HIV-1, Insufficient Sleep and Vascular Endothelial Dysfunction

University of Colorado, Boulder88 enrolled

Overview

The investigators hypothesize that chronic insufficient sleep is associated with diminished endothelium-dependent nitric oxide-mediated vasodilation and tissue-type plasminogen activator release in anti-retroviral (ART)-treated HIV-1-seropositive adults. Furthermore, the investigators hypothesize that the postulated diminishment in endothelial vasodilator and fibrinolytic function with insufficient sleep will be due, at least in part, to increased oxidative stress. Moreover, increasing sleep duration and improving sleep quality will increase both endothelium-dependent nitric oxide-mediated vasodilation and endothelial tissue-type plasminogen activator release in ART-treated HIV-1-seropositive adults. Increases in endothelial vasodilator and fibrinolytic function will be due, at least in part, to reduced oxidative stress.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

HIV-1

Interventions

Eligibility

Sex: ALLMin age: 40 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects will be men and women of all races and ethnic backgrounds aged 40-75 years with documented HIV-1 infection. * Subjects will be HIV-1-seropositive individuals on a stable DHHS approved ART regimen for at least 6 months, with documented virologic suppression (\<50 copies HIV-1 RNA/mL) for at least 3 months. * All subjects must have CD4+ T cell counts \>200 cells/mm3 at the time of study entry. * Subjects will be free of overt CVD as assessed by: a) medical history; b) physical examination; c) electrocardiogram and BP at rest and maximal exercise; d) complete blood chemistries, lipid and lipoprotein, glucose, insulin and hematological evaluation. * All candidates will be sedentary as determined from the Stanford Physical Activity Questionnaire (\<35 kcal/wk) and will not have engaged in any program of regular physical activity for at least 6 months prior to the study. Exclusion Criteria: * Receiving hormone replacement therapy (HRT) currently or in the preceding 3-year period. * Pre- or peri-menopausal women

Outcomes

Primary Outcomes

Phase 1: Forearm Blood Flow (FBF) Response to Acetylcholine (ACh)

FBF was measured via strain-gauge venous occlusion plethysmography in response to saline for 5 minutes and then to ACh (4.0, 8.0 and 16.0 ug/100 mL tissue/min; the doses of Acetylcholine infused into the brachial artery) for 5 minutes at each dose. Flows during the last minute of saline and each drug dose were measured and the mean value reported. Values after saline and after ACh 4.0, 8.0 and 16.0 at week 3 are reported.

Time frame: FBF response to ACh will be measured during Phase 1 at the participants visit 3 which is ~3 weeks from their respective start date.

Phase 2: FBF Response to Acetylcholine (ACh)

FBF to ACh will be measured following the participants 8 week sleep intervention.

Time frame: FBF response to ACh will be measured during Phase 2 at the participants visit 9 which is ~11 weeks from their respective start date

Phase 1: Forearm Blood Flow (FBF) Response to Sodium Nitroprusside (NTP)

Time frame: FBF response to NTP will be measured during Phase 1 at the participants visit 3 which is ~3 weeks from their respective start date.

Phase 2: Forearm Blood Flow (FBF) Response to Sodium Nitroprusside (NTP)

FBF to NTP will me measured following the participants 8 week sleep intervention

Time frame: FBF response to NTP will be measured during Phase 2 at the participants visit 9 which is ~11 weeks from their respective start date

Phase 1: Endothelial Tissue Type Plasminogen Activator (t-PA) Release in Response to Bradykinin (BDK)

Net endothelial release of t-PA antigen in response to BDK was calculated using the following equation: Net release = (Cv-Ca) x (FBF x \[101-hematocrit/100\]) where Cv and Ca represent the concentration in the vein and artery respectively. A positive difference indicated a net release and a negative difference, net uptake. Arterial and venous blood samples were collected simultaneously at the end of saline and each dose of BDK (12.5, 25.0 and 50.0 ng/100mL tissue/min). Enzyme immunoassay was used to determine t-PA antigen concentrations. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the red blood cells.

Time frame: t-PA release will be measured during Phase 1 at the participants visit 3 which is ~3 weeks from their respective start date.

Phase 2: Endothelial t-PA Release in Response to Bradykinin (BDK)

Endothelial t-PA release will me measured following the participants 8 week sleep intervention. Net endothelial release of t-PA antigen in response to BDK was calculated using the following equation: Net release = (Cv-Ca) x (FBF x \[101-hematocrit/100\]) where Cv and Ca represent the concentration in the vein and artery respectively. A positive difference indicated a net release and a negative difference, net uptake. Arterial and venous blood samples were collected simultaneously at the end of saline and each dose of BDK (12.5, 25.0 and 50.0 ng/100mL tissue/min). Enzyme immunoassay was used to determine t-PA antigen concentrations. Hematocrit was measured in triplicate using the standard microhematocrit technique and corrected for trapped plasma volume within the red blood cells.

Time frame: t-PA release will be measured during Phase 2 at the participants visit 9 which is ~11 weeks from their respective start date

Phase 1: FBF Response to ACh+Ng-monomethyl-L-arginine (L-NMMA)

To determine the contribution of nitric oxide to ACh-mediated vasodilation, FBF to ACh was quantified before and after infusion of L-NMMA. After ACh was infused as described in Outcome measure 1 the ACh dose response was repeated with the continuous infusion of L-NMMA.

Time frame: FBF response to ACh+L-NMMA will be measured during Phase 1 at the participants visit 3 which is ~3 weeks from their respective start date.

Phase 1: FBF Response to ACh+Vitamin C

After allowing sufficient time (45 minutes) for FBF to return to levels similar to that of saline Vitamin C was infused at a constant rate (12 mg/100 mL tissue/min) for 5 minutes. This vitamin C concentration has been show to improve endothelium dependent vasodilation in conditions associated with oxidative stress. Vitamin C infusion was maintained at the same rate while the ACh dose response was repeated.

Time frame: FBF response to ACh+Vitamin C will be measured during Phase 1 at the participants visit 3 which is ~3 weeks from their respective start date.

Phase 2: FBF Response to ACh+L-NMMA

FBF to ACh+L-NMMA will me measured following the participants 8 week sleep intervention. To determine the contribution of nitric oxide to ACh-mediated vasodilation, FBF to ACh was quantified before and after infusion of L-NMMA. After ACh was infused as described in Outcome measure 1 the ACh dose response was repeated with the continuous infusion of L-NMMA.

Time frame: FBF response to ACh+L-NMMA will be measured during Phase 2 at the participants visit 9 which is ~11 weeks from their respective start date

Phase 2: FBF Response to ACh+Vitamin C

FBF to ACh+Vitamin C will me measured following the participants 8 week sleep intervention. After allowing sufficient time (45 minutes) for FBF to return to levels similar to that of saline Vitamin C was infused at a constant rate (12 mg/100 mL tissue/min) for 5 minutes. This vitamin C concentration has been show to improve endothelium dependent vasodilation in conditions associated with oxidative stress. Vitamin C infusion was maintained at the same rate while the ACh dose response was repeated.

Time frame: FBF response to ACh+Vitamin C will be measured during Phase 2 at the participants visit 9 which is ~11 weeks from their respective start date

Secondary Outcomes

Nightly Sleep Duration

Nightly sleep duration was calculated as the weighted average of weeknights and weekend values \[(5 x weekday sleep duration)+(2 x weekend sleep duration)/7\].

Time frame: Baseline