ABSTRACT

BACKGROUND Superoxide causes diuretic resistance which limits the treatment of ADHF and right heart failure post LVAD implantation. Formulating IV GTN in 5% GSH is expected to benefit both these conditions with GTN targeting heart failure and GSH preventing diuretic resistance. The purpose of this study is to evaluate the stability of a new formulation of intravenous nitroglycerin (GTN) for use in treating ADHF and right heart failure post LVAD implantation.

METHODS a new protocol for formulating IV GTN in 5% GSH that is buffered with 2% L-arginine was used to create two solutions of GTN in 5% GSH. Following this the pH of two solutions of .2 mg/cc GTN in 5% GSH prepared according to the new protocol was tested. The solutions were then stored at room temperature for one year and observed for evidence of GSH oxidation. After one year, the pH of the solutions was retested.

RESULTS initial pH ranged 4.0 +/-.05 and was unchanged after one year. Both solutions remained clear without evidence of GSH oxidation.

CONCLUSION this new formulation of IV GTN in 5% GSH is stable for use in treating ADHF and right heart failure post LVAD implantation for periods of up to one year. This new formulation has the potential to reduce the need for right ventricular assist devices following LVAD implantation and facilitate the explantation of LVADs thereby reducing the need for heart transplants.

WHAT IS ALREADY KNOWN ON THIS TOPIC Diuretic resistance (DR) is known to be associated with increased heart failure mortality. DR may be increased by superoxide which is intrinsic to the pathophysiology of heart failure. GSH depletion from the use of intravenous nitroglycerin in the treatment of ADHF and RHF leads to superoxide production and DR, both of which may be GSH suppressible.

WHAT THIS STUDY ADDS This study adds a new drug designed to prevent superoxide induced DR.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY This study may lead to improved treatment of ADHF, prevention of RHF following LVAD implantation and facilitation of LVAD explantation for reducing the need for heart transplantation

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

n/a

Funding Statement

Funding for this study provided solely by author

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB approval not applicable - animal and human subjects were not involved

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

available on request

ABREVIATIONSADHFacute decompensated heart failureAHFacute heart failureBH4tetrahydrobiopterinDRdiuretic resistanceeNOSendothelial nitric oxide synthaseGSHglutathioneGTNnitroglycerin, glycerol trinitrateIV GTN/GSHintravenous nitroglycerin in glutathione 5%IRinsulin resistanceLVADleft ventricular assist deviceNACn-acetylcysteineNOnitric oxide OONO-peroxynitritePKCprotein kinase CRHFright heart failureROSreactive oxygen speciesRNSreactive nitrogen speciesRVADright ventricular assist deviceSGLT2sodium glucose transporter 2