Effects of 1 MHz Therapeutic Ultrasound on Limb Blood Flow and Microvascular Reactivity: A Randomized Pilot Trial

A randomized, double-blind, placebo-controlled, cross-over study where continuous therapeutic ultrasound (CUS; at 0.4 W/cm2), pulsed therapeutic ultrasound (PUS; at 20% duty cycle, 0.08 W/cm2), both at 1 MHz, and placebo (equipment on, no energy provided) were randomized and applied over the forearm of the non-dominant arm for 5 min in 10 young, healthy individuals. Absolute and peak forearm blood flow (FBF) were measured via Venous Occlusion Plethysmography. FBF was measured before, halfway, and after (immediately and 5 min after) the therapeutic ultrasound (TUS) intervention. Post-ischemic peak FBF was measured 10 min before and 10 min after the TUS intervention. A two-way repeated measures ANOVA (group × time) was selected to assess differences in FBF before, during, and after TUS treatment, and for peak FBF before and after TUS treatment. FBF increased 5 min after TUS in CUS compared to placebo (2.96 ± 1.04 vs. 2.09 ± 0.63 mL/min/100 mL of tissue, p < 0.05). PUS resulted in the greatest increase in Peak FBF at 10 min after US (Δ = 3.96 ± 2.02 mL/min/100 mL of tissue, p = 0.06). CUS at 1 MHz was an effective treatment modality for increasing FBF up to 5 min after intervention, but PUS resulted in the greatest increase in peak FBF at 10 min after intervention.

New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events.

Abstract P172: Endothelial Function In The Early Years After Delivery: Effect Of Adverse Pregnancy Outcomes And Activity Behaviors

Introduction: Adverse pregnancy outcomes (APOs) are independently associated with cardiovascular disease (CVD). Endothelial dysfunction may indicate early CVD and can be influenced by physical activity (PA) and sedentary behavior (SED). Hypothesis: We hypothesized women with a past APO would have worse endothelial function versus controls and that mid-pregnancy and current PA would be directly related while SED would be inversely related to endothelial function in the years soon after delivery. Methods: We used venous occlusion plethysmography to measure baseline forearm blood flow, reactive hyperemia, and vascular conductance (forearm blood flow/mean arterial pressure) in a case control study of 53 women 6 mo to 3 yrs after a singleton birth; 26% with past APO, 21% African American, mean age=33±1 yrs, mean BMI=27.4±0.9 kg/m 2 . Current and mid-pregnancy leisure time PA and weekday SED were assessed with validated questionnaires. We evaluated differences in endothelial function by APO exposure with t-tests and relations of endothelial function with PA and SED with Spearman correlations. Results: Baseline forearm blood flow (APO: 1.6±0.2; non-APO: 1.8±0.1 ml*min -1 *100 ml -1 tissue, p=0.3) and reactive hyperemia (APO: 13.2±2; non-APO: 11.4±1 ml*min -1 *100 ml -1 , p=0.8) were similar between groups. Vascular conductance was non-significantly lower in women with a past APO: 1.7x10 -2 versus 2.1x10 -2 ml*min -1 *100 ml -1 mmHg -1 in women without a past APO, p<0.10. Vascular conductance was related to current and mid-pregnancy SED (figure) but not PA (r=0.2 and r=0.06, p>0.05 for mid-pregnancy and current PA). Associations of mid-pregnancy and current SED with vascular conductance after delivery persisted after adjustment for age and BMI. Conclusions: Forearm vascular conductance tended to be lower soon after delivery in women with an APO. Mid-pregnancy and current SED were inversely related to forearm vascular conductance and may represent targets for interventions aimed at improving endothelial function after delivery.

Mechanisms Underlying Vascular Endothelial Growth Factor Receptor Inhibition–Induced Hypertension

Drugs targeting the VEGF (vascular endothelial growth factor) signaling pathway are approved for several malignancies. Unfortunately, VEGF inhibitors lead to hypertension in 30% to 80% patients. Reduced nitric oxide synthase activity, microvascular rarefaction, and increased vascular resistance have been proposed as potential mechanisms. We aimed to assess these mechanisms in patients receiving the VEGF inhibitor, pazopanib, for cancer. Twenty-seven normotensive patients with advanced solid malignancies received pazopanib 800 mg od. Endothelial function was assessed using forearm plethysmography with intraarterial infusions of acetylcholine. Detailed hemodynamic measurements were taken. Density and diameter of the conjunctival and episcleral microvasculature were evaluated using hemoglobin video imaging. Measurements were taken at baseline, 2, and 12 weeks after initiation of pazopanib or earlier if patients became hypertensive. By the end of the trial, systolic blood pressure increased by 12 mm Hg (95% CI, 4–19 mm Hg; P =0.003), diastolic by 10 mm Hg (95% CI, 5–15 mm Hg; P <0.001), and peripheral vascular resistance by 888 dynes×s/cm 5 (95% CI, 616–1168 dynes×s/cm 5 ; P <0.001). Forearm blood flow improved: Ratio of acetylcholine response at end of trial/baseline was 2.8 (95% CI, 1.84–4.25; P <0.001). Microvascular density in the sclera was reduced by −15.5% (95% CI, −25.7% to −5.3%; P =0.003) and diameter by −2.09 µm (95% CI, −3.95 to −0.19 µm; P =0.03). A post hoc colorimetric assay revealed that pazopanib inhibited acetylcholinesterase activity by −56% (95% CI, −62% to −52%; P <0.001). Unexpectedly, pazopanib led to an increase in acetylcholine-mediated forearm blood flow response, likely due to the inhibition of acetylcholinesterase activity. Pazopanib increased peripheral vascular resistance and reduced microvascular density and diameter, suggesting that microvascular rarefaction could be one of the key mechanisms behind VEGF inhibition–induced hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01392352.

Cardiovascular and Autonomic Responses after a Single Bout of Resistance Exercise in Men with Untreated Stage 2 Hypertension

The aim of this paper is to assess the integrated responses of ambulatory blood pressure (BP), cardiac autonomic modulation, spontaneous baroreflex sensitivity (BRS), and vascular reactivity after a single bout of resistance exercise (RE) in men with stage 2 hypertension who have never been treated before. Ten hypertensive men were subjected to a RE session of three sets of 20 repetitions and an intensity of 40% of the 1-repetition maximum (RM) test in seven different exercises. For the control (CTR) session, the volunteers were positioned on the exercise machines but did not perform any exercise. Forearm blood flow was measured by venous occlusion plethysmography. We also analyzed the heart rate variability (HRV), ambulatory BP, blood pressure variability (BPV), and BRS. All measurements were performed at different timepoints: baseline, 20 min, 80 min, and 24 h after both RE and CTR sessions. There were no differences in ambulatory BP over the 24 h between the RE and CTR sessions. However, the area under the curve of diastolic BP decreased after the RE session. Heart rate (HR) and cardiac output increased for up to 80 and 20 min after RE, respectively. Similarly, forearm blood flow, conductance, and vascular reactivity increased 20 min after RE ( p < 0.05 ). In contrast, HRV and BRS decreased immediately after exercise and remained lower for 20 min after RE. We conclude that a single bout of RE induced an increase in vascular reactivity and reduced the pressure load by attenuating AUC of DBP in hypertensive individuals who had never been treated with antihypertensive medications.

Blunted Hyperemic Response to Mental Stress in Young, Non-Hispanic Black Men is not Impacted by Acute Dietary Nitrate Supplementation

Non-Hispanic black individuals have an elevated prevalence of cardiovascular disease in large part, related to impaired vascular function, secondary to reduced nitric oxide (NO) bioavailability. Nitrate supplementation increases NO bioavailability and improves vascular function. This study tested the hypothesis that forearm blood flow responses in young, non-Hispanic, black (BL) men during mental stress are blunted relative to, non-Hispanic, white (WH) men and that acute dietary nitrate supplementation would improve this response in BL men. This study was comprised of two parts. Phase 1 investigated the blood flow responses between young, BL and WH men whereas Phase 2 investigated the effect of acute nitrate supplementation in a subset of the BL men. Eleven (9 for Phase 2) BL and 8 WH men (23 ± 3 vs. 24 ± 4 y, respectively) participated. During each visit, brachial artery blood flow was assessed during 3 min of mental stress. Phase 1 was completed in one visit, while Phase 2 was completed over two visits separated by ~1-wk. During Phase 2, data were collected before and 2-h post-consumption of a beverage high in nitrate content or nitrate depleted. In Phase 1, peak forearm blood flow (FBF, P < 0.01), total FBF (P < 0.05), and forearm vascular conductance (P < 0.001) were blunted in the BL. During Phase 2, pre-beverage responses were unaffected following beverage consumption (P > 0.05 for all). Young, BL men have blunted microvascular vasodilatory responses to acute mental stress, which may not be altered following acute nitrate supplementation.

Acute Effect of Coconut Oil on Peak Forearm Blood Flow in Healthy Men: A Randomized Crossover Trial

Background: A high-fat meal can induce vascular dysfunction. Despite containing a high amount of saturated fats, coconut oil is claimed to have cardiovascular health benefits. However, the information regarding the acute effect of coconut oil on vascular function in humans is unknown. Objective: To determine the effects of coconut oil ingestion experiment (Coco) on peak forearm blood flow (FBFpeak) and plasma biomarkers in healthy subjects. Materials and Methods: Seventeen healthy young men completed two separate experimental visits, Coco and control experiment (Con) in random order. The outcomes were FBFpeak measured by venous occlusion plethysmography and biomarkers as plasma triglycerides, free fatty acids, and malondialdehyde. The outcomes were collected at baseline (12 hour fasting), 2-hour and 4-hour after Coco (45 mL) in the Coco visit and at the same timeline in the control visit. Statistical analyses were performed to compare the data between the two experimental groups and within the group. Results: FBFpeak at 4-hour was significantly increased from the baseline (24.2±4.7 versus 21.7±3.8 mL/100 mL tissue.minute, p=0.009). Plasma triglycerides at 2-hour (75±25 mg/dL, p=0.03) and 4-hour (72±22 mg/dL, p=0.039) were significantly increased from the baseline (65±20 mg/dL). Coco significantly increased plasma free fatty acids at 2-hour (125.1±60.3 μEq/L, p=0.042) and at 4-hour (166.9±35.3 μEq/L, p<0.001) compared to the baseline (87.2±34.0 μEq/L). There were no significant changes in vascular resistance and plasma malondialdehyde. Conclusion: Coconut oil augmented vascular function in healthy young men by increasing FBFpeak despite the accompanying postprandial elevations of plasma triglycerides and free fatty acids. Keywords: Virgin coconut oil, Peak forearm blood flow, Vascular function, Saturated fatty acid, Medium chain triglyceride

Regular Aerobic Exercise Counteracts Endothelial Vasomotor Dysfunction Associated With Insufficient Sleep

Insufficient sleep is associated with endothelial vasomotor dysfunction and increased cardiovascular risk. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn, reducing cardiovascular risk. We tested the hypotheses that regular aerobic exercise would: 1) improve endothelial vasodilation; and 2) decrease ET-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep <7 h/night. Thirty-six healthy, middle-aged adults were studied: 16 with normal sleep duration (age: 57±2 yr; sleep duration: 7.4±0.1 h/night) and 20 with short sleep duration (56±1 yr; 6.2±0.1 h/night). The 20 short sleepers completed a 3-month aerobic exercise training intervention. Forearm blood flow was determined (via plethysmography) in response to intra-arterial acetylcholine (ACh), BQ-123 (ETAreceptor antagonist), ACh+BQ-123 and sodium nitroprusside. Forearm blood flow responses to ACh were lower (20%; P<0.05) in the short (from 4.2±0.2 to 10.5±0.6 mL/100 mL tissue/min) vs normal (4.2±0.2 to 12.7±0.6 mL/100 mL tissue/min) sleepers. In response to BQ-123, the short sleep group had a significantly greater increase in resting forearm blood flow than the normal sleep group (~25% vs ~8%). ACh+BQ-123 resulted in a significant (~25%) increase in the ACh-vasodilation in the short sleep group only. After exercise training, although nightly sleep duration was unchanged (6.4±0.1 h/night), ACh-mediated vasodilation was significantly higher (~20%), ET-1-mediated vasoconstriction was significantly lower (~80%) and the vasodilator response to ACh was not increased with ETAreceptor blockade. Regular aerobic exercise, independent of changes in nightly sleep duration, can counteract insufficient sleep-related endothelial vasomotor dysfunction.

Circulating endothelial cell derived microvesicles are elevated with hypertension and associated with endothelial dysfunction

The purpose of this study was to determine (1) if circulating endothelial microvesicles (EMVs) are elevated in hypertensive adults and (2) whether circulating EMVs are associated with hypertension-related endothelial vasodilator dysfunction. Circulating EMVs (CD31+/42b–) were determined in 30 middle-aged adults (55 ± 1 years): 15 normotensive (10 males, 5 females; blood pressure 114/71 ± 2/1 mm Hg) and 15 hypertensive (10 males, 5 females; blood pressure 142/87 ± 2/2 mm Hg). Forearm blood flow (FBF) (via plethysmography) was assessed by intra-arterial infusion of acetylcholine and sodium nitroprusside. Circulating EMVs were ∼65% higher (P < 0.05) in hypertensive (157 ± 10 EMVs/μL) than in normotensive (96 ± 10 EMVs/μL) adults. FBF to acetylcholine was significantly lower (∼30%) in the hypertensive group (from 5.0 ± 0.4 to 11.8 ± 0.8 mL·100 mL tissue–1·min–1 versus from 4.4 ± 0.2 to 15.6 ± 0.8 mL·100 mL tissue–1·min–1). Circulating EMVs were inversely associated with vasodilation (r = –0.65; P < 0.05). Hypertension is associated with elevated circulating levels of EMVs. EMVs may serve as a biomarker of, and contribute to, blood pressure related endothelial dysfunction.