Influence of Physical Activity on Hypertension and Cardiac Structure and Function

Abstract

The global burden of hypertension is rising and accounts for substantial morbidity and mortality. Lifestyle factors such as diet and physical inactivity contribute to this burden, further highlighting the need for prevention efforts to curb this public health epidemic. Regular physical activity is associated with lower blood pressure, reduced cardiovascular risk, and cardiac remodeling. While exercise and hypertension can both be associated with the development of left ventricular hypertrophy (LVH), the cardiac remodeling from hypertension is pathologic with an associated increase in myocyte hypertrophy, fibrosis, and risk of heart failure and mortality, whereas LVH in athletes is generally non-pathologic and lacks the fibrosis seen in hypertension. In hypertensive patients, physical activity has been associated with paradoxical regression or prevention of LVH, suggesting a mechanism by which exercise can benefit hypertensive patients. Further studies are needed to better understand the mechanisms underlying the benefits of physical activity in the hypertensive heart.

Introduction

Globally, hypertension is the leading risk factor for morbidity and mortality, causing an estimated 9.4 million deaths in 2010 [1]. Several end organ effects, particularly compensatory increases in left ventricular (LV) wall thickness and mass, are characteristic features of the hypertensive heart that act as an independent predictor of adverse cardiovascular events. Fortunately, treatment of hypertension can prevent progression or development of LV hypertrophy (LVH) and reduce cardiovascular risk [2–5].

Lifestyle factors, including physical inactivity, are important modifiable risk factors in the development of hypertension. In addition to standard anti-hypertensive therapy, the benefits of physical activity on hypertension and cardiovascular disease have been well demonstrated [6–9]. Accordingly, physical activity and other lifestyle modifications are an important component of American, European, and World Health Organization guidelines for anti-hypertensive therapy [10–12]. Although the effect of physical activity on hypertension and on the heart have each been well described, the mechanisms underlying the protective effect of physical activity on the hypertensive heart are not well understood. Here, we review the most recent evidence for the influence of physical activity on hypertension and cardiac structure and function.

Physical Activity and Hypertension

Exercise is a key component of lifestyle therapy for the primary prevention and treatment of hypertension. A number of studies consistently demonstrate beneficial effects of exercise on hypertension with reductions in both systolic and diastolic blood pressure with as much as 5–7 mmHg reductions in those with hypertension [6,13–16].

Acutely, exercise has been associated with immediate significant reductions in systolic blood pressure. This immediate reduction in blood pressure after exercise can persist for almost 24 hours and is referred to as post-exercise hypotension with the most pronounced effects seen in those with higher baseline blood pressure [13]. More frequent or chronic exercise results in more sustained reductions in blood pressure referred to as the exercise training response [17]. Although age, sex, or ethnicity do not appear to change the blood pressure response to exercise, it should be noted that most studies have been limited by primarily studying only populations of middle-aged men of European descent [18].

The reduction in blood pressure with physical activity is thought to be due to attenuation in peripheral vascular resistance, which may be due to neurohormonal and structural responses with reductions in sympathetic nerve activity and an increase in arterial lumen diameters, respectively [19]. Other proposed mechanisms for blood pressure reduction include favorable changes in oxidative stress, inflammation, endothelial function, arterial compliance, body mass, renin-angiotensin system activity, parasympathetic activity, renal function, and insulin sensitivity [6]. The mechanisms underlying blood pressure reduction with exercise and its associated outcomes are still under investigation with many studies limited by size and marked heterogeneity [20].

Furthermore, the anti-hypertensive response to exercise is highly variable; differences in exercise regimens, environmental factors, and genetic factors may be responsible for considerable inter- and intra-study variability in the blood pressure response to exercise [18]. In one study, 20–25% of those with hypertension were non-responders with no reduction in blood pressure with exercise [21]. Studies investigating the genetic and clinical factors associated with responders and non-responders are ongoing [18].

Cardiac Remodeling

The adaptation to pressure overload states such as that with hypertension differs from that of the volume overload state associated with endurance exercise training. Both states are associated with well-described changes in cardiac structure.

Effect of Hypertension on the Heart

Hypertension is frequently characterized by pathologic left ventricular remodeling with concentric hypertrophy. By the Laplace law, the response to hypertension is initially adaptive with increases in wall thickness to decrease wall stress and oxygen demand. However, in some cases, chronic pressure overload results in a transition to a maladaptive response with concentric hypertrophy, eventual decompensation, and clinical heart failure [22]. Preventing or limiting the hypertrophic response to hypertension may therefore be integral in preserving cardiac function and preventing progression to heart failure and other adverse cardiovascular events. Anti-hypertensive therapy has proven to be an important intervention associated with regression or normalization of LVH in some patients [23].

Although LVH is the most commonly described cardiac adaptation to hypertension, changes in diastolic function and the left atrium are also associated with hypertension. Several studies demonstrate that diastolic dysfunction and left atrial (LA) enlargement are associated with hypertension [24–28]. The chronic afterload of hypertension results in LVH accompanied by impaired LV relaxation or filling, which results in an increase in LA pressure; the resulting chronic LA stretch is thought to induce LA enlargement [29].

The hypertensive heart can also be characterized by right ventricular hypertrophy (RVH) with a prevalence of approximately 30% from a meta-analysis of subjects with systemic hypertension [30,31]. Further studies are needed to evaluate the impact of these RV changes and subsequent anti-hypertensive treatment.

Effect of Physical Activity on the Heart

Much of what is known about the effects of exercise on the heart comes from studies on endurance athletes. Cardiac remodeling among athletes varies by the type of sport and its associated hemodynamic effects on the heart, commonly known as the Morganroth hypothesis [32,33]. Endurance exercise with predominant isotonic physiology typically results in eccentric LV remodeling with chamber enlargement and wall thickening in response to the increased volume load [34]. In contrast, isometric exercise is typically characterized by concentric LV remodeling without chamber enlargement in response to the increase in systemic vascular resistance [34]. Furthermore, athletes in mixed physiology sports have shown variable forms of cardiac remodeling [35]. While usually within normal limits, LV function may also be low normal or slightly depressed in endurance athletes at rest; this is thought to reflect physiologic reserve as these athletes often demonstrate normal or super-normal exercise capacity during provocative testing [36,37].

The Morganroth hypothesis has been recently challenged. The expected cardiac adaptations of eccentric hypertrophy and increased cardiac dimensions have been reproduced in endurance athletes, however, the expected pattern of concentric hypertrophy in strength-trained athletes has not been consistently demonstrated in recent reviews or meta-analyses [38,39]. The absence of cardiac remodeling may be due to the transient and intermittent exposure to pressure overload, that the expected rise in pressure may be balanced by a simultaneous Valsalva maneuver, or due to the limited number and marked heterogeneity in published studies in resistance-trained athletes.

Recent studies have brought more attention to the RV response to exercise. In endurance training, the RV enlarges similarly to the LV in response to the increase in cardiac output and volume overload, suggesting the presence of a balanced response to endurance exercise [40,41]. RV function may also be mildly reduced at rest but as seen in the LV, this may reflect contractile reserve in the endurance athlete [42,43]. RV hypertrophy, however, has not been shown in response to exercise and may reflect abnormal physiology in the absence of coexisting pulmonary hypertension. The pulmonary vasculature is protected from the large rise in intravascular pressure seen in strength-trained athletes, and this may explain the absence of RV changes in response to isometric exercise [43].

The athlete’s heart is also associated with LA enlargement in endurance athletes [44]. LA enlargement in athletes has been associated with normal or super-normal diastolic function [33]. While normal tissue Doppler imaging (TDI) does not exclude a pathologic condition such as hypertrophic cardiomyopathy, the presence of abnormal TDI strongly suggests a pathologic diagnosis [33]. Studies investigating changes in LA and RV structure and function are limited in resistance-trained athletes.

Furthermore, sex and racial differences have been demonstrated in the athlete’s heart. In men and women matched for training history, male athletes develop more marked LVH while female athletes have greater LV dilation [45,46]. Black athletes also demonstrate a greater degree of LVH compared to white athletes [45,47].

The dose response of exercise does not appear to be linear. Prolonged ultra-endurance exercise has been associated with maladaptive changes, including adverse cardiac remodeling and increased fibrosis [40,48,49]. The absence of regression or normalization with detraining is thought to distinguish these athletes from those with physiologic adaptations.

Reducing or abstaining from exercise has been associated with regression of myocardial adaptations to exercise [50–52]. Accordingly, detraining has been prescribed to differentiate physiologic from pathologic hypertrophy [33]. A group of elite male athletes with eccentric LVH demonstrated regression of LV mass and wall thickness to normal values while resolution of LV cavity enlargement remained incomplete with residual LV dilation in 22% of the cohort [51]. Regression of LVH in strength-trained athletes with concentric hypertrophy has also been demonstrated in a small cohort of 5 athletes [53]. The time necessary for meaningful detraining remains unknown.

Physical Activity and Cardiac Remodeling in the Hypertensive Heart

The influence of physical activity on the hypertensive heart, however, is less well described with relatively few published clinical trials in humans. Exercise in the hypertensive patient may be expected to result in LVH given the physiologic and pathologic remodeling typically seen in response to exercise and hypertension, respectively; however, several focused studies have demonstrated a paradoxical response to exercise with favorable effects on LV mass and structure (Table 1) [54–59].

Table 1.

Studies investigating the influence of physical activity on the hypertensive heart.

Authors	Year	Type of Study	Population	Age, y	Follow- up	Findings
Guirado et al.	2012	Prospective	N = 15 - -	68 ± 8	6 months	No change in LV structure or diastolic function with exercise.
Pitsavos et al.	2011	RCT	N= 52 100% Male -	53.5 ± 7.4	4 months	Significant decrease in LVMi with exercise.
Palatini et al.	2009	Prospective	N = 454 69.8% Male -	33.1 ± 8.4	8.3 years	Lower risk of developing LVH in exercise vs. sedentary group by crude and adjusted models.
Boman et al.	2005	RCT substudy	N = 958 58.6% Male -	65.9 ± 6.9	3 years	Significantly lower LV mass and wall thickness in active exercise groups vs. sedentary group in adjusted model.
Hinderliter et al.	2002	RCT	N = 82 45.1% Male 74% White	47 ± 9	6 months	Significant decrease in LV relative wall thickness, posterior wall thickness, and trend toward decreased LVMi in exercise group vs. control group.
Turner et al.	2000	Prospective	N = 18 77.8% Male -	66.5 ± 1.3	7 months	Significant decrease in LV wall thickness and LVMi in exercise group.
Kokkinos et al.	1995	RCT	N= 46 100% Male 100% Black	57.5 ± 14.9	4 months	Significant decrease in IVS, LV mass, and LVMi in exercise group. No significant change in non-exercise group.
Baglivo et al.	1990	Prospective	N= 32 68.8% Male 100% White	50.8 ± 7.9	15.7 ± 5.8 months	No significant change in LV mass with exercise.
Kelemen et al.	1990	RCT	N = 51 100% Male -	45.4 ± 8.3	2.5 months	Significant increase in LVMi with exercise. No change in diastolic function.

RCT-randomized controlled trial, LV-left ventricle, LVH-left ventricular hypertrophy, LVMi-LV mass index

In hypertensive subjects, regular aerobic exercise over a period of 16 weeks in 40 subjects was associated with significant reductions in LV mass index compared to controls whose LV mass did not change over the course of the study [59]. Active subjects also demonstrated significant reductions in systolic and diastolic blood pressure at baseline and at all stages of exercise as well as an improvement in functional capacity.

In a larger cohort of 454 people (ages 18–45) with stage I hypertension, those with regular physical activity had a lower risk of developing LVH compared to sedentary subjects (crude OR=0.15, CI, 0.05–0.52) with a slight decrease in association after controlling for age, sex, family history of hypertension, hypertension duration, follow-up length, smoking status, alcohol and caffeine intake, and baseline blood pressure, BMI, and LV mass (adjusted OR=0.24, CI, 0.07–0.85) [58]. Findings remained unchanged after adjusting for blood pressure and weight changes during follow-up [58]. Furthermore, sedentary participants were more likely to demonstrate an increased LV mass index and wall thickness compared to their active counterparts.

Older hypertensive patients aged 55–80 years also demonstrated a lower LV mass index in those that were physically active compared to those who were sedentary in 958 participants in the LIFE echocardiographic substudy in which subjects had yearly echocardiograms over 3 years of medical therapy [57,60]. This favorable association with lower LV mass in the active group remained after adjustment for BMI and sex. Lower LV mass was also associated with improved cardiovascular outcomes of mortality and stroke over 4.8 years. The reduction in adverse cardiovascular outcomes in the active group was independent of LV mass, suggesting that the benefits of activity and lower LV mass on outcomes are independent [60]. Activity level requirements were modest; the active group participated in greater than 30 minutes of activity twice a week. There was no significant difference in LV dimensions or ejection fraction between activity groups.

At odds with these findings, others have demonstrated no significant change in LV mass or structure with exercise [61]. No change in LV structure or function was seen with activity in a cohort of 23 subjects with heterogeneity in the prevalence of hypertension [62]. In another small cohort of 15 subjects with controlled hypertension, supervised exercise training was associated with improvements in improved physical capacity and muscle strength but no change in cardiac structure or function after 6 months of exercise [63]. Another group demonstrated a significant increase in LV mass with 10 weeks of exercise in 51 men [64]. Ultimately, the response may depend on a number of factors: type, intensity, and amount of exercise training; blood pressure response to exercise; duration of hypertension; and concomitant anti-hypertensive therapy. The response of the RV and LA has not been addressed in these few studies nor is there discussion of the effect of detraining in this population.

Biochemical, Molecular, and Cellular Mechanisms

The molecular and cellular response to exercise in the setting of hypertension has primarily been investigated in animal models, suggesting various potential mechanisms for favorable or maladaptive responses in the heart.

Sympathetic Nervous System

The effect of exercise on the sympathetic nervous system may play an important role in cardiac remodeling in the hypertensive heart. In addition to reductions in blood pressure, regular exercise has been associated with beneficial effects on heart rate and insulin resistance, which have been attributed to decreased sympathetic activity [14]. Significant reductions in plasma norepinephrine by 29%, plasma renin by 20%, and systemic vascular resistance by 7.1% have been demonstrated with exercise training in a subset of a meta-analysis involving up to 18 of 105 study groups [7]. Reduced sympathetic nervous system activity, renin-angiotensin-aldosterone, and systemic vascular resistance may prevent increases in LV mass in hypertensive hearts.

Left Ventricular Hypertrophy

Hypertrophy is a complex response to various stimuli and has been characterized as physiologic or pathologic, both thought to be the results of distinct signaling pathways. Physiologic remodeling is associated with cardiomyocyte hypertrophy with normal or improved cardiac function [65]. Pathologic remodeling, however, is typically characterized by cardiomyocyte loss (apoptosis and necrosis), fibrosis, ventricular dysfunction, and increased risk of heart failure and sudden death [65].

Of the various cardiac signaling pathways, the IGF-1/IGF-1R/Akt axis is thought to play a large role in exercise-induced cardiac remodeling [66,67]. Physiologic hypertrophy is mediated by insulin-like growth factor-1 (IGF-1). Exercise has been associated with increased secretion of IGF-1 in the bloodstream and cardiac expression of IGF-1. IGF-1 receptor activation leads to downstream signaling of key mediators of cell growth and survival (PI3K, Akt1). Mice with over-expression of IGF-1 demonstrate cardiomyocyte hypertrophy and hyperplasia as well as prevention of aging-associated cardiomyocyte attrition, consistent with physiologic hypertrophy [66,68–70]. In humans, IGF-1 levels correlate with LV mass index and LV cavity dimensions [71]. This same pathway appears to play an important protective role in the setting of pathologic stimuli such as hypertension given that mice deficient in PI3K or Akt1 display accelerated heart failure phenotypes [72–74]. In contrast, pathologic hypertrophy appears to be mediated by G protein-coupled receptors (Gαq) activated by angiotensin II and endothelin-1 [65,66,75]. Transgenic mice with inhibition of Gαq signaling do not demonstrate pressure overload-induced hypertrophy [76,77].

In hypertensive hearts, however, the mechanism of reduction in LVH with exercise is not well understood. Swimming in spontaneously hypertensive rats (SHRs) has been associated with a decrease in myocardial fibrosis, increase in myocardial capillary density, and upregulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) expression with improved LV systolic function, resulting in conversion from pathologic to physiologic hypertrophy [78]. This has been further demonstrated at the cellular level by elongation of LV myocytes and an increase in cell length to width ratio [79]. This may allow the heart to better respond to the demands of a pressure-overload state [66]. Other studies in SHRs have demonstrated cardiomyocyte hypertrophy with eccentric remodeling with chronic aerobic exercise training with a relative decrease in apoptosis [79,80]. Further studies are needed to better understand the underlying molecular mechanisms of exercise-induced cardiac remodeling in hypertensive hearts.

Contractility and Calcium Handling

Exercise training has also been associated with improved cardiomyocyte contractility, which has been attributed to alterations in intracellular calcium handling [81]. Improvements in calcium handling, including enhanced calcium sensitivity, contractility, and sarcoplasmic reticulum activity have been associated with exercise [82]. In hypertensive rats, exercise-training has also been associated with an increase in expression of calcium-regulatory proteins (SERCA2a, phospholamban, and ryanodine receptors) [78,83]. Exercise in hypertensive hearts may therefore improve or prevent abnormal calcium handling [79].

Cardiomyocyte Turnover

With regular, moderate endurance exercise, several animal studies have also demonstrated a decrease in age-associated apoptosis and increase in cardiac heat shock protein (HSP70) expression, which inhibits apoptosis [66]. This may, in turn, prevent the cascade of pathologic remodeling. The rate of apoptosis has also been attenuated in hypertensive rats with exercise training relative to sedentary hypertensive rats [80].

Furthermore, recent studies have verified the presence of endogenous cardiac stem and progenitor cells (eCSC) in the adult heart with exchange of up to half of an individual’s cardiomyocytes during a normal lifespan [66,84]. Endurance exercise has been associated with increased proliferation and cardiogenic differentiation of eCSCs, further contributing to the physiologic response [66,80].

MicroRNAs

Given the challenge of targeting a pathway with multiple actions, recent studies have focused on microRNAs (miRNAs), which are small, non-coding RNAs that regulate gene expression. The miRNAs can associate with the 3’-untranslated regions of messenger RNAs (mRNAs) with imperfect base-pairing and negatively impact gene expression by mRNA degradation or inhibition of translation [85]. Several miRNAs have been implicated in hypertension-associated cardiac remodeling, and exercise training has been associated with reversal or prevention of the pathological cascade mediated by these miRNAs. Additional studies are needed to further understand these pathways and identify potential therapeutic targets [18,85–87].

Conclusions

The physiologic and pathologic changes in cardiac structure and function in response to exercise and hypertension have been well demonstrated separately; however, our knowledge regarding the influence of physical activity on the hypertensive heart remains limited. Our current understanding comes from primarily small studies in middle-age white males with variable exercise modalities, intensity, and duration and variable control and duration of hypertension. Despite these limitations, exercise appears to have a positive effect on remodeling of the hypertensive heart with paradoxical regression or prevention of LVH. This regression of pathologic LVH appears be independent of body mass and changes in blood pressure with exercise. Various biochemical, molecular, and cellular pathways are implicated in the cardiac response. Further studies are needed to better understand the response to exercise in the hypertensive heart and which populations may benefit.