Effect of Acute Resistance Exercise and Resistance Exercise Training on Central Pulsatile Hemodynamics and Large Artery Stiffness: Part II

In part I of this series, we dissected the complex hemodynamic response to acute resistance exercise (RE). Unlike the pressure and volume load presented to the systemic circulation by aerobic exercise, the systemic circulation experiences RE as a pressure load. Marked elevations in arterial blood pressure occur as a result of a combination of factors: increased intrathoracic pressure from breath holds (Valsalva maneuvers), muscle compression of the underlying vasculature increasing vascular resistance and pressure from wave reflections, and the exercise pressor reflex. The increases in intrathoracic pressure may constitute a countervailing hemodynamic force to intravascular pressure, serving to minimize transmural pressure across the vessel wall. This is important to consider as transmural pressure is distending pressure (i.e., the pressure causing arterial distension). During RE, large central artery stiffness (i.e., the aorta and carotid arteries) increases from the elevation in arterial pressure. Immediately following acute RE, despite a return of mean arterial pressure (MAP) to resting values (or slight reduction), large arteries remain stiffer compared to before the RE bout. Subacute effects are short-lived (∼30 min). Part II of this series will consider potential mechanisms that may contribute to increased large artery stiffness following a single bout of RE. Consideration of these potential mechanisms is important as it may help explain arterial adaptations that occur with resistance exercise training (RET).

The mechanisms explaining acute increases in large artery stiffness following a single bout of RE are incompletely understood and likely multifactorial. The “usual suspects” proposed in the literature include increased sympathetic vasomotor outflow increasing vascular smooth muscle (VSMC) tone, increased heart rate preventing complete diastolic recoil, barotrauma causing endothelial damage and reduced nitric oxide bioavailability, increased vasoconstrictive factors (e.g., endothelin-1), and/or inflammation/oxidative stress. In support of these potential mechanisms:

• Acute increases in muscle sympathetic nerve activity (MSNA) with lower body negative pressure are associated with increases in aortic stiffness and reductions in carotid compliance in young adults, independent of changes in MAP and heart rate [1‒4].

• Increased heart rate after acute RE affects diastolic pressure decay, affecting the relation between aortic stiffness and myocardial oxygen supply/demand balance [5].

• ET-1 regulates large artery stiffness in vivo [6] and increases after acute RE [7, 8].

• Acute high-intensity RE is associated with a reduction in brachial artery flow-mediated dilation [9‒11], a measure of endothelium-dependent vasodilation, in men but not women [12] and the effect can be normalized with habitual RET (i.e., acute RE does not cause endothelial damage in habitually resistance-trained individuals) [13].

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    However, we have shown that microvascular reactivity assessed with strain-gauge plethysmography increases and carotid endothelial function assessed as carotid artery reactivity measured during a cold pressor test remains unaffected by acute RE [14, 15].

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    Others note favorable changes in circulating endothelial biomarkers (i.e., increased circulating endothelial progenitor cells, NO_x, klotho, VEGF, HIF-1α, erythropoietin) [7, 8, 16‒18] and peripheral vasodilation of active limb vasculature with no changes in oscillatory (i.e., retrograde considered detrimental) shear patterns [19].

• Consumption of antioxidant supplements attenuates delayed-onset vascular stiffening that occurs 48–72 h after high-intensity eccentric RE [20].

Our working hypothesis is that the large artery effects of acute RE are mostly blood pressure-mediated (i.e., load-dependent stiffening from higher BP recruiting collagen fibers as the artery distends) with additional effect modification from changes in VSMC tone and viscoelastic properties of the vessel wall. These acute changes are likely not structural per se. That is, it is unlikely that a single bout of RE leads to substantial elastin degradation (fatigue fracture), collagen deposition, lipid peroxidation, protease digestion, calcification, and/or glycation affecting the vessel ultrastructure. Indeed, modulation of large artery stiffness following a single bout of RE is transient, increasing immediately after and recovering between 30 and 60 min post-RE. However, acute changes in large artery function from applied forces can affect material properties in such a way as to alter arterial stress-strain characteristics and impact the stiffness of the material, affecting deformation and distension (and thus pulse wave velocity [PWV]; see detailed description of PWV in online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000543314). Furthermore, additional effect modification may occur through prolonged increased sympathetic vasomotor outflow and endothelial dysfunction-mediated augmented VSMC tone following the RE bout.

P_meas is the measured diastolic blood pressure. ρ is a blood density constant of 1,050 kg/m³. Load-dependent (Load-D) aortic stiffness is then calculated as the difference between the measured total stiffness value and the calculated structural stiffness value. Only studies that performed direct measures of cf-PWV were considered given concern over oscillometric methods for deriving aortic PWV [22]. Note, that for papers that presented data in bar graph form, we estimated mean PWV values. Results are displayed in Table 1 [14, 23‒27].

As illustrated from the data in Table 1, there are decreases in load-dependent aortic stiffness (associated with values getting “more negative” in this setting) with increases in load-independent (i.e., structural) aortic stiffness. First, we will consider load-dependent factors. MAP is typically regarded as analogous to distending pressure. Following a bout of RE, MAP typically returns to baseline levels and does not differ from pre-exercise values. In some cases, MAP even dips below baseline (i.e., postexercise hypotension) [28]. At these time points, large artery stiffness is still elevated. This observation is often taken to suggest that changes in large artery stiffness following a bout of RE are not due to increased distension pressure. As detailed in part I, arterial pressure is elevated substantially during the performance of RE. Load dependence refers to the interaction of distending pressure with extracellular matrix (ECM) components elastin and collagen. “Elastic” here equates to a more rubber-like material structure and a purely elastic body will return completely to its normal shape. Elastic fibers contain a core of elastin and a covering of microfibrils. Collagen fibers constitute a jacket of less distensible material. This material is attached to other elements of the vascular wall with some slack, normally not under tension. At lower pressure, the elastic fibers within the ECM will stretch and bear much of the pressure load. Stretching these other components first will take up the slack and ultimately transfer load bearing from the more elastic fibers to the less extensible collagen fibers, which are more than 1,000-fold stiffer than elastin fibers, increasing the stiffness of the vessel wall. It is important to underscore that the relation between pressure and the elastic modulus (Ep) (i.e., artery stiffness) here is nonlinear. Additionally, one of the more intriguing observations about the large arteries is that they also demonstrate plastic qualities. “Plastic” in this context means that the material may retain some of the shape/deformation from a previous stress. Thus, the large arteries are not purely elastic and are considered viscoelastic. Large artery viscoelasticity may offer some insight into observations of increased large artery stiffness after acute RE concomitant with no difference in distending pressure (measured as MAP in aforementioned studies).

The large artery response to acute RE measured during recovery may exhibit a residual effect from the BP generated during the RE bout. Since the large arteries are viscoelastic, a sudden increase in stress will result in a nonlinear increase in length (Fig. 1). The artery will distend rapidly at first and then distend more slowly as time progresses and stress is maintained. This is known as stress relaxation or delayed compliance [29]. When exposed to stepwise changes in stress, arterial length will slowly increase, a process known as the “creep phenomenon” [29]. When stress is removed, the artery slowly returns to its control state but follows a different curve, known as a hysteresis loop [29]. The time course for loading (distension) and unloading (recoil) is different. Moreover, energy is dissipated in stretching the artery and allowing it to return to its resting state. This viscous energy loss can be captured as the area within the stress-strain hysteresis loop [29]. Each set performed during RE typically consists of 10–15 repetitions performed to near muscular failure. With each repetition, there are sinusoidal stepwise increases in blood pressure. As muscular failure approaches, more motor units are recruited, more muscle mass is activated, more group III/IV afferents are activated, and more compressive forces are generated, resulting in further increases in blood pressure. Following the removal of the stress, the artery will return to its resting state, but this process will not be instantaneous. There may be residual “stiffening” after the RE bout as a result of viscous energy loss from the repeated exposure of the artery to numerous cycles of cyclic stress and strain (Fig. 1).

The viscoelastic properties of elastin are closely related to its microstructure, hydration level, pressure, temperature, and external mechanical and chemical environments and can be modulated acutely with exposure to increases in pulse pressure (PP) [30‒32]. The large artery wall contains approximately 70% water [33]. Thus, the artery can be considered a bi-phasic material, comprised mainly water enclosed in a matrix of elastin and collagen. Elastin is composed of nonpolar amino acids and, as such, is largely considered hydrophobic. In hydrated elastin, water is found in intrafibrillar (direct interaction with elastin molecules) and extrafibrillar (water between and around elastin) stores [33]. However, the microfibrils covering elastin are composed of glycoproteins which are hydrophilic and attract water. Water is required for elastin to maintain its resilience [34]. Elastin gains elasticity only when swollen with an approximately equal mass of water and a reduction of water in this space by 10% results in an increase in elastin stiffness [33]. A pressure gradient exists between the arterial circulation and the interstitial pressure in the adventitia, generating a transmural water flow radially outward through the arterial wall. The media is a deformable porous layer. Consequently, when this pressure gradient is altered, strain may be induced in the elastic matrix from the imposed hemodynamic stresses. Compressive and tensile strain can alter the conformation of the interstices which accommodate water flow and thus alter the permeability, dislodging water from the media across the adventitia and into the interstitial fluid compartment. Three biomechanical factors can impact the convection of fluid across the wall: pressure (kinetic energy), flow (potential energy), and pulsatility [31]. Increases in PP during RE may create an intravascular hydrostatic force that compresses the wall radially, pushing water out. In this “hypo-hydrated” state, there may exist realignment of elastic fibers, as the elastic lamellae layers are more packed in the radial direction due to water removal [33]. A decrease in spacing induced by water loss will likely lead to an increase in the density of elastic fibers and potential fiber realignment, increasing stiffness. Moreover, water is needed for efficient (endothermic) elastin recoil; elastin recoil is considered to be driven by the hydrophobic effect [35]. The possibility of acute vascular water loss with RE is also in keeping with the well-noted reduction in plasma volume that occurs [36‒39]. During RE, the breakdown of glycogen (which is substantial), production of lactate, and accumulation of other metabolites in the active skeletal muscle increases intracellular osmolarity (i.e., “cell swelling”). This change in osmotic gradient not only increases fluid fluxes from interstitial to intracellular spaces but also vascular to interstitial spaces [38]. As stated previously, although there are no notable differences in MAP during recovery from acute RE, PP remains elevated for upward of 30 min. Interestingly, aortic wall viscosity appears more sensitive to the effects of PP over MAP [40]. During rehydration after compressive forces have been removed, the intrafibrillar compartment expands rapidly, but the extrafibrillar compartment expands slowly [41]. This would also offer insight into the delayed viscoelastic recovery kinetics (stress relaxation) after acute RE. Also, during this 30-min window, plasma volume is restored to pre-exercise levels (independent of fluid consumption suggesting that changes in plasma volume are indeed from redistribution and not fluid loss), which also tracks well with blood lactate clearance [38]. This hydro-elastodynamic hypothesis is speculative and requires additional scrutiny.

VSMC tone is an important contributor to large artery stiffness [42, 43], and in animal models, up to half of total aortic wall stiffness is attributable to the active stiffness of the VSMC [42]. VSMC tone is also important for aortic viscoelasticity [32]. Zou and Zhang [44] (2011) tested the stress relaxation of (1) intact, (2) decellularized, and (3) collagen-digested porcine aortic samples and showed a progressive decrease of stress relaxation after the removal of not only collagen fibers but also VSMCs. VSMC contraction increases aortic viscoelasticity through increased focal adhesion activity and reorganization of elastin fibers [44]. Increased cyclic stretch during RE may attenuate such contraction-induced changes by affecting focal adhesion function. In addition to RE-mediated sympathetic and endothelial factors impacting VSMC tone (mentioned above), there may be muscle-specific factors released during RE (i.e., myokines) that may have the ability to potentiate VSMC function. For example, myostatin is a muscle-secreted growth factor typically linked to muscle growth and repair. Myostatin receptors are abundant in the aorta, and myostatin leads to activation of TGF-β signaling and decreases eNOS phosphorylation in aortic endothelial cells [45, 46]. Lactate produced by VSMCs promotes a conversion from a contractile phenotype to a synthetic phenotype [47]. The synthetic phenotype contributes to the repair of vascular injury and favorable vascular remodeling. During RE, there may be reductions in circulating lactate [48] as it is being used via lactate shuttles and metabolized by other muscle fibers and organs, an effect that becomes more pronounced with each set. Lactate levels then increase during recovery from RE [48]. The increase in lactate may affect VSMC tone and contribute to arterial recovery, although this hypothesis is speculative. More research will be needed to examine the various vascular and nonvascular mechanisms that may alter large artery mechanical properties with acute RE.

Increases in large artery stiffness with acute RE are load-dependent and load-independent. Typical mechanisms suggested for increases in large artery stiffness during recovery from acute RE, when MAP (distension pressure) is not different than resting values include increases in sympathetic activity, residual endothelial damage from elevated pressure, and increases in circulating levels of vasoconstrictors (e.g., ET-1). Alternative hypotheses suggested herein include circulating myokines with vasoactive properties and changes in viscoelastic properties contributing to a delay in stress relaxation and recovery.

As a reduction in radius (r) against a constant transmural pressure will decrease wall tension, active VSMC contraction adds to the elastic tension of large arteries. As noted above, excessive increases in blood pressure coupled with Valsalva maneuver expose the aorta to unique cycles of both static and cyclic stretch and strain. Exposure of the aorta to such hemodynamic perturbations may alter VSMC stiffness as a means of regulating cellular mechanotransduction (VSMC-ECM interactions redistributing tensile forces across elastin and collagen) as a defense mechanism to “normalize” wall stress and prevent dissection or aneurysm [49]. Indeed, the “tensegrity hypothesis” implies that cell stiffness must increase in proportion to the level of the tensile stress [49].

It is commonly believed that the acute vascular and hemodynamic response to exercise is what ultimately instigates chronic cardiovascular adaptations. Indeed, it is during the dynamic recovery period from exercise that most adaptations take root. The exercise recovery period has been proposed as a “window of opportunity” and a “crystal ball” into understanding the training response and future health benefits that may be derived from exercise and a possible trigger to unmask disease risk [50]. The recovery period has also been proposed as a vulnerable state, allowing researchers to study how the body responds to a very complex systemic stress [50]. It could be argued that the recovery period is as important to the arterial adaptive (and possibly maladaptive) process as the exercise stimulus itself [51]. Presently, while there is some evidence to suggest that the acute arterial and blood pressure reactivity to exercise may be prophetic for training responses [52, 53], there is currently no empirical evidence that increases in large artery stiffness with acute RE are predictive of the adaptive response to habitual RET. More research will be needed to explore links between acute arterial responses to RE and arterial adaptations to habitual RET.

Assessing large artery stiffness with acute RE may also offer insight into a “large artery vasoactive range” or large artery “functional stiffness reserve.” Akin to the concept of combining measures of flow-mediated dilation and low flow-mediated constriction to give insight into peripheral conduit vessel vasoactive range [54], assessing large artery dynamic responses to physiologic hypo- and hypertensive stimuli may be useful to assess large artery reactivity. While typically exaggerated responses to exercise are considered detrimental for target organs [55], no response at all may be detrimental to the artery itself. A dynamic increase may be taken to suggest that the artery is responsive (has functional reserve) and can appropriately adjust stiffness (Ep) to maintain wall tension. The inability of an artery to dynamically change may suggest a loss of plasticity. Compliance is required for distension with increased pressure. That is, to obligate functional increases in large artery stiffness, an artery has to be compliant first for it to be able to stiffen.

Increases in large artery stiffness with acute RE may serve to preserve wall tension during times of increased cyclic stress and strain. Studying large artery stiffness during recovery from RE may offer insight into large artery functional reserve (ability to change dynamically during a hypertensive stimulus). Studies are needed to examine links between acute arterial responses to RE and chronic arterial adaptations with RET.

This section will explore the effect of RET on arterial and hemodynamic adaptations following controlled interventions. In 2004, Miyachi et al. [56] performed the first randomized intervention study to examine the effect of RET on large artery stiffness in 28 young and middle-aged men. Fourteen previously untrained men underwent 4 months of RET (3 days per week). After the intervention, there were significant reductions in carotid compliance and parenthetically significant increases in carotid β-stiffness. Making these findings even more compelling, after a 4-month detraining epoch (i.e., removal of the RE stimulus), carotid compliance and stiffness reverted completely back to baseline values. There were also significant increases in left ventricular mass following RET and changes in carotid compliance were strongly associated with changes in left ventricular mass. There were no significant changes in carotid IMT or augmentation index (AIx; defined in online suppl. material) with RET. The authors concluded that “in marked contrast to the beneficial effect of regular aerobic exercise, several months of resistance training “reduces” central arterial compliance in healthy men” and “does not exert beneficial effects on arterial wall buffering functions.” The authors also stressed that the volume, frequency, and intensity used were greater than the recommended dosage for general health and muscular fitness and questioned whether such an approach would be appropriate for high-risk clinical populations. Dr. Cortez-Cooper (working in the laboratory of Dr. Hiro Tanaka) replicated findings from Miyachi et al. in 23 young women, finding that 11 weeks of high-intensity RET increased aortic stiffness and carotid AIx [57]. Authors noted that findings were in contrast to AET which demonstrated beneficial effects on large artery stiffness and concluded that high-intensity RET causes an increase in large artery stiffness and wave reflection in young women, an effect similar to what occurs in young men.

How could a mode of exercise with numerous health benefits possibly be detrimental to large artery buffering capacity and thus cardiovascular function? This question prompted additional studies in an attempt to further unpack the effect of RET on large artery structure and function. Dr. Mark Rakobowchuk (in Dr. Maureen MacDonald’s laboratory at McMaster University) examined the effect of 12 weeks of RET on carotid stiffness and carotid PP in 28 young men [58]. Rakobowchuk et al. [58] found no change in carotid stiffness with a reduction in carotid PP. Similarly, work from Dr. Darren Casey (then studying with Drs. Randy Braith and Wilmer Nichols at the University of Florida) and our group at the University of Illinois added to this emerging literature, noting that RET did not affect large artery stiffness or measures of central pulsatile hemodynamics, namely, AIx [59, 60]. Relying exclusively on AIx to infer changes in wave reflections is not without limitations. For example, RET may result in slight decreases in heart rate which is important because there is an inverse association between heart rate and AIx. Many studies report AIx as a contrived measure standardized to an arbitrary heart rate of 75 bpm (based on an early cardiac pacing study performed in a small sample) [61]. AIx also suffers from what Dr. Gary Mitchell refers to as the “tip of the iceberg” effect [62]. That is, based on the timing of wave reflections and the magnitude of the forward wave, the augmented pressure used to calculate AIx may not be truly reflective of wave reflection magnitude. As such, the American Heart Association encourages use of wave separation analyses from measures of blood flow and pressure wherever possible when assessing central pulsatile load and wave reflection magnitude [63]. Unfortunately, few studies have utilized wave separation analysis to examine the effect of RET on central pulsatile hemodynamics. With the assistance of Drs. James Sharman, Justin Davies, Sae Young Jae, and Chen-Huan Chen (among others), Heffernan et al. [64] explored the effect of a 12-week randomized RET intervention on measures of central pulsatile hemodynamics in a small group of 11 prehypertensive and hypertensive adults. Compared to a non-exercise control group (n = 10), RET resulted in significant reductions in both brachial and aortic blood pressure. There were no changes in AIx derived from pulse contour analysis or Pb derived from wave separation analysis. Interestingly, there were reductions in Pf and reservoir wave pressure [64]. Thus, RET appears to lower central BP in older adults with hypertension by lowering forward wave pressure and reservoir wave pressure, and not via modulation of pressure from wave reflections.

Over time, a rather complex literature has developed with some studies supporting that RET increases large artery stiffness [57] and others noting no effect [65‒69]. Interestingly, we are approaching a point where there are now almost as many meta-analyses on this topic as there are RCTs. There is even a systematic review of systematic reviews [70]. The results from meta-analyses have yielded different conclusions:

• Higher volume/intensity RET may increase large artery stiffness in younger individuals with lower baseline stiffness values but may not affect or even reduce large artery stiffness in individuals with higher baseline stiffness [71‒74].

• RET does not affect large artery stiffness [75‒79].

In general, there is a growing body of evidence that contradicts earlier findings of increased large artery stiffness with RET. Most contemporary studies note that RET does not affect large artery stiffness (and may even reduce arterial stiffness) in a variety of healthy and clinical populations, regardless of participant characteristics, training volume, or load [29‒33]

The reason for the marked arterial heterogeneity in intraindividual responses to RET is unknown but may be related to ECM-VSMC interactions. When arterial pressures are normalized to each organism’s MAP, the incremental Ep of the aorta for all species remarkably converges to a similar value [80]. To achieve this comparable functional modulus, each organism must adjust the mix of ECM components in the vessel wall to produce the mechanical properties to match different hemodynamic stresses [80]. In this context, the VSMC must monitor the changing arterial wall tensile forces and adjust the matrix accordingly. The finding of a universal vessel wall modulus that applies across species and in vessels with different ECM components implies that there must be strong evolutionary pressure to ensure that all elastic arteries have similar mechanical properties at each organism’s MAP [80]. Thus, like a baroreflex, the arterial wall may have an operating point within a viscoelastic operating range. The endothelium and VSMC have “stretch receptors” (PIEZO ion channels that respond to cyclic strain and transduce hemodynamic forces to regulate vascular homeostasis) that can dynamically regulate smooth muscle stiffness in response to distension [81‒83]. Arterial wall properties may be reset (phenotype switch) when confronted with acute changes in pressure and remodel with chronic exposure to conserve the Ep [84].

where r is radius, ρ is blood density and h is wall thickness.

With an acute increase in pressure, small increases in PWV will increase E, as will increases in r and reductions in h. Reductions in h may not be desired given its effects on wall tension (see Law of LaPlace above). Thus, to balance stress and strain at a higher MAP during RE, there will be dynamic increases in PWV and changes in VSMC tone that increase r and h (i.e., VSMC contraction may increase wall thickness [85]). Over time, the arterial set point may be reset to a higher operating range in anticipation of high-pressure exposure. Increases in PWV, diameter, and wall thickness may occur with RET [86]. These adaptations would serve little value at rest, particularly given that MAP is either unchanged or slightly lower with RET, but may be desired to conserve E during RE. Whether increases in vessel wall stiffness and VSMC tone would impact responsiveness or sensitivity to pressure changes requires additional consideration.

Recently, Dr. Ryan Pewowaruk proposed that the effect of VSMC tone on arterial stiffness depends on the ECM-VSM stiffness ratio [87]. In settings where VSMC is stiffer than ECM, increased VSMC tone will increase arterial stiffness. In settings where ECM is stiffer than VSMC, increased VSMC tone will decrease arterial stiffness. Such changes may preserve the Ep. This hypothesis offers a potential explanation for why changes in VSMC tone can have different effects on arterial stiffness [87, 88]. RET may increase large artery stiffness in younger adults with low baseline levels while RET may reduce large artery stiffness in older adults with higher baseline levels [71, 73].

Although cross-sectional studies have limitations as they do not allow for testing of direct exposure to the stimulus, they still can offer important physiological insights. Cross-sectional studies allow for the examination of chronic/habitual RET (years of training) on large artery adaptations. Among the first to explore the effect of habitual RET on large artery stiffness and pulsatile hemodynamics in 1999, David Bertovic et al. [89] (working with Dr. Bronwyn Kingwell) performed an expansive vascular and hemodynamic assessment on 19 strength-trained men, comparing them to age-matched controls (∼26 years of age). Strength-trained adults were not concomitantly performing aerobic exercise and were not using anabolic agents. Both groups had a moderately high level of cardiorespiratory fitness (VO₂ max ∼41–44 mL/kg/min on a cycle ergometer) supporting that both groups were not entirely sedentary (which may be viewed as a disease state in-and-of itself). Left ventricular mass and function were assessed using standard M-mode echocardiography. Whole body arterial compliance was assessed from pulse contour analysis of the carotid pressure waveform, measured via applanation tonometry. Applanation tonometry was also used to assess cf and femoral-ankle PWV. The simultaneous measurement of pressure and flow was used to measure aortic input and characteristic impedance and also perform wave separation analyses to derive Pf and Pb pressure waves and a wave reflection factor (analogous to a reflection coefficient or the ratio of Pb to Pf). Given the concern that cf-PWV neglects the ascending aorta and aortic arch as the very nature of the measure “subtracts out” this region, investigators also assessed proximal aortic stiffness as the stiffness index β and Ep using diameter changes in the transverse aortic arch measured via echocardiographic M-mode imaging and carotid pressure from tonometry. Overall, Bertovic et al. found that the strength athletes had higher brachial and carotid PP, higher carotid wave reflection magnitude, lower systemic arterial compliance, higher input and characteristic impedance, and higher aortic β-stiffness and Ep compared with controls. Aortic geometry was similar between groups as were cf-PWV, wave reflection magnitude, relative left ventricular mass and left ventricular function (i.e., fractional shortening, E/A ratio, and deceleration time). Thus, the habitual strength-trained individuals had greater pulsatile blood pressure which was likely a result of greater proximal aortic stiffness and impedance. Authors concluded that the group differences in aortic stiffness were likely of structural origin, alluding to the possibility that chronic elevations in central pulsatile load may cause proximal aortic remodeling and changes in vessel wall composition with increases in smooth muscle and collagen at the expense of elastin. Interestingly, the differences in afterload did not equate to differences in relative left ventricular mass or function. Bertovic et al. ended their investigation with what would become a provocative question – what are the clinical implications of such large artery adaptations concerning CVD risk?

As can be seen, this study was truly a landmark study incorporating numerous exceptional measures of large artery stiffness and pulsatile hemodynamics including the reference standard cf-PWV and pressure wave dynamics obtained from pressure-flow measures and wave separation analyses. Findings were intriguing and ushered in an important area of cardiovascular exercise physiology that still seeks to understand this epiphenomenon. In 2003, Miyachi et al. [90] (working with Dr. Hirofumi Tanaka) advanced this area of scholarship by including both young and middle-aged habitually resistance-trained and untrained men (n = 62 total) and shifting focus to the carotid artery. Overall, investigators found no differences in carotid artery compliance between younger sedentary and resistance-trained adults. But, compared to middle-aged sedentary controls, middle-aged resistance-trained individuals had lower carotid compliance and higher carotid AIx. Interestingly, middle-aged resistance-trained individuals also had higher carotid IMT and left ventricular mass and there were associations between carotid compliance with IMT and a left ventricular hypertrophy index (a ratio of left ventricular wall thickness to left ventricular internal end-diastolic diameter). As stated initially by Bertovic et al., Miyachi and colleagues reiterated that the clinical significance of the greater age-associated difference in large artery compliance remained to be determined.

Others have gone on to show that habitually strength-trained adults may have higher cf-PWV, although this is not universally seen [91‒94], increased proximal aortic stiffness [95, 96], and increased carotid stiffness [97], and findings that have also been extended specifically to habitually RE-trained women [98]. The majority of cross-sectional studies support that habitual RET adults (i.e., resistance-trained adults, strength athletes, powerlifters, and bodybuilders) have increased large artery stiffness compared to their age-matched non-lifting peers.

As stated in part I and above, it is often suggested that the large pressor response with each RE bout may trigger endothelial damage and repeated cycles of cyclic stress-strain may cause elastin fatigue fracture and breakdown, collagen deposition, and fibrosis. Increases in large artery stiffness may in turn perpetuate a greater pressor response to exercise [99], further driving arterial adaptations. While aortic geometry, wall stiffness, and BP all affect peak wall stress, systolic aortic stretch may indeed be the most critical modifier of wall stress [100]. Thus, with habitual RET, the artery may be remodeled to preserve wall tension and balance the Ep. Unlike animal studies showing that aerobic exercise training can affect arterial structural wall components and stiffness [101, 102], there are no such data to support that RET results in passive (structural) changes to vessel wall material properties (i.e., changes in ECM components elastin or collagen composition). It should also be noted that habitual RET attenuates the pressor response to static muscle contractions and RE [103‒105] and may also attenuate acute RE-mediated endothelial dysfunction [10, 13]. While habitually RE-trained adults have similar reductions in peripheral artery stiffness after acute cycling exercise compared to non-RE-trained adults [91], it is currently unknown whether habitual RET blunts the increase in large artery stiffness in response to acute RE compared to novices.

Select studies note increased sympathetic modulation and elevations in norepinephrine concentrations following RET [106], an effect that may be attenuated with habituation [107]. There have also been reports of increased endothelin-1 with habitual RET [93, 108]. Large central arteries have their own blood supply (vasa vasorum) and neural supply (nervi vasorum). Thus, vasoactive peptide-mediated and/or neurally mediated VSMC contraction and cross-bridge cycling could alter vessel wall (Young’s) Ep and contribute to chronic increases in large artery stiffness (see discussion above). Studies support that habitual RET may also increase IMT [90], and studies in vivo support that changes in VSMC tone can manifest as changes in vessel wall thickness [85]. Increases in large artery stiffness from habitual RET have been associated with lower cardiovagal baroreflex sensitivity [109] and increased MSNA [110], with MSNA being linked to higher AIx. Higher aortic stiffness in strength athletes is associated with increased left ventricular mass and reduced left ventricular end-diastolic volume (i.e., concentric hypertrophy). Increased large artery stiffness in habitually RE-trained adults is associated with increased cerebral pulsatility [111]. Based on these data, statements that higher large artery stiffness with RET may be detrimental to end-organ structure and function are not unfounded and should continue to be studied.

Compared with RET intervention studies, cross-sectional studies more consistently find increased large artery stiffness in habitual practitioners of RET. Effects are more pronounced with age and the length of RET experience. Interestingly, select studies note that RET-mediated increases in large artery stiffness have similar detrimental systemic effects on end-organ structure and function as age-associated increases in large artery stiffness.

A final point worth considering is exploring arterial effects produced by the outcome of the behavior. That is, there is a robust literature linking cardiorespiratory fitness (i.e., the outcome from habitual AET) with lower large artery stiffness and better cardiovascular outcomes. Concerning RET, the outcomes include muscle strength and muscle mass. The two constructs are often conflated but, in actuality, capture distinct aspects of physiology and health. Dankel et al. [112] have shown that strength is a more important predictor of all-cause mortality than self-reported strength training. Indeed, muscular strength is cardioprotective [113‒115]. Muscular strength is inversely associated with aortic stiffness, aortic calcification, aortic AIx, and carotid intima-media and extra-media thickness [116‒125]. Additionally, muscular strength is associated with lower PP and better vascular endothelial function [126, 127]. Muscular strength is also associated with a lower risk of developing obesity, metabolic syndrome, incident hypertension, sudden cardiac death, and cardiovascular mortality [128‒136]. Parenthetically, lower muscular strength (i.e., dynapenia) is a significant predictor of the development of heart failure and CVD events later in life, independently of cardiorespiratory fitness [137‒139]. Moreover, muscle mass is inversely associated with large artery stiffness and AIx [140‒142]. This observation becomes relevant with aging when considering loss of muscle mass (i.e., sarcopenia). Thus, the “byproducts” of RET are not related to detrimental arterial adaptations and may confer cardioprotection. Presently, it remains a challenge to reconcile the paradoxical observation that strength-trained athletes have increased large artery stiffness, yet strength is inversely associated with large artery stiffness.

Both muscle strength and muscle mass are inversely associated with large artery stiffness, thickness, and pulsatile central hemodynamics.

In general, habitually RE-trained individuals do not experience an increased incidence of hypertensive or atherosclerotic CVD and enjoy a typical lifespan (albeit not the extended lifespan conferred by aerobic/endurance training) [143, 144]. In a very nice review paper prepared by DC Lee and I-Min Lee [145], it was concluded that “more may not be better for dose-response relations of RE with CVD and mortality.” Observational data suggest 40–60 min/week of RE may be an optimum dose for maximum CVD and mortality benefits, and 130–140 min/week of RE is a safe upper limit (maximum dose) [146]. Beyond this, more RE may start to increase the risk of CVD and premature mortality [146]. Interestingly, authors proposed two potential mechanisms through which higher RE doses may confer possibly greater CVD risk: (1) inflammation and (2) increased large artery stiffness [145], but studies are warranted to support or refute these hypotheses.

As more studies continue to emerge in this area, hopefully, a consensus may be reached regarding the effects of RET on large artery structure and function. Presently, it appears that RET has negligible effects on large artery stiffness and central hemodynamic pressure pulsatility in most individuals. However, large inter-individual variations and observations of increases in large artery stiffness and central hemodynamic pressure pulsatility in habitually RE-trained individuals cannot and should not be dismissed (Fig. 2). Whether such changes confer an increased risk (or resiliency) for CVD must be scrutinized. Additional studies are also needed to study effect modification from biological sex, race, and ethnicity. Finally, given that RET is suggested as one part of a general exercise prescription that includes aerobic exercise, flexibility, and neuromotor function, all of which may reduce large artery stiffness [77, 79, 147‒149], studies that explore the intersection and optimal dosage of these exercise modalities for optimal vascular health will be needed. Based on the available literature, the benefits of RET, particularly when performed as recommended and as part of a comprehensive fitness plan, far outweigh any potential risks [150‒152].

In closing, we would like to reiterate a conclusion drawn by Dr. Michael O’Rourke and Dr. Junichiro Hashimoto in their review paper on vascular aging [153]: “In the interim, the old advice stands. Exercise regularly; watch the calories, the coffee, and the salt. No cigarettes. Enjoy yourself, and take advantage of your heart’s beat before it wears you out!”

To this, we would add – for exercise, do both aerobic exercise and RE. For volume, not too much, not too little. For intensity, not too easy, but not too hard (unless you feel like adding some high-intensity intervals from time to time, but that is a conversation for another paper), do some stretching, train your neuromotor function (work on your balance). Move more, sit less, put the phone down unless it is to call a friend or loved one (maintain positive social connections), get a good night’s sleep, have a big glass of water, and always remember “live, laugh, love, and lift.”

This review paper does not include original human subjects data. All views and opinions expressed are those of the authors.

We have no conflicts of interest to disclose.

D.J.W. and K.S.H. have no funding sources to disclose. G.L.P. is supported by the Russell B. Day and Florence D. Day Endowed Chair in Liberal Arts and Sciences at the University of Iowa.

D.J.W. and K.S.H. were equally responsible for manuscript conceptualization, writing, and editing. D.J.W. additionally contributed figures. G.L.P. assisted with manuscript editing and final proofing. D.J.W., K.S.H., and G.L.P. approved the final version of the manuscript.

This review paper does not include any human participant data.