Andrew Haynes

Brachial artery adaptation to lower limb exercise training: Role of shear stress

Lower limb exercise increases upper limb conduit artery blood flow and shear stress, and leg exercise training can enhance upper limb vascular function. We therefore examined the contribution of shear stress to changes in vascular function in the nonexercising upper limbs in response to lower limb cycling exercise training. Initially, five male subjects underwent bilateral brachial artery duplex ultrasound to measure blood flow and shear responses to 30-min cycling exercise at 80% of maximal heart rate. Responses in one forearm were significantly (P < 0.05) attenuated via cuff inflation throughout the exercise bout. An additional 11 subjects participated in an 8-wk cycle training study undertaken at a similar intensity, with unilateral cuff inflation around the forearm during each exercise bout. Bilateral brachial artery flow-mediated dilation responses to a 5-min ischemic stimulus (FMD%), an ischemic handgrip exercise stimulus (iEX), and endothelium-independent NO donor administration [glyceryl trinitrate (GTN)] were measured at 2, 4, and 8 wk. Cycle training increased FMD% in the noncuffed limb at week 2, after which time responses returned toward baseline levels (5.8 ± 4.1, 8.6 ± 3.8, 7.4 ± 3.5, 6.0 ± 2.3 at 0, 2, 4 and 8 wk, respectively; ANOVA: P = 0.04). No changes in FMD% were observed in the cuffed arm. No changes were evident in response to iEX or GTN in either the cuffed or noncuffed arms (P > 0.05) across the 8-wk intervention period. Our data suggest that lower limb cycle training induces a transient increase in upper limb vascular function in healthy young humans, which is, at least partly, mediated via shear stress.

Evidence for Shear Stress–Mediated Dilation of the Internal Carotid Artery in Humans

Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries. To explore the hypothesis that shear stress contributes to hypercapnic internal carotid dilation in humans, temporal changes in internal and common carotid shear rate and diameter, along with changes in middle cerebral artery velocity, were simultaneously assessed in 18 subjects at rest and during hypercapnia (6% carbon dioxide). Middle cerebral artery velocity increased significantly (69±10–103±17 cm/s; P<0.01) along with shear in both the internal (316±52–518±105 1/s; P<0.01) and common (188±40–275±61 1/s; P<0.01) carotids. Diameter also increased (P<0.01) in both carotid arteries (internal: +6.3±2.9%; common: +5.8±3.0%). Following hypercapnia onset, there was a significant delay between the onset of internal carotid shear (22±12 seconds) and diameter change (85±51 seconds). This time course is associated with shear-mediated dilation of larger conduit arteries in humans. There was a strong association between change in shear and diameter of the internal carotid (r=0.68; P<0.01). These data indicate, for the first time in humans, that shear stress is an important stimulus for hypercapnic vasodilation of the internal carotid artery. The combination of a hypercapnic stimulus and continuous noninvasive, high-resolution assessment of internal carotid shear and dilation may provide novel insights into the function and health of the clinically important extracranial arteries in humans.

Eccentric Cycling: A Promising Modality for Patients with Chronic Heart Failure

Purpose Chronic heart failure (CHF) is characterized by dyspnea and poor exercise tolerance, which decreases aerobic capacity (V˙O2peak), a measure strongly correlated with quality of life and mortality. In healthy populations, eccentric (ECC) cycling can be performed at a lower oxygen demand for matched workload, compared with concentric (CON) cycling, but few studies have previously investigated ECC cycling in CHF. We hypothesized that, when matched for external workload (W), an ECC cycling bout would be performed at a lower cardiorespiratory load (V˙O2) than CON in patients with CHF. Methods Eleven CHF patients (10 males) with impaired left ventricular systolic function (ejection fraction 31% ± 12%) completed a CON V˙O2peak test, with the subsequent ECC and CON protocols set at 70% of individual maximal CON power (W). Oxygen consumption (V˙O2), RER, minute ventilation (V˙E), HR, and rate pressure product were compared between conditions. Results ECC was performed at a lower V˙O2 (12.3 ± 1.3 vs 14.1 ± 0.8 mL·kg−1·min−1, P = 0.01), RER (0.92 ± 0.02 vs 0.96 ± 0.01, P = 0.01), and V˙E (36.5 ± 4.4 vs 40.2 ± 2.0 L·min−1, P = 0.04) in comparison with CON, despite both conditions being performed at matched workloads. HR (101 ± 5 vs 96 ± 1 bpm, P = 0.06) and rate pressure product (13,539 ± 788 vs 11,911 ± 227 bpm·mm Hg−1, P = 0.15) were not significantly different between conditions. Conclusion When matched for external workload, ECC cycling can be performed with a lower oxygen demand than CON in patients with CHF. Eccentric cycling is a promising modality for cardiac rehabilitation in severely deconditioned patients with CHF.

Acute impact of conventional and eccentric cycling on platelet and vascular function in patients with chronic heart failure

Evidence-based guidelines recommend exercise therapy for patients with chronic heart failure (CHF). Such patients have increased atherothrombotic risk. Exercise can transiently increase platelet activation and reactivity and decrease vascular function in healthy participants, although data in CHF are scant. Eccentric (ECC) cycling is a novel exercise modality that may be particularly suited to patients with CHF, but the acute impacts of ECC cycling on platelet and vascular function are currently unknown. Our null hypothesis was that ECC and concentric (CON) cycling, performed at matched external workloads, would not induce changes in platelet or vascular function in patients with CHF. Eleven patients with heart failure with reduced ejection fraction (HFrEF) took part in discrete bouts of ECC and CON cycling. Before and immediately after exercise, vascular function was assessed by measuring diameter and flow-mediated dilation (FMD) of the brachial artery. Platelet function was measured by the flow cytometric determination of glycoprotein IIb/IIIa activation and granule exocytosis in the presence and absence of platelet agonists. ECC cycling increased baseline artery diameter (pre: 4.0 ± 0.8 mm vs. post: 4.2 ± 0.7 mm; P = 0.04) and decreased FMD%. When changes in baseline artery diameter were accounted for, the decrease in FMD post-ECC cycling was no longer significant. No changes were apparent after CON. Neither ECC nor CON cycling resulted in changes to any platelet-function measures (all P > 0.05). These results suggest that both ECC and CON cycling, at a moderate intensity and short duration, can be performed by patients with HFrEF without detrimental impacts on vascular or platelet function.NEW & NOTEWORTHY This is the first evidence to indicate that eccentric (ECC) cycling can be performed relatively safely by patients with chronic heart failure (CHF), as it did not result in impaired vascular or platelet function compared with conventional cycling. This is important, as acute exercise can transiently increase atherothrombotic risk, and ECC cycling is a novel exercise modality that may be particularly suited to patients with CHF.

Relationship between monocyte‐platelet aggregation and endothelial function in middle‐aged and elderly adults

Low‐grade inflammation, endothelial dysfunction, and platelet hyper‐reactivity to agonists are associated with an increased risk of cardiovascular events. In vitro and animal studies infer an inverse mechanistic relationship between platelet activation and the production of endothelium‐derived nitric oxide and prostacyclin. This concept is supported by evidence of an inverse relationship between endothelial function and platelet activation in high‐risk cardiac patients. The aim of this study was to investigate what relationship, if any, exists between platelet and endothelial function in healthy, middle‐aged, and elderly adults. In 51 participants (18 male, 33 post menopausal female), endothelial function was assessed by flow‐mediated dilation (FMD). Platelet function was assessed by flow cytometric determination of glycoprotein IIb/IIIa activation (measured by PAC‐1 binding), granule exocytosis (measured by surface P‐selectin expression), and monocyte‐platelet aggregates (MPAs), with and without stimulation by canonical platelet agonists adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Correlation analysis indicated there was no significant (all P => 0.05) relationship between FMD and any marker of in vivo platelet activation (MPAs R = 0.193, PAC‐1 R = −0.113, anti‐CD62P R = −0.078) or inducible platelet activation by ADP (MPA R = −0.128, anti‐CD62P R = −0.237), AA (MPA R = −0.122, PAC‐1 R = −0.045, anti‐CD62P R = −0.142), or collagen (MPA R = 0.136, PAC‐1 R = 0.174, anti‐CD62P R = −0.077). Our findings contrast with two previous studies performed in high‐risk cardiac patients, which reported inverse relationships between platelet activation and endothelial function, suggesting that some compensatory redundancy may exist in the relationship between platelet and endothelial function in preclinical populations.

Impact of commonly prescribed exercise interventions on platelet activation in physically inactive and overweight men

The exercise paradox infers that, despite the well‐established cardioprotective effects of repeated episodic exercise (training), the risk of acute atherothrombotic events may be transiently increased during and soon after an exercise bout. However, the acute impact of different exercise modalities on platelet function has not previously been addressed. We hypothesized that distinct modalities of exercise would have differing effects on in vivo platelet activation and reactivity to agonists which induce monocyte‐platelet aggregate (MPA) formation. Eight middle‐aged (53.5 ± 1.6 years) male participants took part in four 30 min experimental interventions (aerobic AE, resistance RE, combined aerobic/resistance exercise CARE, or no‐exercise NE), in random order. Blood samples were collected before, immediately after, and 1 h after each intervention, and incubated with one of three agonists of physiologically/clinically relevant pathways of platelet activation (thrombin receptor activating peptide‐6 TRAP, arachidonic acid AA, and cross‐linked collagen‐related peptide xCRP). In the presence of AA, TRAP, and xCRP, both RE and CARE evoked increases in MPAs immediately post‐exercise (P < 0.01), whereas only AA significantly increased MPAs immediately after AE (P < 0.01). These increases in platelet activation post‐exercise were transient, as responses approached pre‐exercise levels by 1 h. These are the first data to suggest that exercise involving a resistance component in humans may transiently increase platelet‐mediated thrombotic risk more than aerobic modalities.

Beneficial impacts of regular exercise on platelet function in sedentary older adults: Evidence from a randomized 6-month walking trial

Platelet activation, including the formation of monocyte platelet aggregates (MPAs), contributes to atherosclerosis, thrombus formation, and acute coronary syndromes. Regular participation in exercise can lower cardiovascular risk, but little is known regarding the impact of exercise training on platelet function. We investigated the effect of 6 mo of walking exercise on platelet function in sedentary older adults without significant cardiovascular disease. Twenty-seven participants were randomly allocated to 6 mo of either: no-exercise ( n = 13) or 3 × 50 min/wk of supervised center-based walking ( n = 14). Circulating and agonist-induced MPAs were assessed using flow cytometry before [ month 0 (0M)] and after [ month 6 (6M)] the intervention. Circulating MPAs increased from 0M (3.7 ± 1.0%) to 6M (4.7 ± 1.6%) in the no-exercise group ( P = 0.009), whereas a nonsignificant decrease was observed in the walking group (0M 4.3 ± 1.7 vs. 6M 3.7 ± 1.2 %, P = 0.052). The change in MPAs between groups was significant ( P = 0.001). There were no differences between groups in platelet responses to agonists across the interventions (all P > 0.05). Collectively, these data suggest that the absence of regular exercise may increase MPAs, which are cellular mediators involved in atherosclerosis, while regular walking inhibits such increases. The thrombotic function of platelets appears to be relatively unaltered by exercise training. This study provides novel data related to the cardioprotective effects associated with participation in exercise. NEW & NOTEWORTHY Monocyte-platelet aggregates contribute to atherosclerosis and exercise can lower cardiovascular risk. This is the first study to discover that a lack of regular physical activity is associated with increased monocyte-platelet aggregates over a 6-mo intervention period. In contrast, walking exercise inhibits increased monocyte-platelet aggregates in the circulation. This study highlights a novel pathway by which regular participation in exercise exerts its cardioprotective effects.

Acute Impact of Different Exercise Modalities on Arterial and Platelet Function

Purpose Acute coronary syndromes and ischemic stroke are associated with arterial events involving platelets, the endothelium, and atherosclerosis. Although regular physical activity is associated with lower risk of cardiovascular events and mortality, risk is transiently increased during and immediately after participation in an acute bout of exercise. No previous study has investigated the acute impact of exercise on platelet activation and arterial function in the same participants; it is also unknown if responses are dependent on exercise modality. We hypothesized that commonly adopted, yet physiologically distinct, modalities of exercise (“aerobic” vs “resistance”) have differing effects on in vivo platelet activation and conduit artery diameter. Methods Eight apparently healthy middle-age (53.5 ± 1.6 yr) male subjects took part in four 30-min experimental interventions (aerobic exercise, resistance exercise, combined aerobic/resistance exercise, or no-exercise), in random order. Blood samples were collected, and the measurement of brachial artery diameter by ultrasound was performed before, immediately after, and 1 h after each intervention. Platelet activation was determined by the positive binding of antibodies to surface receptors exposed on activated platelets (anti-CD62P and PAC-1). Results Brachial artery diameter increased immediately after all three exercise modalities (P < 0.001) and remained above preexercise levels 1 h after resistance exercise and after combined aerobic/resistance exercise. No changes were observed in markers of in vivo platelet activation with any experimental protocol. Conclusions These data suggest that postexercise enhancement in arterial function may mitigate the acute impact of exercise on platelet activation.

Reply to Drs. Pageaux et al.: Cognitive demand of eccentric versus concentric cycling

to the editor: We completely agree with Pageaux et al. ([3][1]) that acute and chronic perceptual responses to eccentric cycling should be investigated further to extend the use of eccentric cycling to patients with heart failure or other chronic diseases. It is expected that eccentric cycling will