© 2019 by ITC Team |  Terms of Use  |   Privacy Policy

Project Information

Background

In the past decades, as a result of advances in pharmacological, reperfusion and preventive strategies, prognosis of patients with ST-elevated myocardial infarction has substantially improved and mortality has decreased.  


However, permanent myocardial injury related to the ischemia and subsequent reperfusion is still observed in the vast majority (88%) of patients and harbors a risk of heart failure development. Although many advances have been made, there is no specific treatment that targets myocardial reperfusion injury, which is considered to be a paradoxical form of myocardial damage that occurs as a result of the restoration of vessel patency [1]. Reducing myocardial reperfusion injury is expected to further decrease infarct size, decreasing adverse cardiac remodeling and improving cardiac function as well as clinical outcome. 


Currently, H2S has been shown to protect from (myocardial) ischemia reperfusion injury in various experimental animal models [2-8]. It reduces infarct size and apoptosis and attenuates cardiac function. Inhibition of leukocyte endothelial cell interactions, neutralization of reactive oxygen species (ROS) and the reduction of apoptotic signaling are the suggested as additional mechanisms underlying the cardioprotective effect of H2S [3, 9-11]. 


An intermediate of H2S, sodium thiosulfate (STS), which acts as a H2S donor, can safely be administered intravenously to humans [12, 13]. STS has an orphan drug registration in the treatment of cyanide poisoning, prevention of ototoxicity in children receiving cisplatinum chemotherapy and in the treatment of calciphylaxis. The GIPS-IV study will be the first study to determine the efficacy of a H2S-donor to reduce myocardial infarct size in patient with ST-elevated myocardial infarction.

 

Study design


The primary objective of the GIPS IV trial is to evaluate the efficacy of STS compared to placebo treatment to reduce myocardial infarct size in patients presenting with STEMI in a randomized, double blind trial. During hospitalization a total of 380 patients, undergoing primary PCI for a first STEMI and deemed amenable by the investigator, will be treated with STS 12.5g intravenously (i.v.) or matched placebo immediately after arrival at the catheterization laboratory (cath-lab). A repeated dose will be administered 6 hours after the first dose, both on top of standard treatment.


The primary efficacy parameter will be infarct size 4 months after randomization as measured by late gadolinium enhancement (LGE) Cardiac Magnetic Resonance (CMR) imaging.

Secondary efficacy and safety objectives include:


•    Left ventricular ejection fraction and myocardial perfusion reserve at 4 months follow-up;
•    Myocardial hemorrhage, microvascular obstruction and myocardial salvage index obtained from non-        mandatory CMR-imaging during hospitalization; 
•    NT-proBNP levels at 4 months;
•    Enzymatic infarct size, as assessed by peak CK-Mb, during hospitalization
•    All-cause mortality and combined incidence of Major Adverse Cardiovascular Events (MACE) up to 2          years after randomization;

 

 

This research is also registered at www.clinicaltrials.gov. You can find the GIPS-IV trial under registration number 2015-001006-34 NL.

 

 

 

References

 


[1] Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. Sep 13 2007;357(11):1121-1135.

[2] Polhemus DJ, Lefer DJ. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule
in cardiovascular disease. Circ Res. Feb 14 2014;114(4):730-737.

[3] Elrod JW, Calvert JW, Morrison J, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion
injury by preservation of mitochondrial function. Proc Natl Acad Sci U S A. Sep 25 2007;104(39):15560-15565.

 

[4] Sodha NR, Clements RT, Feng J, et al. Hydrogen sulfide therapy attenuates the inflammatory response in a porcine model of myocardial ischemia/reperfusion injury. J Thorac Cardiovasc Surg. Oct 2009;138(4):977-984.

 

[5] Sodha NR, Clements RT, Feng J, et al. The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia-reperfusion injury. Eur J Cardiothorac Surg. May 2008;33(5):906-913.

 

[6] Toldo S, Das A, Mezzaroma E, et al. Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice. Circ Cardiovasc Genet. Jun 2014;7(3):311-320.

 

[7] Calvert JW, Jha S, Gundewar S, et al. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res. Aug 14 2009;105(4):365-374.

 

[8] King AL, Polhemus DJ, Bhushan S, et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci U S A. Feb 25 2014;111(8):3182-3187.
 

[9] Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med. 2011;17(11):1391-1401. 
 

[10] Snijder PM, de Boer RA, Bos EM, et al. Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism. PLoS One. 2013;8(5):e63291. 
 

[11] Sen U, Vacek TP, Hughes WM, et al. Cardioprotective role of sodium thiosulfate on chronic heart failure by modulating endogenous H2S generation. Pharmacology. 2008;82(3):201-213. 
 

[12] Kolluru GK, Shen X, Bir SC, Kevil CG. Hydrogen sulfide chemical biology: pathophysiological roles and detection. Nitric Oxide. Nov 30 2013;35:5-20.

 

[13] Olson KR, Deleon ER, Gao Y, et al. Thiosulfate: a readily accessible source of hydrogen sulfide in oxygen sensing. Am J Physiol Regul Integr Comp Physiol. Sep 15 2013;305(6):R592-603.