Inhalation of hydrogen gas after myocardial infarctionScientific Research

The Effects of Hydrogen Gas Inhalation on Adverse Left Ventricular Remodeling After Percutaneous Coronary Intervention for ST-Elevated Myocardial Infarction　― First Pilot Study in Humans ―

https://doi.org/10.1253/circj.CJ-17-0105

Yoshinori Katsumata, Fumiya Sano, Takayuki Abe, Tomoyoshi Tamura, Taishi Fujisawa, Yasuyuki Shiraishi, Shun Kohsaka, Ikuko Ueda, Koichiro Homma, Masaru Suzuki, Shigeo Okuda, Yuichiro Maekawa, Eiji Kobayashi, Shingo Hori, Junichi Sasaki, Keiichi Fukuda, Motoaki Sano

Abstract

Abstract
Background: In a rat model of acute myocardial infarction (AMI), hydrogen gas (HI) inhalation reduces infarct size and attenuates unnecessary left ventricular (LV) remodeling. We designed a prospective, open-label, rater-blind clinical study of patients with ST-segment elevation myocardial infarction (STEMI).

METHODS AND RESULTS

Twenty patients with an initial diagnosis of STEMI were assigned to either the HI group (1.3% H2 and 26% oxygen) or the control group (26% oxygen).

There were no serious adverse events related to HI. In the entire analysis set, the cardiac salvage index assessed by cardiac magnetic resonance imaging 7 days after primary percutaneous coronary intervention (PCI) showed no significant difference between the two groups (HI: 50.0 ± 24.3%; control group: 60.1 ± 20.1%; P = 0.43). However, at 6 months, some surrogate outcomes from day 7 were numerically greater in the HI group than in the control group, including the LV stroke volume index (HI: 9.2 ± 7.1 mL/m2; control: -1.4 ± 7.2 ml /m2; P = 0.03) and LV ejection fraction (HI: 11.0% ± 9.3%; control: 1.7% ± 8.3%; P = 0,11).

Conclusions

The first clinical study demonstrated that HI during PCI is feasible and safe, promoting reverse LV remodeling even 6 months after STEMI. The study was not designed to test efficacy, and another large-scale study is needed. (Clinical trial registration number: UMIN00006825)

References

• • . Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361: 13–20.

 

• • 2. Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–2619.

 

• • 3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121–1135.

 

• • 4. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): Two randomised trials. Lancet 2007; 370: 1483–1493.

 

• • 5. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359: 473–481.

 

• • 6. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 2015; 373: 1021–1031.

 

• • 7. Ohta S. Molecular hydrogen as a novel antioxidant: Overview of the advantages of hydrogen for medical applications. Methods Enzymol 2015; 555: 289–317.

 

• • 8. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13: 688–694.

 

• • 9. Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Maekawa Y, et al. H(2) gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc 2012; 1: e003459.

 

• • 10. Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Ohta S, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation 2014; 130: 2173–2180.

 

• • 11. Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome: First-in-human pilot study. Circ J 2016; 80: 1870–1873.

 

• • 12. Homma K, Yoshida T, Yamashita M, Hayashida K, Hayashi M, Hori S. Inhalation of hydrogen gas is beneficial for preventing contrast-induced acute kidney injury in rats. Nephron Exp Nephrol 2014; 128: 116–122.

 

• • 13. Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 2008; 373: 30–35.

 

• • 14. Yoshida A, Asanuma H, Sasaki H, Sanada S, Yamazaki S, Asano Y, et al. H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs. Cardiovasc Drugs Ther 2012; 26: 217–226.

 

• • 15. Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, Arheden H. Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: Quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging 2009; 2: 569–576.

 

• • 16. Masci PG, Ganame J, Strata E, Desmet W, Aquaro GD, Dymarkowski S, et al. Myocardial salvage by CMR correlates with LV remodeling and early ST-segment resolution in acute myocardial infarction. JACC Cardiovasc Imaging 2010; 3: 45–51.

 

• • 17. Wright J, Adriaenssens T, Dymarkowski S, Desmet W, Bogaert J. Quantification of myocardial area at risk with T2-weighted CMR: Comparison with contrast-enhanced CMR and coronary angiography. JACC Cardiovasc Imaging 2009; 2: 825–831.

 

• • 18. Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012; 33: 1491–1499.

 

• • 19. Roberts R, Rogers WJ, Mueller HS, Lambrew CT, Diver DJ, Smith HC, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation 1991; 83: 422–437.

 

• • 20. Smith DH, Neutel JM, Lacourciere Y, Kempthorne-Rawson J. Prospective, randomized, open-label, blinded-endpoint (PROBE) designed trials yield the same results as double-blind, placebo-controlled trials with respect to ABPM measurements. J Hypertens 2003; 21: 1291–1298.

 

• • 21. Bondarenko O, Beek AM, Hofman MB, Kuhl HP, Twisk JW, van Dockum WG, et al. Standardizing the definition of hyperenhancement in the quantitative assessment of infarct size and myocardial viability using delayed contrast-enhanced CMR. J Cardiovasc Magn Reson 2005; 7: 481–485.

 

• • 22. Friedrich MG, Abdel-Aty H, Taylor A, Schulz-Menger J, Messroghli D, Dietz R. The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance. J Am Coll Cardiol 2008; 51: 1581–1587.

 

• • 23. Yan X, Shichita T, Katsumata Y, Matsuhashi T, Ito H, Ito K, et al. Deleterious effect of the IL-23/IL-17A axis and gammadeltaT cells on left ventricular remodeling after myocardial infarction. J Am Heart Assoc 2012; 1: e004408.

 

• • 24. Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, Endo J, et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J Mol Cell Cardiol 2013; 62: 24–35.

 

• • 25. Yan X, Hegab AE, Endo J, Anzai A, Matsuhashi T, Katsumata Y, et al. Lung natural killer cells play a major counter-regulatory role in pulmonary vascular hyperpermeability after myocardial infarction. Circ Res 2014; 114: 637–649.

 

• • 26. Katsumata Y, Shinmura K, Sugiura Y, Tohyama S, Matsuhashi T, Ito H, et al. Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension 2014; 63: 80–87.

 

• • 27. Sugiura Y, Katsumata Y, Sano M, Honda K, Kajimura M, Fukuda K, et al. Visualization of in vivo metabolic flows reveals accelerated utilization of glucose and lactate in penumbra of ischemic heart. Sci Rep 2016; 6: 32361.

 

• 28. Nagata Y, Konno T, Hayashi K, Kawashiri MA. Myocardial tissue characterization of left ventricular reverse remodeling in ischemic cardiomyopathy. Circ J 2016; 80: 2427–2428.