Locomotor Muscle Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction

While there is emerging evidence of peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction (HFpEF) that may be related to systemic inflammation and redox imbalance, disease-related changes in locomotor muscle microvascular responsiveness have not been determined. This study combined passive leg movement and biomarker assessments of inflammation and oxidative damage to determine the magnitude and mechanisms of lower limb microvascular function in patients with HFpEF (71±1 years; n=44) compared with healthy, similarly aged controls (68±2 years; n=39). Leg blood flow, heart rate, mean arterial pressure, and stroke volume were assessed, and plasma biomarkers of inflammation and oxidative damage were also determined. A significantly attenuated passive leg movement–induced peak change in leg blood flow (263±25 versus 371±31 mL/min, HFpEF versus control) and leg vascular conductance (2.99±0.32 versus 3.88±0.34 mL/min per mm Hg, HFpEF versus control) was observed in patients compared with controls. Similarly, the total hyperemic response to passive leg movement, expressed as leg blood flow AUC and leg vascular conductance AUC , was ≈40% less in patients with HFpEF versus control. Significantly greater C-reactive protein, IL-6 (interleukin-6), and malondialdehyde were observed in patients with HFpEF but were not correlated with passive leg movement responses. These data provide new evidence of a decline in lower limb microvascular function within a milieu of vascular inflammation that may contribute to locomotor muscle dysfunction in patients with HFpEF.

Control of low flow regions in the cortical vasculature determines optimal arterio-venous ratios

The energy demands of neurons are met by a constant supply of glucose and oxygen via the cerebral vasculature. The cerebral cortex is perfused by dense, parallel arterioles and venules, consistently in imbalanced ratios. Whether and how arteriole–venule arrangement and ratio affect the efficiency of energy delivery to the cortex has remained an unanswered question. Here, we show by mathematical modeling and analysis of the mapped mouse sensory cortex that the perfusive efficiency of the network is predicted to be limited by low-flow regions produced between pairs of arterioles or pairs of venules. Increasing either arteriole or venule density decreases the size of these low-flow regions, but increases their number, setting an optimal ratio between arterioles and venules that matches closely that observed across mammalian cortical vasculature. Low-flow regions are reshaped in complex ways by changes in vascular conductance, creating geometric challenges for matching cortical perfusion with neuronal activity.

ATP and acetylcholine interact to modulate vascular tone and α1-adrenergic vasoconstriction in humans

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α1‑adrenergic vasoconstriction compared to combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6F, 7M) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP+ACh, SNP+ACh, and ATP+SNP wherein the second dilator was co-infused after attaining steady-state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48±4; ACh: 57±6; SNP: 53±6 ml·min-1·100 mmHg-1; P≥0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP+ACh: 45±9 vs. SNP+ACh: 18±7 and ATP+SNP: 26±4 ml·min-1·100 mmHg-1, P<0.05). Phenylephrine was subsequently infused to evaluate α1‑adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh vs. SNP (ΔFVC, -25±3 and -29±4 vs. -48±3%; P<0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP+ACh (-13±3%; P<0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP+ACh: -26±3%; ATP+SNP: -31±4%; both P<0.05 vs. ATP+ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α1‑adrenergic vasoconstriction in humans.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

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.

Improvements in vascular function in response to acute lower limb heating in young healthy males and females

Regular exposure to passive heat stress improves vascular function, but the optimal heating prescription remains undefined. Local limb heating is more feasible than whole body heating, but the evidence demonstrating its efficacy is lacking. The purpose of this study was to determine whether acute improvements in vascular function can be achieved with lower limb heating in 16 young healthy individuals (8 female, 8 male). In separate visits, participants underwent 45-min of ankle- and knee-level hot water immersion (45 °C). A subset of 7 participants also participated in a time-control visit. Endothelial function was assessed through simultaneous brachial and superficial femoral artery flow-mediated dilation (FMD) tests. Macrovascular function was quantified by %FMD, while microvascular function was quantified by vascular conductance during reactive hyperemia. Arterial stiffness was assessed through carotid-femoral and femoral-foot pulse wave velocity (PWV). Plasma concentrations of interleukin-6 and extracellular heat shock protein-72 (eHSP72) were used as indicators of inflammation. Our findings showed that 45-min of lower limb heating - regardless of condition - acutely improved upper limb macrovascular endothelial function (i.e., brachial %FMD; Pre: 4.6±1.7 vs. Post: 5.4±2.0%; P=0.004) and lower limb arterial stiffness (i.e., femoral-foot PWV; Pre: 8.4±1.2 vs. Post: 7.7±1.1 m/s; P=0.011). However, only knee-level heating increased upper limb microvascular endothelial function (i.e., brachial peak vascular conductance; Pre: 6.3±2.7 vs. Post: 7.8±3.5 ml/min⋅mmHg; P≤0.050) and plasma eHSP72 concentration (Pre: 12.4±9.4 vs. Post: 14.8±9.8 ng/ml; P≤0.050). These findings show that local lower limb heating acutely improves vascular function in younger individuals, with knee-level heating improving more outcome measures.

Platelets Do Not Alter Flow-Mediated Dilation or Arterial Conduction in vivo

The aim of this study was to investigate whether platelets contribute to shear stress and vascular conductance in the iliac vascular bed in vivo. Flow-mediated dilation of pig iliac was induced by downstream injection of acetylcholine (50 μg), and separately, conductance (ΔF/ΔP) was calculated. This was carried out before and after removal of 1 L of arterial blood in 240 mL increments, and each 240 mL was spun in a centrifuge (1,500 rcf for 7 min); platelet-rich plasma was replaced with equal volume of heparinised saline and reinjected. The circulating platelet count fell from 369 × 10⁹/L (<i>n</i> = 5) to 165 × 10⁹/L (<i>p</i> = 0.01; <i>n</i> = 4; Student’s unpaired <i>t</i>). An increase in flow led to an increase in the iliac diameter by 0.49 ± 0.03 mm (mean ± SEM) before platelet reduction and 0.55 ± 0.05 mm after (<i>p</i> = 0.36, Student’s paired <i>t</i>, <i>n</i> = 5); the change in arterial conductance was also not significantly affected by platelet reduction, control: 1.44 ± 0.34 mL/min/mm Hg, after platelet reduction: 1.39 ± 0.04 mm (<i>p</i> = 0.55, Student’s paired <i>t</i>, <i>n</i> = 4). Therefore, platelets do not contribute to shear stress or conductance in vivo.

Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension

We have previously shown that elevations in intracranial pressure (ICP) within physiological ranges in normotensive animals increase arterial pressure; termed the intracranial baroreflex. Hypertension is associated with alterations in reflexes which maintain arterial pressure however, whether the intracranial baroreflex is altered is not known. Hence, in the present study, we tested the hypothesis that in hypertension, physiological increases in ICP would not be accompanied with an increase in arterial pressure. Renovascular hypertension was associated with no change in heart rate, renal blood flow or ICP levels compared to the normotensive group. ICV infusion of saline produced a ramped increase in ICP of 20 ± 1 mmHg. This was accompanied by an increase in arterial pressure (16 ± 2 mmHg) and a significant decrease in renal vascular conductance. ICV infusion of saline in the hypertensive group also increased ICP (19 ± 2 mmHg). However, the increase in arterial pressure was significantly attenuated in the hypertensive group (5 ± 2 mmHg). Ganglionic blockade abolished the increase in arterial pressure in both groups to increased ICP. Our data indicates that physiological increases in ICP lead to increases in arterial pressure in normotensive animals but this is severely attenuated in renovascular hypertension.