Nicotinamide Riboside in LVAD Recipients
关键词
抽象
描述
This Pilot Study will examine the following Aims:
Aim 1: Enroll 5 participants scheduled for elective left ventricular assist device (LVAD) placement into an open-label study of nicotinamide riboside (NR).
a. Participants will have labs (including safety panels) drawn at baseline (Day 1), then receive escalating doses of NR to a maximum dose of 1000mg twice daily by Day 3. Participants will be continued on NR at 1000mg twice daily until LVAD implantation surgery.
On the morning of LVAD implantation Surgery (Day 5 or later), participants will have final labs drawn. Samples of fresh cardiac tissue removed from the left ventricular apex during LVAD implantation surgery will be collected in the operating room. The primary analyses will be performed on NR-treated participants who were on the maximum NR dose of 1000mg twice daily for at least 2 days prior to LVAD implantation surgery. The maximum duration of NR administration will be capped at 14 days. If the surgery doesn't happen by then, the participant will be withdrawn from the study.
Aim 2: Determine the effect of NR (as compared to historical controls) on levels of the oxidized and reduced forms of nicotine-adenine dinucleotide (NAD+ and NADH, respectively), mitochondrial function and its regulation through modifications of the epigenome in the failing myocardium.
1. Measure NAD+ and NADH levels in the blood and myocardium of the participants.
2. Assess mitochondrial morphology and function in cardiac tissue using, respectively, electron microscopy (EM) and isolated mitochondria.
3. Determine protein acetylation in the mitochondrial and non-mitochondrial compartments and changes in nuclear gene regulation.
Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory response in heart failure (HF) patients receiving NR (as compared to historical controls).
1. Measure mitochondrial function in peripheral blood mononucleated cells (PBMC).
2. Determine the inflammatory response in PBMC.
3. Compare effects on the circulating inflammasome vs. myocardial inflammation.
日期
| 最后验证: | 06/30/2019 |
| 首次提交: | 10/15/2018 |
| 提交的预估入学人数: | 10/30/2018 |
| 首次发布: | 10/31/2018 |
| 上次提交的更新: | 07/29/2019 |
| 最近更新发布: | 07/31/2019 |
| 实际学习开始日期: | 09/25/2018 |
| 预计主要完成日期: | 11/25/2018 |
| 预计完成日期: | 11/25/2018 |
状况或疾病
干预/治疗
Dietary Supplement: Open-label nicotinamide riboside
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Experimental: Open-label nicotinamide riboside Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) according to the following administration schedule:
Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg)
Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily
Washout Day of LVAD Surgery and/or Day 15: None | Dietary Supplement: Open-label nicotinamide riboside nicotinamide riboside supplied as 250mg capsules |
| No Intervention: Baseline controls Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion Criteria: - Diagnosis of advanced heart failure. - Planned elective LVAD implantation surgery with patient agreements for candidacy in place as required by UWMC. - Hospital inpatient at time of enrollment. - Ability to undergo Study procedures. - Willingness/ability to provide informed consent. Exclusion Criteria: - Current smoking - Receiving certain concurrent supplements (to be determined at discretion of the PI). Note that UWMC Nutrition Care standards call for a general multivitamin (1 tab PO daily) as part of the advanced heart failure therapy (AHFT) work-up. - Known allergies to niacin or nicotinamide. - Hepatic, renal, endocrine, or neurological disease that disqualify them from consideration for LVAD implantation. - Inability to perform Study visits or procedures. - Unwillingness/inability to provide informed consent. - Women who are currently pregnant or who wish to become pregnant over the course of the study follow-up are not allowed to join this study. This exclusion is built into the LVAD candidate selection process. |
结果
主要结果指标
1. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [Up to 14 days]
次要成果指标
1. Effect of NR on whole blood NAD+ levels [Duration of NR treatment]
2. Effect of NR on mitochondrial respiration (Seahorse assay) in isolated peripheral blood mononuclear cells (PBMCs) [Up to 14 days]
3. Between-group comparison of whole blood NAD+ levels [Up to 14 days]
4. Between-group comparison of mitochondrial respiration in PBMCs [Up to 14 days]
