Vascular Diseases
Conditions
Brief summary
Contemporary left ventricular assist device (LVAD) therapy improves survival during advanced heart failure but vascular aging develops rapidly leading to major adverse events including stroke and bleeding in nearly half of patients. In this study, the study team aims to investigate whether sildenafil pharmacotherapy, which has anti-fibrotic effects, can reduce vascular aging during LVAD support. An aim of this study is to compare changes in small blood vessels in the gastrointestinal tract between participants receiving sildenafil or placebo. Video capsule endoscopy (VCE) will be used to assess these changes in small blood vessels.
Detailed description
Over 6.5 million individuals in the United States suffer from heart failure (HF), with the burden of this disease expected to grow over the next decade. Approximately 300,000 of these patients have advanced HF and may benefit from durable left ventricular assist device (LVAD) therapy, which can improve outcomes during advanced HF. However, despite advancements in device design that have increased survival rates, large registries of real- world cases reveal that nearly half of patients experience severe vascular adverse events, including stroke and bleeding, during prolonged contemporary LVAD support. This elevated adverse-event rate remains a major barrier to safely expanding the use and durability of LVAD therapy. Vascular remodeling or aging of the large and small blood vessels is known to promote stroke and bleeding within the general population. Critically, such remodeling is rapidly accelerated under conditions of reduced pulsatility produced by LVADs, evidenced by large vessel stiffening and fibrosis, small vessel angiodysplasia, and endothelial dysfunction. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are prescribed to select LVAD patients with pulmonary hypertension and right heart failure. However, given that these agents enhance nitric oxide-cGMP signaling in platelets and vascular smooth muscle cells, leading to anti-thrombotic and anti-fibrotic effects, they may also reduce vascular remodeling and related adverse events. Here, based on preliminary findings, a double-blind, randomized, placebo-controlled trial will be conducted to determine the effects of chronic sildenafil administration on vascular remodeling during LVAD support.
Interventions
DRUGSildenafil
Orally administered phosphodiesterase-5 (PDE-5) inhibitor, which enhances nitric oxide signaling in platelets and blood vessels.
OTHERPlacebo
Matched capsule not containing any medication
Sponsors
Montefiore Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Over 18 years of age * Supported by a durable LVAD or planned to undergo placement of a durable LVAD * Be able to give informed consent
Exclusion criteria
* History of pre-existing aortic valve prosthesis or an aortic graft * Allergy to sildenafil * Taking any nitric oxide (NO) donor medications * History of complete carotid occlusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Aortic Pulse Wave Velocity | From Baseline to 180 days | Pulse wave velocity (PWV) will be measured by vascular ultrasound. PWV will be calculated by dividing the distance between the carotid and femoral artery waveform acquisition sites (in meters) by the carotid-femoral transit time (change in time, in seconds). Change in group mean PWV from baseline will be summarized. Increases in PWV can be an indicator of vascular fibrosis and are associated with increased risk of cardiovascular comorbidities. |
| Change in Gastrointestinal Angiodysplasia (GIAD) Foci | From Baseline to 180 days | Microvascular angiodysplasia will be assessed by video capsule endoscopy (VCE). VCE is a minimally invasive technique used to identify gastrointestinal lesions and diagnose GIAD. Change in the group mean number of GIAD foci/lesions per patient from baseline to 180 days will be determined. GIAD formation will only be assessed at baseline and at 180 days unless the patient(s) experiences an episode of gastrointestinal bleeding prior to 180 days. |
| Change in Vascular Reactivity Index | From Baseline to 180 days | Endothelial function will be determined by the finger vascular reactivity index (VRI) during LVAD support. VRI will be assessed by a non-invasive method using the Endothelix device. VRI is determined by measuring fingertip temperature change before and after cuff deflation. Change in group median VRI values from baseline will be summarized. Positive changes from baseline are associated with improved endothelial function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urinary Protein to Creatinine Ratio (PCR) | From Baseline to 180 days and, as available, 12, 18, and 24 months | Urine samples will be assessed to determine the protein to creatinine ratio. Urinary PCR is calculated by dividing the concentration of protein (mg/dL) in the urine sample by the creatinine concentration (mg/dL). Change in group mean urinary protein to creatine ratios from baseline will be summarized. Elevated ratios of protein to creatinine are associated with increased risk of renal disease and microvascular dysfunction. |
| Platelet Gene Expression | Baseline, 3 months, and 6 months | Platelet samples will be assessed for changes in gene expression using RNA sequencing analysis. Platelets will be isolated from whole blood samples collected at baseline, 3 months, and 6 months from participants in each group. Equal number of isolated platelets will be lysed in Trizol and DNAse treated total RNA will be isolated. RNA sequencing will be performed using HiSeq 50 Cycle Single Read Sequencing after library preparation. Differentially expressed genes (DEGs) will be ranked by their expression change between groups. DEGs with \> 1.5-fold change in expression after LVAD at a sequence depth of \>30 million reads per sample will be ranked by study arm. |
Countries
United States
Contacts
CONTACTOmar Saeed, MD
CONTACTLorenzo D'Angelo, MD
PRINCIPAL_INVESTIGATOROmar Saeed, MD
Montefiore Medical Center
Outcome results
None listed