Cardiac Effects of Exercise Training in Hypertension

Hypertension is a signi�cant health concern. Hypertension leads to compensatory pathologic hypertrophy and impaired cardiac function. Lifestyle modi�cations such as exercise are encouraged for hypertensive patients. Some studies have shown that exercise training can reverse pathological hypertrophy. Conversely, studies on animal models of hypertension have shown increased cardiac growth with exercise training. Despite the further induction of hypertrophy, exercise training seems protective against cell death and may increase cardiomyocyte proliferation, leading to a putative phenotype. �ne of the hallmark bene�cial effects of exercise in hypertension is an improvement in myocardial ββ adrenergic responsiveness. e focus of this paper is to discuss how exercise training impacts cardiac remodeling and function in the hypertensive heart with speci�c reference to ββ adrenergic signaling.


Hypertension and Blood
Pressure with Exercise Hypertension is a signi�cant health concern, as it a�icts over 65 million individuals in the United States [1] and 1 billion people worldwide [2].e residual lifetime risk for developing hypertension in middle and older ages is 90% [1,3] and its prevalence has increased by 30% over the last decade [1].Moreover, with the number of older individuals on the rise, the prevalence of hypertension is certain to increase.is is a signi�cant issue in the epidemiology of cardiovascular disease, as hypertension increases the risk of ischemic heart disease, stroke, and heart failure [1].A key initiative in offsetting the consequences of hypertension is preventing or attenuating its negative sequelae in the �rst place.In this regard, several expert joint panel reports support the idea of lifestyle modi�cations such as exercise/physical activity, diet, and smoking cessation in the initial management of hypertension [1].e effects of chronic exercise training on blood pressure have been well studied.In normotensive subjects, there is an approximate 3-4 mmHg reduction in resting systolic and diastolic blood pressure following training [4][5][6].In hypertensive subjects, the reduction in blood pressure is even greater, that is, 6-7 mmHg reduction aer training [6][7][8][9].Aerobic exercise training has also been shown to reduce blood pressure during exercise [7,10] and ambulation [7,11,12].Acute aerobic exercise has even been shown to cause a relative hypotension during the postexercise recovery phase [13].us the overall reduction in blood pressure with aerobic exercise training attenuates aerload on the heart and is the hypothetical basis by which exercise may mitigate cardiac hypertrophy in hypertension.

Heart Remodeling with Hypertension
2.1.Compensatory Hypertrophy.Chronic hypertension negatively impacts both myocardial structure and function by serving as a substrate for the induction of pathological, concentric hypertrophy (Figure 1).It is thought that the hypertrophic cardiac response to increased pressure overload is an attempt to normalize le ventricular wall stress thus helping to maintain cardiac function in the face of an enhanced hemodynamic load.is process is referred to as "compensatory hypertrophy." With compensated myocardial hypertrophy, the heart remodels by the parallel addition of sarcomeres that characteristically increases cardiomyocyte area and width [14,15].F 2:  adrenergic signaling is impaired in hypertensive cardiomyocytes via GRK2 (red arrows).Exercise training attenuates GRK2 and calcineurin abundance in hypertension (green arrows) thereby allowing greater phosphorylation of PKA targets (green + ) such as phospholamban (PLB), ryanodine receptor (RyR), and the L-type Ca 2+ channel leading to improved systolic and diastolic functions during stress and exertion.Exercise also alters the agonist binding affinity for AR receptors (green arrows).SR: sarcoplasmic reticulum; AC: adenylyl cyclase; NOS: nitric oxide synthase; Gs: G stimulatory protein; Gi: G inhibitory protein.
Compensatory concentric hypertrophy is frequently manifested with altered myocardial systolic and diastolic function, for example, increased LV chamber stiffness [16] and �brosis [15].Diastolic abnormalities are clinically signi�cant, as diastolic heart failure accounts for nearly one-half of total heart failure cases and signi�cantly increases �ve-year mortality up to 10 fold [17].e development of compensated hypertrophy is regulated by mechanical loading factors in concert with the activation of endocrine, paracrine, and autocrine growth factors.ese factors activate cardiomyocyte hypertrophic growth by signaling through speci�c G-protein coupled ligand receptors [18,19].ese signaling pathways also regulate Ca 2+ transients in relation to the enhanced aerload of the hypertensive heart.However, chronic activation of these signaling pathways and subsequent chronic elevations in intracellular Ca 2+ concentrations induces cardiomyocyte growth via Ca 2+ -calmodulin-related mechanisms [19,20].In particular, the Ca 2+ -calmodulin-activated protein phosphatase, calcineurin, is centrally involved in hypertensioninduced compensatory hypertrophy.Activated calcineurin dephosphorylates members of the NFAT transcription factor family in the cytoplasm of cardiomyocytes thereby promoting nuclear translocation and the induction of a fetal gene program [18][19][20][21][22]. Transgenic overexpression of calcineurin has been shown to markedly increase heart size and induce heart failure, whereas calcineurin inhibition prevents these pathological sequences [19,20].Both cyclosporine A and FK506 have successfully been used to attenuate the development of cardiac hypertrophy by suppressing calcineurin abundance [18,21].Of interest, although calcineurin inhibition arrests cardiac hypertrophy in the face of pressure overload, it does not induce short-term hemodynamic compromise [22].e development of agonist-induced cardiac hypertrophy with phenylephrine and angiotensin II infusions has also been blunted with various techniques of calcineurin inhibition [23,24].

Apoptosis and Proliferation.
Compensatory cardiac remodeling with pressure overload is also in�uenced by the number of functioning cardiomyocytes.us understanding the balance between cardiomyocyte proliferation and apoptosis in pressure-induced hypertrophy is important [25].Several reports have shown that the heart contains resident cardiac stem cells that are capable of generating new cardiac tissue including cardiomyocytes [26][27][28].We have recently shown that hypertension slightly increases cardiomyocyte proliferation and the number of c-Kit+ cells in hypertensive rodent myocardium [25].However, hypertension-induced cell death occurs to a greater extent than cell proliferation, perhaps rendering the hypertensive myocardium with lesser number of functional cells relative to normotensive controls.As my laboratory has shown, the increased ratio of cell death to cell proliferation may also be linked to compromised LV systolic functional performance in the hypertensive heart [29].Even early in the hypertensive cascade, systolic elastance is lower in hypertensive hearts relative to normotensive controls [29,30].Whether this is related to hypertension-induced increases in apoptosis remains unknown, but is important to consider given that apoptosis induces cell shrinkage, membrane blebbing, DNA fragmentation, chromatin condensation, and cell death [31,32].e apoptotic death program is triggered by both internal and external signaling pathways.Cell death is typically replaced by �brosis [33] and is likely associated with the transition from compensated LV hypertrophy to heart failure [34] (Figure 1).
One molecule that is centrally involved in cell survival is protein kinase B or Akt.Akt-mediated phosphorylation of Bad promotes sustained activation of prosurvival factors that induce cell survival by decreasing mitochondrial membrane destabilization and cytochrome c release [35][36][37].Akt can also phosphorylate caspase 9 and decrease its activity [38].e Akt pathway has been shown to be upregulated with aerobic exercise and is linked to physiologic hypertrophy and may provide protection from apoptosis [39][40][41].However, it is unclear whether training upregulates Akt in the hypertensive heart [25,30].

Downregulation of Cardiac 𝛽𝛽-Adrenergic Receptors.
Of signi�cance, compensatory hypertrophy secondary to pressure overload is associated with a reduction in adrenergic receptor (AR) responsiveness and subsequent altered myocardial inotropic and lusitropic function in response to sympathetic stress [42].Although some studies have shown a decreased AR density in hypertension [43], abnormalities "downstream" from the AR are also involved in the impaired adrenergic responsiveness of the hypertrophied heart.For example, AR kinase (ARK1 or GRK2) has been shown to be centrally involved in blunting AR signaling in pressure overload hypertrophy [44] (Figure 2).Moreover, calcineurin-dependent signaling is also involved in AR downregulation, and recent data have shown that calcineurin opposes protein kinase A (PKA) activity [45,46].Our laboratory has shown that the calcineurin antagonism corrects impaired  adrenergic responsiveness in hypertensive hearts [46].Shis in  adrenergic responsiveness are also involved in diastolic dysfunction, secondary to a limited PKA-driven phosphorylation of phospholamban.
e AR pathway is the primary physiological means by which sympathetic stimulation controls myocardial inotropy, lusitropy, and chronotropy.us, this pathway is very important in regulating cardiovascular function during stress and exercise.ARs are members of the 7transmembrane domain receptor family which are coupled to GTP-binding proteins (Figure 2).ere are several isoforms of ARs in the heart (AR1, AR2, and AR3).Activation of AR1s causes bound GDP to be exchanged for GTP and stimulates adenylyl cyclase [47].e activation of adenylyl cyclase causes an elevation in cyclic AMP and subsequently activates cyclic AMP-dependent PKA.PKA phosphorylates key Ca 2+ cycling proteins including troponin I, L-type Ca 2+ channels, phospholamban, and ryanodine Ca 2+ release channels.e phosphorylation of L-type Ca 2+ channels enhances Ca 2+ current and stimulates sarcoplasmic reticulum (SR) Ca 2+ uptake and release upon being agonized with  agonists.Also AR1 activation decreases myo�lament Ca 2+ sensitivity secondary to phosphorylation of troponin I. Activation of AR also increases cardiac metabolism and glycogenolysis.
Overstimulation of ARs can cause them to become desensitized in seconds to minutes.ARs are found to be downregulated in both hypertension and heart failure which are both conditions of high sympathetic tone [42,44,46].Downregulation of ARs involves the phosphorylation of serine on carboxy-terminal end of the AR receptor by GRK2 and/or PKA [44,48].is can set the stage for ARs to be internalized by  arrestin, with the internalized ARs receptors being either recycled or degraded, leading to impaired inotropic and lusitropic function [49].
AR2 activation can produce the same effects as AR1s.However, AR2s are coupled to both Gs and Gi proteins [50].Agonism of AR2 likewise induces a PKA-mediated increase in inotropy and Ca 2+ ; however, their augmentation on cAMP concentrations and phospholamban phosphorylation are not as great as in AR1 agonism.In heart failure the ratio of AR1/AR2 falls and may be related to impaired cardiac performance with stress.Lastly, AR3 activation induces negative inotropic effects through nitric oxide signaling (NO) [51].NO production in ventricular myocytes stimulates guanylyl cyclase, cGMP production, and activates protein kinase G.While AR3s lack serine, they do not appear to be desensitized by GRK2.Agonism of AR3's has been shown to decrease myo�lament Ca 2+ sensitivity and Ca 2+ current [52].

Exercise Training
3.1.Cardiac Remodeling.Chronic exercise training causes a bene�cial adaptive response of the cardiovascular system, that is, decreased resting and submaximal heart rates and increased LV �lling time, venous return, and stroke volume [53,54].Chronic exercise training has been shown to enhance myocardial diastolic function [55][56][57], alters calcium uptake in the SR [57], and induces sinus bradycardia [53].Interestingly, exercise conditioning may potentially reverse diastolic dysfunction-associated pathologic hypertrophy [58] and/or with minimal effects on ischemia/reperfusion injury [59] while also lessening ageassociated declines in diastolic function [54].
Exercise training induces physiologic, eccentric cardiomyocyte hypertrophy where cardiomyocytes increase in cell length by approximately 7% [57].Lengthening of cardiomyocytes causes enlargement of the le ventricular cavity and focal areas of increased wall thickness.Aerobic exercise activates cardiomyocyte growth by stretch via increased plasma volume as well as activation of growth signals like insulin-like growth factors [39,40].It should be appreciated that there is a good correlation between le ventricular function during diastole and aerobic �tness [60].Exerciseinduced cardiac remodeling has not been typically shown to increase interstitial �brosis.Some reports even suggest that exercise training can reduce the development of �brosis in established pathologic hypertrophy [61].However, a very recent paper has shown that high levels of wheel running velocity in SHR rats can induce a pro�brotic phenotype and is positively correlated with LV mRNA of TGF-1, collagen III, and biglycan, whereas wheel running velocity was negatively correlated with SERCA2A to Na + -Ca 2+ exchanger ratio [62].
e effects of exercise training on cardiac remodeling in hypertensive human subjects have been reviewed elsewhere [63] and have shown equivocal results with some studies showing no change in le ventricular mass [64][65][66][67][68][69], a decrease in le ventricular mass/le ventricular mass index [64,[70][71][72][73][74], and an increase in le ventricular mass/le ventricular mass index [5,66].e majority of these studies showed that systolic and diastolic blood pressure was reduced following exercise, and imaging was most oen measured with M-mode and 2D guided echocardiography.ese studies also suggest that exercise can potentially reduce le ventricular mass, independent of the blood pressure lowering effects of exercise [68].Disparities in results concerning LV hypertrophy following exercise training may be secondary to variations in study designs, subject characteristics, exercise paradigms, and medication use.
In hypertensive animal studies, exercise training has been shown to reduce or delay the development of hypertension [75].Voluntary activity wheel running has been shown to reduce sympathetic tone and also results in resting bradycardia and attenuation of the tachycardia response during progressive exercise in SHR [76,77].is effect can, in part, be attributed to a signi�cantly reduced adrenergic tone controlling heart rate during exercise [78].
However, even though chronic exercise training reduces heart rate and blood pressure, it has been shown to increase hypertrophy at both the whole heart and cellular level in laboratory animals [25].Our laboratory has reported whole heart hypertrophy with echocardiography and histomorphometry with exercise training that is dispersed across several walls of the le ventricular myocardium (anterior, posterior, and septal walls).Isolated cardiomyocytes from exercise trained SHR were both longer and wider relative to sedentary controls [25].Similar �ndings in swim-trained animals have been reported, such that swim training increased le ventricular weight and le ventricular internal diastolic diameter in the spontaneously hypertensive rats [61].Swimming also increased cardiomyocyte cross-sectional area, reduced apoptosis, and normalized calcineurin without any signi�cant changes in the Akt pathway.is led to reduced �brosis, improved vascularization, and enhanced fractional shortening on echocardiography [61].us even though exercise potentiates cardiomyocyte growth, cardiac function is enhanced relative to sedentary controls.
Our studies have also found that training mitigated calcineurin gene and protein expression in hypertension [30], illustrating that exercise superimposed on hypertension induces cell growth by other signaling mechanisms beyond Akt [25].We have also reported a reduction in overall cell death with training, despite an increased expression of caspase 3 in hypertensive trained hearts [30].is is similar to recent data by Huang et al. who showed a reduction in Fas ligand and mitochondrial-mediated apoptosis in SHR following training [79].We have also found that the rate of cardiomyocyte proliferation is increased with training and hypothesize that training may bene�cially preserve overall cardiomyocyte number and phenotype in hypertension [25].us one of the major bene�ts of exercise training in hypertension is the preservation of cardiomyocyte cell number.Despite the potential for exercise training to increase myocardial mass in pressure overload, most studies have reported an improved phenotype aer training [25,30,46,61,[80][81][82][83][84][85][86][87].One of the most proli�c bene�ts of exercise training is its improvement on adrenergic signaling.

𝛽𝛽-Adrenergic
Responsiveness.Studies in both normotensive and hypertensive humans and animals have shown that exercise training enhances AR responsiveness [46, throughout the lifespan.One study in postmenopausal women did not show a putative effect in AR responsiveness with training [90].Interestingly, a study by Scott et al. showed that postexercise AR responsiveness was maintained in women to a greater extent than men following exhaustive exercise.is is a signi�cant �nding given that postexercise AR desentization is hypothesized to be an element of cardiac dysfunction aer acute, exhaustive exercise [112].
While treadmill running is typically used as the exercise modality, swimming has also been shown to be effective in increasing AR responsiveness in increasing agonist-binding affinity and increased AR responsiveness, despite a reduction in myocardial AR density [94].While AR binding affinity has also been shown to increase following training [107], such �ndings iterate the importance of downstream signaling adaptations with training [46,81].
In general, cardiac AR density has been shown to decline with exercise training without changing the ratio of AR1 to AR2s subtypes [96][97][98].Still other studies have shown an attenuation of AR1s with training without altering AR2s.Conversely, Stones et al. showed that AR1 inotropic responsiveness was not changed following voluntary wheel running.However, AR2 speci�c adrenergic inotropic responses were attenuated in trained animals [92].Exercise training has also been reported to attenuate the contractile responses to AR2 stimulation in dogs while restoring AR1 adrenergic receptor protein content [99][100][101].Whether training exerts its effects on downregulating AR2s is an interesting idea that requires further testing.
Our work in SHR animals has shown that despite the induction of hypertrophy with treadmill running, exercise improved AR responsiveness by attenuating the characteristic rise of GRK2 in the hypertensive heart [46].Iemitsu et al. also showed that GRK, BMP, ACE, and ET-1 mRNA were reduced in swim-trained SHR rats compared to SHR sedentary animals [85].Exercise training has also been shown to alter PKA-mediated phosphorylation of key calcium handling proteins such as the ryanodine receptor and phospholamban [46].Our studies have also shown that exercise training potentiates the inotropic responses to forskolin [81].is is consistent with other studies showing that adenylyl cyclase activity increases with exercise.Exercise training has been shown to increase adenylyl cyclase activity in the absence of a AR agonist [102] or in the presence of a AR agonist [110].ere are, however, data that show no change or even a decrease in adenylyl cyclase activity with training [102,103].us exercise training improves AR responsiveness in hypertension, but the underlying mechanisms have not been fully elucidated.A reduction in GRK2 and calcineurin with training in hypertension have been shown to be mechanistic component of the adaptive response [46,85,105,106] (Figure 2).
Beyond improved AR responsiveness with training in hypertension, exercise has generally been shown to improve the overall heart phenotype and prolong survival [86,87].While extreme levels of acute and chronic exercise may be deleterious to the heart by increasing apoptosis, �brosis, and ischemic dysfunction [62,113,114], moderate levels of exercise seem protective from cardiac damage.ese animal studies support the American College of Sports Medicine recommendation for encouragement of exercise on most, if not all, days of the week, at moderate intensities, by accumulating 30 minutes or greater of endurance-style physical activity [7].

Summary
Compensated le ventricular hypertrophy in hypertension involves cardiomyocyte hypertrophy, apoptosis, and proliferation of cardiomyocytes.Exercise affects each of these pathways, but the contributory role of speci�c signaling pathways is not clear.Calcineurin expression is attenuated with exercise training, but in animal studies, exercise instead increases cardiomyocyte hypertrophy while decreasing apoptosis and �brosis.High volume�intensity exercise in hypertension, however, may be deleterious to the heart by increasing apoptosis and cardiac dysfunction.In humans, exercise training shows equivocal morphometric results, with some studies showing a reduction in LV mass and others no change.In both humans and animals, exercise improves the overall phenotype of the heart.is effect appears to be independent of the blood pressure lowering effects of exercise.One of the hallmark phenotypical shis with hypertension is a downregulation of the AR system.Exercise training improves AR responsiveness in the heart, perhaps by increasing AR binding affinity or through downstream effects such as a suppression of GRK2 and calcineurin.Despite the underlying mechanisms, participation in exercise and physical activity is important for prehypertensive and hypertensive patients and should be performed at low intensities.Patients should closely consult with their healthcare providers in structuring an exercise program.

F 1 :
Compensatory pathologic hypertrophy induces cardiac remodeling.Concentric cardiomyocyte hypertrophy via increased calcineurin signaling, increased cell death per cardiomyocyte proliferation, increased �brosis, impaired cardiac function, and decreased  adrenergic signaling are all hallmarks of compensatory pathologic hypertrophy.Exercise training decreases blood pressure and rate pressure product in hypertension.However, its effects on overall heart remodeling are unclear.Data in humans show an equivocal response with the heart either getting smaller or showing no change.In animal studies, whole heart enlargement with cardiomyocyte hypertrophy occurs, despite a reduction of calcineurin protein expression.�raining decreases the cell death�proliferation ratio, decreases �brosis, and improves the overall phenotype of the hypertensive heart.