Brain Disease, Endothelial Dysfunction, Kidney Injury, Vascular Diseases, Vascular Inflammation
Conditions
Brief summary
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: 1. Does soluble guanylyl cyclase stimulation improve blood vessel function compared to placebo? 2. 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
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.
Interventions
DRUGVericiguat
Vericiguat 10 mg administered orally starting 2 days prior to heart surgery through the day of surgery
DRUGPlacebo
Matched placebo administered orally starting 2 days prior to heart surgery through the day of surgery
Sponsors
Vanderbilt University Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years 2. Elective open-heart surgery, defined as surgery on the heart or aorta that requires sternotomy or thoracotomy
Exclusion criteria
1. Intolerance to vericiguat 2. Use of other soluble guanylyl cyclase stimulators or current use of phosphodiesterase-5 inhibitors 3. Pregnancy or breast feeding. Pregnancy will be excluded in women of child-bearing potential by a urine or serum beta hcg test 4. Renal replacement therapy within 30 days prior to screening 5. Estimated glomerular filtration rate \<15 ml/min per 1.73 m2 per Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation at time of screening 6. Systolic blood pressure less than 120 mmHg at the time of screening 7. Prior kidney transplantation 8. History of significant liver dysfunction (defined as Child-Pugh class C) 9. Surgery scheduled to be performed with circulatory arrest 10. Surgery scheduled to correct a major congenital heart defect 11. Extracorporeal membrane oxygenation (ECMO) prior to surgery 12. Active systemic infection or surgery for infectious endocarditis 13. Ventricular assist device or intraaortic balloon pump support prior to surgery 14. Prisoners
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brachial artery flow-mediated dilation | Day of surgery | Percent change in brachial artery diameter from baseline to maximum post-forearm ischemia adjusted for shear-rate (Aim 1 primary outcome). |
| Ex vivo vascular relaxation | Day of surgery | Ex vivo arterial relaxation (percent) in participants with available vascular tissue (Aim 1 primary outcome) |
| Ubiquitin C-terminal hydrolase L1 (UCHL1) plasma concentration | Enrollment through postoperative day 2 | UCHL1 will be measured in plasma to quantify effects of vericiguat vs. placebo on neuronal injury (Aim 2 primary neuronal outcome) |
| Neutrophil gelatinase associated lipocalin (NGAL) urine concentration | Enrollment through postoperative day 2 | NGAL will be measured in urine to quantify effects of vericiguat vs. placebo on markers of renal injury (Aim 2 primary renal outcome) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phosphorylated vasodilator stimulated phosphoprotein (phospho-VASP) | Enrollment through postoperative day 2 | Soluble guanylyl cyclase stimulation will be further quantified as arterial phospho-VASP/VASP ratio(Aim 1 secondary outcome) |
| Endothelial barrier breakdown - claudin-5 | Enrollment through postoperative day 2 | Endothelial barrier breakdown will be quantified as plasma concentration of claudin-5 (Aim 1 secondary outcome) |
| Endothelium mediated inflammation and coagulation - plasminogen activator inhibitor-1 (PAI-1) | Enrollment through postoperative day 2 | Endothelium mediated inflammation and coagulation will be quantified as plasma concentration of PAI-1 (Aim 1 secondary outcome) |
| Endothelial Activation - intercellular adhesion molecule 1 (ICAM1) | Enrollment through postoperative day 2 | Endothelial activation will be quantified as plasma concentrations of ICAM1 (Aim 1 secondary outcome) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMarcos Lopez, MD
Vanderbilt University Medical Center
Outcome results
None listed