On the 400th anniversary of Harvey's Lumleian lectures, this review focuses on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural ...adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity.
Moderate to vigorous physical activity (MVPA) is strongly associated with risk reductions of noncommunicable diseases and mortality. Cardiovascular health status may influence the benefits of MVPA. ...We compare the association between MVPA and incident major adverse cardiovascular events (MACE) and mortality between healthy individuals, individuals with elevated levels of cardiovascular risk factors (CVRF), and cardiovascular disease (CVD).
A cohort study was performed in the 3 northern provinces of the Netherlands, in which data were collected between 2006 and 2018, with a median follow-up of 6.8 years (Q25 5.7; Q75 7.9). A total of 142,493 participants of the Lifelines Cohort Study were stratified at baseline as (1) healthy; (2) CVRF; or (3) CVD. Individuals were categorized into "inactive" and 4 quartiles of least (Q1) to most (Q4) active based on self-reported MVPA volumes. Primary outcome was a composite of incident MACE and all-cause mortality during follow-up. Cox regression was used to estimate hazard ratios (HRs), 95% confidence intervals (CIs) and P values. The main analyses were stratified on baseline health status and adjusted for age, sex, income, education, alcohol consumption, smoking, protein, fat and carbohydrate intake, kidney function, arrhythmias, hypothyroid, lung disease, osteoarthritis, and rheumatoid arthritis. The event rates were 2.2% in healthy individuals (n = 2,485 of n = 112,018), 7.9% in those with CVRF (n = 2,214 of n = 27,982) and 40.9% in those with CVD (n = 1,019 of n = 2,493). No linear association between MVPA and all-cause mortality or MACE was found for healthy individuals (P = 0.36) and individuals with CVRF (P = 0.86), but a linear association was demonstrated for individuals with CVD (P = 0.04). Adjusted HRs in healthy individuals were 0.81 (95% CI 0.64 to 1.02, P = 0.07), 0.71 (95% CI 0.56 to 0.89, P = 0.004), 0.72 (95% CI 0.57 to 0.91, P = 0.006), and 0.76 (95% CI 0.60 to 0.96, P = 0.02) for MVPA Q1 to Q4, respectively, compared to inactive individuals. In individuals with CVRF, HRs were 0.69 (95% CI 0.57 to 0.82, P < 0.001), 0.66 (95% CI 0.55 to 0.80, P < 0.001), 0.64 (95% CI 0.53 to 0.77, P < 0.001), and 0.69 (95% CI 0.57 to 0.84, P < 0.001) for MVPA Q1 to Q4, respectively, compared to inactive individuals. Finally, HRs for MVPA Q1 to Q4 compared to inactive individuals were 0.80 (95% CI 0.62 to 1.03, P = 0.09), 0.82 (95% CI 0.63 to 1.06, P = 0.13), 0.74 (95% CI 0.57 to 0.95, P = 0.02), and 0.70 (95% CI 0.53 to 0.93, P = 0.01) in CVD patients. Leisure MVPA was associated with the most health benefits, nonleisure MVPA with little health benefits, and occupational MVPA with no health benefits. Study limitations include its observational nature, self-report data about MVPA, and potentially residual confounding despite extensive adjustment for lifestyle risk factors and health-related factors.
MVPA is beneficial for reducing adverse outcomes, but the shape of the association depends on cardiovascular health status. A curvilinear association was found in healthy and CVRF individuals with a steep risk reduction at low to moderate MVPA volumes and benefits plateauing at high(er) MVPA volumes. CVD patients demonstrated a linear association, suggesting a constant reduction of risk with higher volumes of MVPA. Therefore, individuals with CVDs should be encouraged that "more is better" regarding MVPA. These findings may help to optimize exercise prescription to gain maximal benefits of a physically active lifestyle.
Advancing age may be the most potent independent predictor of future cardiovascular events, a relationship that is not fully explained by time‐related changes in traditional cardiovascular risk ...factors. Since some arteries exhibit differential susceptibility to atherosclerosis, generalisations regarding the impact of ageing in humans may be overly simplistic, whereas in vivo assessment of arterial function and health provide direct insight. Coronary and peripheral (conduit, resistance and skin) arteries demonstrate a gradual, age‐related impairment in vascular function that is likely to be related to a reduction in endothelium‐derived nitric oxide bioavailability and/or increased production of vasoconstrictors (e.g. endothelin‐1). Increased exposure and impaired ability for defence mechanisms to resist oxidative stress and inflammation, but also cellular senescence processes, may contribute to age‐related changes in vascular function and health. Arteries also undergo structural changes as they age. Gradual thickening of the arterial wall, changes in wall content (i.e. less elastin, advanced glycation end‐products) and increase in conduit artery diameter are observed with older age and occur similarly in central and peripheral arteries. These changes in structure have important interactive effects on artery function, with increases in small and large arterial stiffness representing a characteristic change with older age. Importantly, direct measures of arterial function and structure predict future cardiovascular events, independent of age or other cardiovascular risk factors. Taken together, and given the differential susceptibility of arteries to atherosclerosis in humans, direct measurement of arterial function and health may help to distinguish between biological and chronological age‐related change in arterial health in humans.
Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease ...(CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.
The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular ...risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk.
Flow-mediated dilation (FMD) is a noninvasive index of endothelial function and vascular health in humans. Studies examining the role of nitric oxide (NO) are not conclusive. In this article, we ...quantified the contribution of NO in FMD of conduit arteries and explored the effect of the protocol (ie, distal cuff, ≈5-minute ischemia) and method of analysis (ie, automated and continuous edge detection) on the NO dependency of this test. A systematic review and 3-stage meta-analysis of published crossover studies that measured FMD under local infusion of saline or the NO synthase blocker N(G)monomethyl-L-arginine (L-NMMA) was undertaken. Twenty studies met the inclusion criteria for stage 1 (374 individual comparisons). The meta-analyzed outcome was the difference in FMD between infusion of saline (ie, FMD(saline)) and NO synthase blocker (ie, FMD(L-NMMA)). Overall, FMD(saline) was 8.2% (95% confidence interval CI, 6.8%-9.6%) compared with FMD(L-NMMA) of 3.7% (95% CI, 3.1%-4.3%; P<0.001). Stage 2 analysis focused on studies that used the most commonly adopted approach in healthy volunteers (ie, distal cuff placement, ≈5-minute occlusion), which similarly revealed a significant NO contribution to FMD (FMD(saline), 6.5% 95% CI, 5.7%-7.3%; FMD(L-NMMA), 0.9% 95% CI, 0.5%-1.3%; P<0.001). Stage 3 meta-analyzed the studies that adopted the commonly adopted approach and automated, continuous method of analysis, which also revealed a significant contribution of NO to the FMD (FMD(saline), 6.9% 95% CI, 6.0%-7.8%; FMD(L-NMMA), 2.4% 95% CI, 1.1%-3.7%; P<0.001). This comprehensive analysis demonstrates that FMD of conduit arteries in humans is, at least in part, mediated by NO.
Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in ...humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate (P<0.005) and flow-mediated dilation percentage (P<0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 (P<0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb (P<0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans.
Although the effects of exercise training on vascular function have been well studied, less is known about the effects of acute exercise bouts. This synthesis summarizes and integrates knowledge ...derived from papers relating acute impacts of exercise on artery function, specifically endothelial function assessed by flow-mediated dilatation (FMD). We propose that an immediate decrease in FMD ("nadir") occurs soon after exercise cessation and that this is followed by a (supra)normalization response. The magnitude of the nadir and (supra)normalization and duration of this biphasic pattern of response appears to be influenced by numerous factors, including the nature of the exercise stimulus (e.g., type, duration, intensity), the subject population (e.g., trained vs. untrained), and various methodological factors. The impact of these factors on the biphasic pattern are most likely mediated through stimuli that underpin altered FMD postexercise, including shear and oxidative stress, changes in arterial diameter, and antioxidant status. We propose that a combination of these stimuli act synergistically to balance the vasomotor responses postexercise. Finally, we discuss the potential (clinical) relevance of the biphasic response after acute exercise, as the immediate nadir may represent an essential response for subsequent training-induced adaptations but may also represent a transient period of increased cardiovascular risk leading to the "exercise paradox."
Thickening of the carotid artery wall has been adopted as a surrogate marker of pre-clinical atherosclerosis, which is strongly related to increased cardiovascular risk. The cardioprotective effects ...of exercise training, including direct effects on vascular function and lumen dimension, have been consistently reported in asymptomatic subjects and those with cardiovascular risk factors and diseases. In the present review, we summarize evidence pertaining to the impact of exercise and physical activity on arterial wall remodelling of the carotid artery and peripheral arteries in the upper and lower limbs. We consider the potential role of exercise intensity, duration and modality in the context of putative mechanisms involved in wall remodelling, including haemodynamic forces. Finally, we discuss the impact of exercise training in terms of primary prevention of wall thickening in healthy subjects and remodelling of arteries in subjects with existing cardiovascular disease and risk factors.
Changes in arterial shear stress induce functional and structural vasculature adaptations. Recent studies indicate that substantial retrograde flow and shear can occur through human conduit arteries. ...In animals, retrograde shear is associated with atherogenic effects. The aim of this study was to examine the impact of incremental levels of retrograde shear on endothelial function in vivo. On 3 separate days, we examined bilateral brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men (24+/-3 years) before and after a 30-minute intervention consisting of cuff inflation to 25, 50, or 75 mm Hg. Cuff inflations resulted in "dose"-dependent increases in retrograde shear rate, compared with the noncuffed arm, within subjects (P<0.001). Flow-mediated dilation in the cuffed arm did not change in response to the 25-mm Hg stimulus but decreased significantly after both the 50- and 75-mm Hg interventions (P<0.05). The decrease in flow-mediated dilation after the 75-mm Hg intervention was significantly larger than that observed after a 50-mm Hg intervention (P=0.03). In the noncuffed arm, no changes in shear rate or flow-mediated dilation were observed. These results demonstrate that an increase in retrograde shear rate induces a dose-dependent attenuation of endothelial function in humans. This finding contributes to our understanding regarding the possible detrimental effects of retrograde shear rate in vivo.
PDF
