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Background We investigated the effects of individualised combined resistance and aerobic exercise on microvascular and macrovascular function in rheumatoid arthritis (RA) patients. Methods Forty age-matched, gender-matched and body mass index (BMI)-matched patients were allocated to either an exercise group, receiving a 6 months tailored aerobic and resistance exercise intervention, or controls receiving only information about the benefits of exercise. Participants were assessed for microvascular (acetylcholine (Ach) and sodium nitroprusside (SNP)) and macrovascular (flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)) endothelial function, maximal oxygen uptake, disease activity and severity (C-reactive protein (CRP), disease activity score 28 and health assessment questionnaire). Data were collected at baseline, 3 months and at the end of the intervention (6 months). Results At baseline, demographic, anthropometric, disease-related characteristics and endothelial function parameters were similar between the exercise and control groups (p>0.05). Repeated measures analysis of variance revealed a significant improvement in endothelial function parameters at 3 (GTN: p<0.001) or 6 months (Ach: p=0.016, SNP: p=0.045, FMD: p=0.016) in the exercise but not in the control group. Generalised estimated equations detected that maximal oxygen uptake was a strong predictor for the observed changes in Ach (p=0.009) and GTN (p<0.001) whereas logCRP for SNP (p=0.017) and GTN (p=0.008). Conclusions An exercise programme designed to meet individual needs and physical abilities significantly improves microvascular and macrovascular function in parallel with disease-related characteristics in RA patients. The potential long-term beneficial effects of such interventions at reducing cardiovascular risk in these patients merit further exploration. Clinical Trial Registration ISRCTN50861407.

Background No standardized index exists to assess cardiovascular responsiveness to angiotensin-II. We hypothesized that a standardized index of initial blood pressure response to angiotensin-II treatment would be associated with clinical outcomes. Methods Using data from the Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we developed an Angiotensin-II Initial MAP Response Index of Treatment Effect (AIMRITE) defined as (MAP at hr1 – MAP at baseline)/study drug dose. We assessed AIMRITE continuously and, based on observed distributions, we additionally categorized patients as “responsive” or “resistant”, with responsiveness defined by an AIMRITE ≥ 0.90 mmHg/ng/kg/min. The primary clinical outcome was 28-day mortality. Secondary outcomes included days alive and vasopressor- or ventilator- or renal replacement therapy-free at day-7. Biological outcomes included baseline renin, angiotensin-II, and renin/angiotensin-II ratio, and their change at hr3. Results Of 158 placebo patients, as expected, 157 (99%) had AIMRITE < 0.90 mmHg/ng/kg/min (median AIMRITE 0.02; IQR − 0.03–0.10). In contrast, 163 patients assigned to angiotensin-II had a median AIMRITE of 1.43 mmHg/ng/kg/min (IQR 0.35–2.83). Of these, 97 (60%) were responsive (median AIMRITE 2.55; IQR 1.66–4.12) and 66 (40%) were resistant (median AIMRITE 0.24; IQR 0.10–0.52). Each 1.0-unit increase in AIMRITE was associated with a 16% lower hazard of death (HR: 0.84 per-mmHg/ng/kg/min [95% CI 0.74–0.95], p  = 0.0062). Responsive patients had half the mortality hazard than resistant patients (HR: 0.50 [95% CI 0.32–0.78], p  = 0.0026) and placebo patients (HR 0.58 [95% CI 0.40–0.86], p  = 0.0064). Resistant patients had a similar mortality hazard to placebo (HR 1.17 [95% CI 0.80–1.72], p  = 0.41). Compared to resistant patients, responsive patients had lower baseline renin and renin/angiotensin-II ratio, but a greater decrease in both at hr3. When stratified by baseline renin level, mortality was highest in placebo patients with high renin (69%) and angiotensin-II resistant patients with low renin (61%). Conclusions Among patients with catecholamine-refractory vasodilatory shock treated with angiotensin-II, the AIMRITE was associated with mortality at day-28. Responsive angiotensin-II patients had higher survival versus both angiotensin-II resistant patients and those treated with placebo plus standard vasopressors. This index may serve as a prognostic indicator and early identifier of patients most likely to benefit from angiotensin-II.

Afferent neural transmission of temperature sensation from skin thermoreceptors to the central thermoregulatory system is important for the defense of body temperature against environmental thermal challenges. Here, we report a thermosensory pathway that triggers physiological heat-defense responses to elevated environmental temperature. Using in vivo electrophysiological and anatomical approaches in the rat, we found that neurons in the dorsal part of the lateral parabrachial nucleus (LPBd) glutamatergically transmit cutaneous warm signals from spinal somatosensory neurons directly to the thermoregulatory command center, the preoptic area (POA). Intriguingly, these LPBd neurons are located adjacent to another group of neurons that mediate cutaneous cool signaling to the POA. Functional experiments revealed that this LPBd-POA warm sensory pathway is required to elicit autonomic heat-defense responses, such as cutaneous vasodilation, to skin-warming challenges. These findings provide a fundamental framework for understanding the neural circuitry maintaining thermal homeostasis, which is critical to survive severe environmental temperatures.

To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia–peripheral arterial tonometry (RH-PAT) from the index finger. The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. clinicaltrials.gov Identifier: NCT02086526.

To examine the effects of low-intensity resistance exercise training (LIRET) and whole-body vibration training (WBVT) with an external weighted vest on arterial stiffness, wave reflection, brachial flow-mediated dilation (FMD), and physical performance in postmenopausal women. Thirty-three postmenopausal women were stratified by age, body mass index (BMI), and maximal voluntary contraction (MVC) (age, 65 ± 4 years; BMI, 23.3 ± 2.6 kg/m ; MVC, 17.4 ± 2.6 kg) and randomized into LIRET, WBVT, or a nonexercising control group for 12 weeks. Arterial stiffness, augmentation index (AIx), augmented pressure (AP), brachial FMD, gait speed and leg strength were measured at baseline and 12 weeks. WBVT induced improvements in pulse pressure amplification (PPA) (0.04 ± 0.02) compared to control (P = 0.048) and in wave reflection indices [AIx (-4.3 ± 1.4%) and AP (-2.9 ± 1.3 mmHg)] compared to LIRET (P = 0.039 and 0.048, respectively). WBVT (3.8 ± 1.4%) and LIRET (5.0 ± 1.5%) induced similar improvements in FMD compared to control (P = 0.029 and 0.008, respectively). WBVT and LIRET elicited similar increases in leg strength (P = 0.001 and 0.019, respectively), compared to no improvement in the control group. LIRET significantly increased gait speed compared to WBVT (P = 0.043). Although both WBVT and LIRET increased brachial artery FMD (systemic effect), WBVT seemed to be more efficacious in improving wave reflection and cardiac pulsatile load. Interestingly, LIRET elicited a significant improvement in gait speed. Both modalities seem effective in improving systemic endothelial function and muscle strength in postmenopausal women.

PurposeThis study examined physiological and perceptual parameters related to cold-induced vasodilation (CIVD) in the fingers and toes of people with paraplegia and compared them with responses observed in able-bodied individuals.MethodsSeven participants with paraplegia and seven able-bodied individuals participated in a randomized matched-controlled study involving left-hand and -foot immersion in cold water (8 ± 1 °C) for 40 min during exposure to cool (16 ± 1 °C), thermoneutral (23 ± 1 °C), and hot (34 ± 1 °C) ambient conditions.ResultsSimilar CIVD occurrence was observed in the fingers in the two groups. In toes, three of the seven participants with paraplegia revealed CIVDs: one in cool, two in thermoneutral, and three in hot conditions. No able-bodied participants revealed CIVDs in cool and thermoneutral conditions, while four revealed CIVDs in hot conditions. The toe CIVDs of paraplegic participants were counterintuitive in several respects: they were more frequent in cool and thermoneutral conditions (compared to the able-bodied participants), emerged in these conditions despite lower core and skin temperatures of these participants, and were evident only in cases of thoracic level lesions (instead of lesions at lower spinal levels).ConclusionOur findings demonstrated considerable inter-individual variability in CIVD responses in both the paraplegic and able-bodied groups. While we observed vasodilatory responses in the toes of participants with paraplegia that technically fulfilled the criteria for CIVD, it is unlikely that they reflect the CIVD phenomenon observed in able-bodied individuals. Taken together, our findings favor the contribution of central over peripheral factors in relation to the origin and/or control of CIVD.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T‐type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L‐ and T‐type calcium channel blocker (CCB)) or nifedipine (L‐type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium‐dependent vasodilator) and sodium nitroprusside (endothelium‐independent vasodilator) both with and without co‐infusion of N‐acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra‐arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co‐infusion of NAC did not affect endothelium‐dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks’ inhibition of T‐ and L‐type calcium channels augments endothelium‐dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T‐type calcium channel inhibition can counteract endothelial dysfunction. What is the central question of this study? Does T‐type calcium channel inhibition prevent age‐related endothelium dysfunction in humans? What is the main finding and its importance? Eight weeks of L+T‐type calcium channel blockade (CCB) increased endothelium‐dependent vasodilatation in the leg of otherwise healthy elderly males, while 8 weeks of L‐type CCB only did not. Thus, T‐type calcium channels may be involved in endothelium dysfunction.

PurposeCold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI).MethodsEleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured.ResultsFlavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05).ConclusionThese data suggest that cocoa flavanol ingestion does not alter finger CIVD.Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.

Abstract Rationale Exposure to combustion-derived air pollution is associated with an early (1–2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. Objectives To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation. Methods Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 μg/m3) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100–1,000 pmol/min), acetylcholine (5–20 μg/min), sodium nitroprusside (2–8 μg/min), and verapamil (10–100 μg/min) infusions. Measurements and Main Results Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were similar 24 hours after either exposure. Diesel exhaust increased plasma cytokine concentrations (tumor necrosis factor-α and interleukin-6, p < 0.05 for both) but appeared to reduce acetylcholine (p = 0.01), and bradykinin (p = 0.08) induced forearm vasodilatation. In contrast, there were no differences in either endothelium-independent (sodium nitroprusside and verapamil) vasodilatation or bradykinin-induced acute plasma tissue plasminogen activator release. Conclusions Twenty-four hours after diesel exposure, there is a selective and persistent impairment of endothelium-dependent vasodilatation that occurs in the presence of mild systemic inflammation. These findings suggest that combustion-derived air pollution may have important systemic and adverse vascular effects for at least 24 hours after exposure.

Purpose The dietary egg-protein hydrolysate Newtricious (NWT)-03 has previously demonstrated improvements in blood pressure and metabolic profiles. However, the long-term effects on vascular function and cardiometabolic risk markers are unknown. Methods Forty-four older (aged 60–75) adults with overweight/obesity experiencing elevated Subjective Cognitive Failures (SCF) were randomized into a 36-week, double-blind, placebo-controlled trial. Participants either consumed 5.7 g of an egg-protein hydrolysate (NWT-03) or maltodextrin placebo. Endothelial function (brachial artery flow-mediated vasodilation [FMD] and carotid artery reactivity [CAR] responses after a cold pressor test), arterial stiffness (carotid-to-femoral pulse wave velocity [PWV c-f ]), retinal microvascular calibers, and cardiometabolic risk markers (insulin sensitivity using a 7-point oral glucose tolerance test, serum lipid profiles, and blood pressure) were evaluated. Results FMD observed a non-significant trend towards a 0.3 percentage point (pp) increase in the intervention compared to the placebo group (95% CI: [0.0, 0.7]; p = 0.08), and a significant intervention effect was observed on CAR responses based on a 0.7 pp improvement after a cold pressor test (95% CI: [0.1, 1.3]; p = 0.03). No significant overall changes were observed for arterial stiffness as measured by PWV c-f . Retinal microvascular calibers and cardiometabolic parameters also did not change. Conclusion Long-term supplementation with 5.7 g of the egg-protein hydrolysate NWT-03 for 36 weeks improved vascular endothelial function in older adults with overweight/obesity experiencing elevated SCF, which may benefit cardiovascular disease risk. No overall changes in other vascular function markers, retinal microvascular calibers or cardiometabolic risk markers were observed. Clinical Trial Registration The study was registered at ClinicalTrials.gov in January 2021 as NCT04831203: https://clinicaltrials.gov/study/NCT04831203