lightweight gas and abundant chemical element in the universe. Recent evidence has shown that H2 is a potent antioxidant, antiapoptotic and anti-inflammatory agent and so may have potential medical applications in cells, tissues and organs. The antioxidant advantages of H2 gas include: a high bio-membrane penetration and intracellular diffusion capability which enable it to reach subcellular compartments like mitochondria; selectively scavenging the deleterious hydroxyl radical while preserving other important reactive oxygen and nitrogen species for normal signaling regulation. The efficacy of molecular H2 for prevention and treatment of various diseases, with underlying pathological conditions of ischemia-reperfusion injury, has been reported by numerous non-clinical and clinical studies. Preliminary data. H2 gas inhalation reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model. A recent phase I clinical study in Japan has shown that H2 inhalation during primary percutaneous coronary interventions (pPCI) is feasible and safe and may also promote LV reverse remodeling. Aims. To evaluate the efficacy of a H2 inhalation on top of standard care when compared to standard care alone, on LV function and remodeling in reperfused STEMI. Primary outcome. The primary efficacy endpoint is the global LV function assessed as ejection fraction (EF) changes from pPCI (day Ministero dell'Università e della Ricerca MUR - BANDO 2022 1) to 6 months later. LV will be evaluated by echocardiography with imaging data independently analyzed in a central core echo lab. Secondary outcomes. Concentration of cardiac troponins, CK-MB/CK, and natriuretic peptides after pPCI; incidence of ≥70% resolution of ST-segment elevation 1hr after pPCI; early LVEF change at day 4; LV end-diastolic volume at 3 months; MI size by cardiac magnetic resonance at 4 days after pPCI and at 6 months; rehospitalization for cardiovascular reasons; cardiovascular death, heart failure, and cardiogenic shock at 6 months. Study design. Randomized, controlled, phase II trial. The study population comprises patients >18 years with a first STEMI. After informed consent, patients are randomized 1:1 to 1.3% H2 in 26% O2 or 26% O2 only. H2 inhalation will be achieved through a face mask upon arrival at the emergency room and continued during pPCI and for the first 2 hr after reperfusion. Considering a 15% LVEF improvement at 6 months after pPCI in the H2 group compared to standard of care, we plan to enroll a total of 120 STEMI patients (60 patients per group; 80% power, 5% 2-sided α).

Background. Early, successful restoration of myocardial perfusion after a ST-segment elevation myocardial infarction (STEMI) is the most effective way to reduce final infarct size and improve clinical outcome. However, experimental and clinical data have shown that reperfusion per se may have harmful effects, the “myocardial reperfusion injury” is identified as a target for cardioprotection. Molecular hydrogen (H2) is the most lightweight gas and abundant chemical element in the universe. Recent evidence has shown that H2 is a potent antioxidant, antiapoptotic and anti-inflammatory agent and so may have potential medical applications in cells, tissues and organs. The antioxidant advantages of H2 gas include: a high bio-membrane penetration and intracellular diffusion capability which enable it to reach subcellular compartments like mitochondria; selectively scavenging the deleterious hydroxyl radical while preserving other important reactive oxygen and nitrogen species for normal signaling regulation. The efficacy of molecular H2 for prevention and treatment of various diseases, with underlying pathological conditions of ischemia-reperfusion injury, has been reported by numerous non-clinical and clinical studies. Preliminary data. H2 gas inhalation reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model. A recent phase I clinical study in Japan has shown that H2 inhalation during primary percutaneous coronary interventions (pPCI) is feasible and safe and may also promote LV reverse remodeling. Aims. To evaluate the efficacy of a H2 inhalation on top of standard care when compared to standard care alone, on LV function and remodeling in reperfused STEMI. Primary outcome. The primary efficacy endpoint is the global LV function assessed as ejection fraction (EF) changes from pPCI (day Ministero dell'Università e della Ricerca MUR - BANDO 2022 1) to 6 months later. LV will be evaluated by echocardiography with imaging data independently analyzed in a central core echo lab. Secondary outcomes. Concentration of cardiac troponins, CK-MB/CK, and natriuretic peptides after pPCI; incidence of ≥70% resolution of ST-segment elevation 1hr after pPCI; early LVEF change at day 4; LV end-diastolic volume at 3 months; MI size by cardiac magnetic resonance at 4 days after pPCI and at 6 months; rehospitalization for cardiovascular reasons; cardiovascular death, heart failure, and cardiogenic shock at 6 months. Study design. Randomized, controlled, phase II trial. The study population comprises patients >18 years with a first STEMI. After informed consent, patients are randomized 1:1 to 1.3% H2 in 26% O2 or 26% O2 only. H2 inhalation will be achieved through a face mask upon arrival at the emergency room and continued during pPCI and for the first 2 hr after reperfusion. Considering a 15% LVEF improvement at 6 months after pPCI in the H2 group compared to standard of care, we plan to enroll a total of 120 STEMI patients (60 patients per group; 80% power, 5% 2-sided α).