SGC Stimulation, Perioperative Vascular Reactivity, and Organ Injury in Cardiac Surgery

Study Overview
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Brief Summary
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The goal of this mechanistic clinical trial is to learn about the effects of medications called soluble guanylyl cyclase stimulators on vascular function and markers of kidney and brain injury in patients having heart surgery. The main questions it aims to answer are: Does soluble guanylyl cyclase stimulation improve blood vessel function compared to placebo? Does soluble guanylyl cyclase stimulation decrease markers of kidney injury and brain injury compared to placebo? Participants will be randomized to a soluble guanylyl cyclase stimulator called vericiguat or placebo, and researchers will compare vascular function and markers of brain and kidney injury to see if vericiguat improves vascular function and reduces markers of injury. This will provide important information to determine the underlying reasons that patients have some kidney and brain function problems after having heart surgery.

Detailed Description
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Patients undergoing elective cardiac surgery will be randomized to the soluble guanylyl cyclase stimulator vericiguat versus placebo before surgery through the day of surgery and vascular function will be quantified using ultrasound and direct assessment of arterial relaxation ex-vivo. Markers of brain and kidney injury will be measured in plasma and urine.

Official Title
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The Effects of Soluble Guanylyl Cyclase Stimulation on Perioperative Vascular Reactivity and Organ Injury in Cardiac Surgery

Conditions
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Endothelial Dysfunction, Vascular Diseases, Kidney Injury, Brain Disease, Vascular Inflammation

Intervention / Treatment
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* Drug: Vericiguat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Elective open-heart surgery, defined as surgery on the heart or aorta that requires sternotomy or thoracotomy Exclusion Criteria: Intolerance to vericiguat Use of other soluble guanylyl cyclase stimulators or current use of phosphodiesterase-5 inhibitors Pregnancy or breast feeding. Pregnancy will be excluded in women of child-bearing potential by a urine or serum beta hcg test Renal replacement therapy within 30 days prior to screening Estimated glomerular filtration rate <15 ml/min per 1.73 m2 per Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation at time of screening Systolic blood pressure less than 120 mmHg at the time of screening Prior kidney transplantation History of significant liver dysfunction (defined as Child-Pugh class C) Surgery scheduled to be performed with circulatory arrest Surgery scheduled to correct a major congenital heart defect Extracorporeal membrane oxygenation (ECMO) prior to surgery Active systemic infection or surgery for infectious endocarditis Ventricular assist device or intraaortic balloon pump support prior to surgery Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vericiguat<br>10 mg vericiguat administered orally once daily for three days (through day of surgery) | Drug: Vericiguat<br>* Vericiguat 10 mg administered orally starting 2 days prior to heart surgery through the day of surgery<br>|
| Placebo Comparator: Placebo<br>placebo administered orally once daily for three days (through day of surgery) | Drug: Placebo<br>* Matched placebo administered orally starting 2 days prior to heart surgery through the day of surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial artery flow-mediated dilation | Percent change in brachial artery diameter from baseline to maximum post-forearm ischemia adjusted for shear-rate (Aim 1 primary outcome). | Day of surgery | 
| Ex vivo vascular relaxation | Ex vivo arterial relaxation (percent) in participants with available vascular tissue (Aim 1 primary outcome) | Day of surgery | 
| Ubiquitin C-terminal hydrolase L1 (UCHL1) plasma concentration | UCHL1 will be measured in plasma to quantify effects of vericiguat vs. placebo on neuronal injury (Aim 2 primary neuronal outcome) | Enrollment through postoperative day 2 | 
| Neutrophil gelatinase associated lipocalin (NGAL) urine concentration | NGAL will be measured in urine to quantify effects of vericiguat vs. placebo on markers of renal injury (Aim 2 primary renal outcome) | Enrollment through postoperative day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylated vasodilator stimulated phosphoprotein (phospho-VASP) | Soluble guanylyl cyclase stimulation will be further quantified as arterial phospho-VASP/VASP ratio(Aim 1 secondary outcome) | Enrollment through postoperative day 2 | 
| Endothelial barrier breakdown - claudin-5 | Endothelial barrier breakdown will be quantified as plasma concentration of claudin-5 (Aim 1 secondary outcome) | Enrollment through postoperative day 2 | 
| Endothelium mediated inflammation and coagulation - plasminogen activator inhibitor-1 (PAI-1) | Endothelium mediated inflammation and coagulation will be quantified as plasma concentration of PAI-1 (Aim 1 secondary outcome) | Enrollment through postoperative day 2 | 
| Endothelial Activation - intercellular adhesion molecule 1 (ICAM1) | Endothelial activation will be quantified as plasma concentrations of ICAM1 (Aim 1 secondary outcome) | Enrollment through postoperative day 2 |