Ashley D. Nelson

Evidence of microvascular dysfunction in heart failure with preserved ejection fraction

Objective While vascular dysfunction is well defined in patients with heart failure (HF) with reduced ejection fraction (HFrEF), disease-related alterations in the peripheral vasculature of patients with HF with preserved ejection fraction (HFpEF) are not well characterised. Thus, we sought to test the hypothesis that patients with HFpEF would demonstrate reduced vascular function, at the conduit artery and microvascular levels, compared with controls. Methods We examined conduit artery function via brachial artery flow-mediated dilation (FMD) and microvascular function via reactive hyperaemia (RH) following 5 min of ischaemia in 24 patients with Class II–IV HFpEF and 24 healthy controls matched for age, sex and brachial artery diameter. Results FMD was reduced in patients with HFpEF compared with controls (HFpEF: 3.1±0.7%; Controls: 5.1±0.5%, p=0.03). However, shear rate at time of peak brachial artery dilation was lower in patients with HFpEF compared with controls (HFpEF: 42 070±4018/s; Controls: 69 018±9509/s, p=0.01), and when brachial artery FMD was normalised for the shear stimulus, cumulative area-under-the-curve (AUC) at peak dilation, the between-group differences were eliminated (HFpEF: 0.11±0.03%/AUC; Controls: 0.09±0.01%/AUC, p=0.58). RH, assessed as AUC, was lower in patients with HFpEF (HFpEF: 454±35 mL; Controls: 660±63 mL, p<0.01). Conclusions Collectively, these data suggest that maladaptations at the microvascular level contribute to the pathophysiology of HFpEF, while conduit artery vascular function is not diminished beyond that which occurs with healthy aging.

Symmorphosis and skeletal muscle V̇O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human.

The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption ( V̇O2 max ) such that no single process is limiting or in excess at V̇O2 max . The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance‐trained humans. Among untrained individuals, V̇O2 max is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals, V̇O2 max is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity.

Impaired skeletal muscle vasodilation during exercise in heart failure with preserved ejection fraction

BACKGROUND Exercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately increase blood flow to the exercising muscle. METHODS We evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients (n=21; 68 ± 2 yrs) and healthy controls (n=20; 71 ± 2 yrs). RESULTS HFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0-5-10-15 W; HFpEF, n=13; Controls, n=16), LBF was not different at 0 W and 5 W, but was 15-25% lower in HFpEF compared to controls at 10 W and 15 W (P<0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0 W and 5 W, but was 15-20% lower in HFpEF compared to controls at 10 W and 15 W (P<0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. CONCLUSIONS These data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population.

Nitric oxide-mediated vascular function in sepsis using passive leg movement as a novel assessment: a cross-sectional study

Post-cuff occlusion flow-mediated dilation (FMD) is a proposed indicator of nitric oxide (NO) bioavailability and vascular function. FMD is reduced in patients with sepsis and may be a marker of end organ damage and mortality. However, FMD likely does not solely reflect NO-mediated vasodilation, is technically challenging, and often demonstrates poor reproducibility. In contrast, passive leg movement (PLM), a novel methodology to assess vascular function, yields a hyperemic response that is predominately NO-dependent, reproducible, and easily measured. This study evaluated PLM as an approach to assess NO-mediated vascular function in patients with sepsis. We hypothesized that PLM-induced hyperemia, quantified by the increase in leg blood flow (LBF), would be attenuated in sepsis. In a cross-sectional study, 17 subjects in severe sepsis or septic shock were compared with 16 matched healthy controls. Doppler ultrasound was used to assess brachial artery FMD and the hyperemic response to PLM in the femoral artery. FMD was attenuated in septic compared with control subjects (1.1 ± 1.7% vs. 6.8 ± 1.3%; values are means ± SD). In terms of PLM, baseline LBF (196 ± 33 ml/min vs. 328 ± 20 ml/min), peak change in LBF from baseline (133 ± 28 ml/min vs. 483 ± 86 ml/min), and the LBF area under the curve (16 ± 8.3 vs. 143 ± 33) were all significantly attenuated in septic subjects. Vascular function, as assessed by both FMD and PLM, is attenuated in septic subjects compared with controls. These data support the concept that NO bioavailability is attenuated in septic subjects, and PLM appears to be a novel and feasible approach to assess NO-mediated vascular function in sepsis.

Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise

We investigated the contribution of group III/IV muscle afferents to carotid baroreflex resetting during electrically evoked (no central command) and voluntary (requiring central command) isometric knee extension exercise. Lumbar intrathecal fentanyl was used to attenuate the central projection of μ‐opioid receptor‐sensitive group III/IV leg muscle afferent feedback. Spontaneous carotid baroreflex control was assessed by loading and unloading the carotid baroreceptors with a variable pressure neck chamber. Group III/IV muscle afferents did not influence spontaneous carotid baroreflex responsiveness at rest or during exercise. Afferent feedback accounted for at least 50% of the exercise‐induced increase in the carotid baroreflex blood pressure and heart rate operating points, adjustments that are critical for an appropriate cardiovascular response to exercise. These findings suggest that group III/IV muscle afferent feedback is, independent of central command, critical for the resetting of the carotid baroreflex blood pressure and heart rate operating points, but not for spontaneous baroreflex responsiveness.

Single passive leg movement assessment of vascular function: Contribution of nitric oxide

Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol 123: 1468-1476, 2017. First published August 31, 2017; doi:10.1152/japplphysiol.00533.2017.-The assessment of passive leg movement (PLM)-induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCAUC). l-NMMA significantly attenuated ΔLBFpeak [492 ± 153 (l-NMMA) vs. 719 ± 238 (control) ml/min], LBFAUC [57 ± 34 (l NMMA) vs. 147 ± 63 (control) ml], ΔLVCpeak [4.7 ± 1.1 (l-NMMA) vs. 8.0 ± 3.0 (control) ml·min-1·mmHg-1], and LVCAUC [0.5 ± 0.3 (l-NMMA) vs. 1.6 ± 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for ΔLBFpeak, r = 0.85 for LBFAUC, r = 0.94 for ΔLVCpeak, and r = 0.95 for LVCAUC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability.

Altered skeletal muscle mitochondrial phenotype in COPD: disease vs. disuse

Patients with chronic obstructive pulmonary disease (COPD) exhibit an altered skeletal muscle mitochondrial phenotype, which often includes reduced mitochondrial density, altered respiratory function, and elevated oxidative stress. As this phenotype may be explained by the sedentary lifestyle that commonly accompanies this disease, the aim of this study was to determine whether such alterations are still evident when patients with COPD are compared to control subjects matched for objectively measured physical activity (PA; accelerometry). Indexes of mitochondrial density [citrate synthase (CS) activity], respiratory function (respirometry in permeabilized fibers), and muscle oxidative stress [4-hydroxynonenal (4-HNE) content] were assessed in muscle fibers biopsied from the vastus lateralis of nine patients with COPD and nine PA-matched control subjects (CON). Despite performing similar levels of PA (CON: 18 ± 3, COPD: 20 ± 7 daily minutes moderate-to-vigorous PA; CON: 4,596 ± 683, COPD: 4,219 ± 763 steps per day, P > 0.70), patients with COPD still exhibited several alterations in their mitochondrial phenotype, including attenuated skeletal muscle mitochondrial density (CS activity; CON 70.6 ± 3.8, COPD 52.7 ± 6.5 U/mg, P < 0.05), altered mitochondrial respiration [e.g., ratio of complex I-driven state 3 to complex II-driven state 3 (CI/CII); CON: 1.20 ± 0.11, COPD: 0.90 ± 0.05, P < 0.05), and oxidative stress (4-HNE; CON: 1.35 ± 0.19, COPD: 2.26 ± 0.25 relative to β-actin, P < 0.05). Furthermore, CS activity ( r = 0.55), CI/CII ( r = 0.60), and 4-HNE ( r = 0.49) were all correlated with pulmonary function, assessed as forced expiratory volume in 1 s ( P < 0.05), but not PA ( P > 0.05). In conclusion, the altered mitochondrial phenotype in COPD is present even in the absence of differing levels of PA and appears to be related to the disease itself. NEW & NOTEWORTHY Chronic obstructive pulmonary disease (COPD) is associated with debilitating alterations in the function of skeletal muscle mitochondria. By comparing the mitochondrial phenotype of patients with COPD to that of healthy control subjects who perform the same amount of physical activity each day, this study provides evidence that many aspects of the dysfunctional mitochondrial phenotype observed in COPD are not merely due to reduced physical activity but are likely related to the disease itself.

Symmorphosis in patients with chronic heart failure

to the editor: Considering our groups interest in the mechanisms that constrain aerobic capacity in various populations (1–4), we read the article by van der Zwaard et al. ([6][1]) with great interest. Indeed, we commend the authors on their work, which certainly had several innovative components

Impact of age on the development of fatigue during large and small muscle mass exercise

To examine the impact of aging on neuromuscular fatigue following cycling (CYC; large active muscle mass) and single-leg knee-extension (KE; small active muscle mass) exercise, 8 young (25 ± 4 years) and older (72 ± 6 years) participants performed CYC and KE to task failure at a given relative intensity (80% of peak power output). The young also matched CYC and KE workload and duration of the old (iso-work comparison). Peripheral and central fatigue were quantified via pre-/postexercise decreases in quadriceps twitch torque (∆Qtw, electrical femoral nerve stimulation) and voluntary activation (∆VA). Although young performed 77% and 33% more work during CYC and KE, respectively, time to task failure in both modalities was similar to the old (~9.5 min; P > 0.2). The resulting ΔQtw was also similar between groups (CYC ~40%, KE ~55%; P > 0.3); however, ∆VA was, in both modalities, approximately double in the young (CYC ~6%, KE ~9%; P < 0.05). While causing substantial peripheral and central fatigue in both exercise modalities in the old, ∆Qtw in the iso-work comparison was not significant (CYC; P = 0.2), or ~50% lower (KE; P < 0.05) in the young, with no central fatigue in either modality ( P > 0.4). Based on iso-work comparisons, healthy aging impairs fatigue resistance during aerobic exercise. Furthermore, comparisons of fatigue following exercise at a given relative intensity mask the age-related difference observed following exercise performed at the same workload. Finally, although active muscle mass has little influence on the age-related difference in the rate of fatigue at a given relative intensity, it substantially impacts the comparison during exercise at a given absolute intensity.