Cardiac Hypertrophy Exercise


It is well-known that regular physical activity plays an important role in the prevention and reduction of chronic diseases including cardiovascular disease and is an important, modifiable behavioral risk factor.[1] Cardiac dysfunction is associated with hypertrophy via multiple signaling pathways, metabolic abnormalities, apoptosis, remodeling, and fibrosis. While exercise is considered beneficial in individuals with normal heart function, special considerations must be made in people with various forms of heart disease. It is critical to determine whether exercise is beneficial to cardiac function in pathological conditions, and if so, the intensity, duration, and frequency that is most advantageous and safe in these individuals. In addition, it's important to determine if differences exists across populations (i.e., between genders) which may have additional implications of prescribed exercise programs. Alongside acquired pathology, inherited cardiac hypertrophy and the implications of exercise must also be considered. As discussed in the cell biology of cardiac hypertrophy page, two classifications of hypertrophy exist: physiological and pathological hypertrophy. It is important to determine the point at which physiological adaptations become pathological in response to exercise.


Cardiac cellular and molecular remodeling and exercise training


Figure 1. Cardiac Cellular and Molecular Remodeling[2]

Regular exercise and physical activity elicits benefits on the cardiovascular system by reducing one’s risk for developing cardiac injury/disease as well as directly impacting the remodeling of the heart in both a cellular and molecular manner.[2] There has been an extreme change in the approach to treating and preventing heart disease in the past 30 years that now incorporates moderate-vigorous exercise prescription.[2]With regular exercise training, the structure of the myocardium is restructured via a balanced enhancement of the myocardial mass.[2] The myocardial mass includes hypertrophy of the myocytes, as well as neo-angiogenesis, which is more commonly referred to as “the athlete’s heart.”[2] Athletes that are endurance-trained exhibit mostly eccentric hypertrophy of the left ventricle, consisting of a significant increase in the dilation of the left ventricle and increased wall thickness.[2] Athletes focused on strength training typically demonstrate mostly concentric hypertrophy, as evident by a mild-moderate increase in left ventricle dilation and thickened left ventricle wall.[2] When you combine the two types of training, these are the athletes that will demonstrate the greatest amount of dilation and wall thickening of the left ventricle.[2]

Although its mechanism and clinical relevance are not fully understood, recent studies conducted in healthy adults have found that regular exercise leads to increased levels of cardiac troponin.[3] Elevated cardiac troponin concentration is typically evident as a result of damage to the heart; however Shave et al[3] concluded that in healthy adults the increase appears to be benign in nature. Alternatively, regular moderate endurance training has been consistently shown to have negligible effect on cell death within the heart.[2] For example, in a study that looked at rats that completed treadmill training for 60 minutes, 5 days/week displayed signs of improved cardiac function and no presence of apoptosis at week 4, 10, and 13.[4]

Hypertrophic Signaling Pathways

Acute exercise causes multiple changes in the heart, including increased mechanical load, heart rate, stroke volume, and sympathetic nervous system activity.[5] The associated increases in pressure and volume ultimately induce a stretch to cardiac myocytes,[5][6] and subsequently activate the hypertrophic MAPK signaling pathways.[7]

Table 1. Effects of exercise on hypertrophic signaling pathways in normal hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Moreira-Gonçalves et al 2011[8] Male rats Moderate 14 week progressive aerobic (treadmill) program: 5 days/week, duration and speed were gradually increased over the first 3 weeks until 90 minutes/day at 30m/min, 0% grade (approx 70% VO2max) Improved exercise tolerance; No pathologic signalling pathways activated; No abnormal remodeling
Libonati et al (2011)[9] Female rats Moderate 12 week aerobic (treadmill) program: 5 days/week; speed 25 m/min, 0% grade, 60 minutes Improved beta-adrenergic responsiveness
Iemitsu et al (2006)[10] Male rats Moderate Experiment 1: Treadmill running at 30m/min (approximately 70% VO2max)for 5, 15, and 30 minutes followed by 0.5, 1, 3, 6, 12, or 24 hours of rest; Experiment 2: 4, 8, or 12 weeks of treadmill training gradually increased over the course of 1 week to 60 minutes/day at 30 m/min Experiment 1: (+): increased activation of ERK, JNK, p38 MAPKs and associated MAPKKs and early genes after single bout of exercise in untrained rats; effect not seen in trained rats; Experiment 2: (+): Decreased MAPK response to a single bout of exercise; response absent after 12 week-training
Wilkins et al (2004)[11] Male & female mice Moderate Voluntary wheel running or swimming for various lengths of time Significant physiological hypertrophy; no increase in calcineurin-NFAT signaling pathway
Kemi et al (2008) [12] 34 female mice High intensity Interval treadmill training at 85-90% VO2max, 1.5 hours/day, 5 days/week for 6 weeks Increased activation of IGF which stimulates the PI3K-Akt-mTOR pathway; enhanced protein synthesis and contractility of the heart
Vichaiwong et al (2009)[13] Male rats Moderate 6 week progressive treadmill training program: Speed and duration were gradually increased to 25 m/min at 10% grade for 40–70 min/day over 3 weeks; In weeks 4–6, speed and duration were maintained at 20–25 m/min at 5–15% grade for 90 min/day Negative H202 (oxidative stress) effects on skeletal muscle insulin sensitivity and p38 decreased after exercise
Boluyt et al (2003)[14] Female rats Low, medium, high intensities; chronic exercise Experiment 1: Rats assigned to either low intensity (10 min, 15 m/min at 0%); medium (10 min, 33 m/min at 0%); high (10 min, 33 m/min at 25%); long duration (30 min, 15 m/min at 0%) Experiment 2: 6 week high-intensity treadmill training JNK and c-Jun activation increased following single bout of exercise in linear correlation with intensity; no activation of JNK and c-Jun after single bout in chronic exercisers
Li et al (2011)[15] IL-6-deficient male mice Low 12 weeks of treadmill training for 60 minutes/day, 5 days/week at 15 m/min at 10% incline; another cohort at 23 m/min Exercise improved insulin sensitivity, increased PGC1-α phosphorylation; no differences between exercise intensities

In the normal healthy heart, acute left ventricular (LV) overload is initially a physiological adaptation. However, overtime it has the potential to trigger detrimental signaling pathways leads to pathological cardiac hypertrophy. Due to lack of evidence, Libonati et al (2011)[9] and other studies have proven that exercise training improves cardiac β-adrenergic responsiveness in young, normal myocardium. Thus, prolonged exercise improves the heart's beta-adrenergic responsiveness and left ventricular contractility. Another study[8] in healthy hearts also demonstrated moderate exercise training improves the heart's tolerance to acute LV pressure-overload, prevents hypertensive dysfunction, reduces susceptibility to pathologic conditions, and thus promotes a cardioprotective phenotype.

A 2006 study[10] observing trained and untrained rats demonstrated the increased activation of multiple MAPK signaling pathways (ERK, JNK, p38) in the heart in an exercise duration-dependent manner immediately following a single bout of exercise in untrained animals. Expression of the hypertrophic c-fos, c-Jun, and c-myc genes, the downstream targets of ERK, JNK and p38, was also increased in untrained animals, as well as AP-1 at the level of the DNA. This activation pattern was not seen in trained rats. Interestingly, chronic exercise training for 4-12 weeks decreased the response of MAPK pathways to a single bout of exercise. More specifically, after 12 weeks of training this activation response disappeared, although physiological hypertrophy was present.

Similarly, JNK is activated by exercise-induced changes in hemodynamics that induce stretch on the myocardial wall, as well as rises in angiotensin II.[18] Endurance training has been shown to decrease the inhibitory effect of oxidative stress, a stimulant of the p38 and JNK MAPK hypertrophic signaling cascade, on insulin action in skeletal muscle and p38 levels in sedentary rats.[13] A single 10-minute bout of aerobic exercise in untrained rats was shown to activate JNK and the associated c-Jun gene.[14] This activation shared a positive, linear relationship with intensity such that as intensity increased, so did JNK activation. This effect, however, was not demonstrated in the hearts of trained rats that showed physiological hypertrophy.[14] Therefore, the hypertrophic stimulant JNK was not activated in the hearts of chronically trained rats following acute stress, maintaining cellular homeostasis. It should be noted that the critical difference between pathological cardiac hypertrophy and physiological hypertrophy is the duration of stimulus activation. With exercise, there is a transient or short-term activation of these pathways, whereas a chronic activation ultimately leads to pathological hypertrophy. Acute activation through daily exercise may help desensitize the cellular responses to stress and therefore maintain a balance in the hypertrophic MAPK signaling pathways.[19]

Thus, evidence supports and reinforces the model of prevention in cardiovascular health. Further leading to an exercise prescription of moderate aerobic intensity, most days of the week.


Table 2. Effects of exercise on the mitochondria in normal hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Strom et al (2005)[20] Male rats High 7.5 weeks treadmill training for 2 hours/day, 5 days/week at 8° incline with 20 min warm-up: running speed gradually increased from 15 m/min to 32.5 m/min and duration reduced from 100 to 80 minutes for last 2.5 weeks Up-regulation of genes involved in beta-oxidation of fatty acids or FAO after training
Li et al (2011)[15] IL-6-deficient male mice Low-Moderate 12 weeks of treadmill training for 60 minutes/day, 5 days/week at 15 m/min at 10% incline; another cohort at 23 m/min No effect on mitochondrial biogenesis: no increases in mRNA, mtDNA, PGC-1 α, citrate synthase; insignificant increases in AMPK; no differences between exercise intensities
Shoepe et al (2012)[21] Male rats Moderate and High 10 weeks of treadmill training: 4 days/week at 25 m/min at either a 16% (high intensity) or 10% (moderate) incline; Duration progressively increased 15 minutes weekly from 30 min/day to 120 min/day for the last 4 weeks At 6 weeks (high-intensity only): Decreased mitochondrial oxidative capacity, ETC activity and myocardial contractility; At 10 weeks: Effects listed above absent; LV hypertrophy and normal cardiac function noted; no adverse changes throughout protocol with better contractility and less hypertrophy present at 10 weeks at lower-intensity
Ascens et al (2006)[22] Male rats Moderate endurance 14 weeks of treadmill training: 5 days/week at 25 m/min at 0% grade; duration gradually increased to 60 min/day by second week Training significantly attenuated the mitochondrial respiratory chain dysfunction following induced anoxia-reoxygenation seen in sedentary rats

Decreased mitochondrial quality and function are associated with cardiovascular disease, obesity, hypertension, and Type II diabetes, among other conditions. [23][24] Furthermore, an associated decrease in myocardial fatty acid oxidation (FAO), the mitochondrial energy system, has been shown to be characteristic of cardiac hypertrophy and heart failure associated with hypertension.[25][26][27] Several studies have proven high-intensity exercise to be beneficial in increasing FAO in healthy and injured rats. Following 7 weeks of high-intensity treadmill training, a change in gene expression was noted with physiological hypertrophy and normal cardiac function in the hearts of healthy rats.[20] Gene expression changes were associated with an up-regulation in genes involved in beta-oxidation of fatty acids, a group typically down-regulated in pathological hypertrophy. This change presumably increases FAO and oxidative capacity, and was not evident in pathological hypertrophy. However, it is worth noting that the exercise protocol was extremely vigorous and time-consuming; animals were exercise at extremely high intensities for up to 2 hours per day, 5 days per week. These parameters are very unfavorable and likely inapplicable to humans. Similar results regarding FAO were noticed in pathological hearts following high-intensity exercise.[91]

In physiologic hypertrophy, there is an increased activation of P13K, PGC-1 α, and AMPK, all which promote the mitochondrial biogenesis required to maintain or improve the required cardiac metabolism and function.[28][29] On the contrary, in pathological hypertrophy there is a decrease in expression or activity of PGC-1 α and mtDNA.[28] In response to exercise, muscle adapts to the increasing energy requirements via production of new mitochondria and the components of its respiratory chain in order to produce adequate energy or ATP.[30] Increasing levels of IL-6, P13K, PGC-1 α, and AMPK in skeletal muscle are also associated with exercise. However, this effect remains controversial in cardiac muscle.

A recent study[15] showed mitochondrial biogenesis was increased in skeletal muscle but not the left ventricle after 3 months of moderate-intensity treadmill training, 5 days/week for 60 minutes, in both wild-type and IL-6 knockout mice. Results in the heart showed no increases in mRNA or mtDNA content or PGC-1 α activation with training. Interestingly, AMPK activation was increased in the LV even in the absence of IL-6, its activator, with associated improvements in insulin sensitivity in both skeletal and cardiac muscle. These results were similar with low and moderate intensity levels, posing the question of whether the intensity was high enough to induce similar positive changes seen with FAO with higher intensity exercise.

Lastly, a 2012 study[21] showed that high intensity training may lead to temporary mitochondrial and contractility dysfunction in the healthy heart. After 6 weeks of high-intensity treadmill training, rats were found to have decreased mitochondrial oxidative capacity and ETC activity and myocardial contractility. This effect was absent at 10 weeks, when LV hypertrophy with normal cardiac function was noted. Interestingly, rats participating in moderate-intensity treadmill training showed less hypertrophy and normal mitochondrial function and contractility throughout the intervention. Results from this study suggest that high-intensity training may be disadvantageous or unsafe temporarily, and moderate-intensity is consistently safe. It should be noted that following 10 weeks of exercise, both groups (moderate and high-intensity) did not make improvements beyond baseline in mitochondrial oxidative capacity. Authors suggest that a longer duration, presumably 14 weeks, would have led to significant improvements with such. Ascens et al[22] demonstrated the effectiveness of this duration on mitochondrial function. A 14-week, moderate-intensity endurance training model was effective at significantly attenuating the adverse effects of an anoxic injury on mitochondrial oxidative capacity in the heart. Thus, this type of training served as a form of cardioprotection against applied stress.[22]


Table 3. Effects of exercise on remodeling in normal hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Kemi et al (2002)[31] 36 Male and 40 female adult mice High intensity Treadmill running for 2 hours/day, 5 days/week, at 85-90% VO2max, for 8 weeks 20-32% increase in cardiomyocte dimensions in males and 17-23% increase in females
Kemi et al (2008)[12] 34 female mice High intensity Interval treadmill training at 85-90% VO2max, 1.5 hours/day, 5 days/week for 6 weeks Cardiomyocyte size increase; enhanced contractility

In both of the above studies by Kemi et al[31][12], high intensity interval treadmill training for 6-8 weeks lead to a significant increase in cardiomyocyte size as well as enhanced contractility and function of the heart.


Based on our research, there is no information regarding the implications of exercise on normal myocardium and apoptosis.


Table 4. Effects of exercise on fibrosis in normal hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Kwak et al (2011)[32] 20 young and 20 old hybrid rats free of cardiovascular disease Moderate Treadmill running at 75% max aerobic capacity for 45 min/day, 5 days/week for 12 weeks Age-related fibrotic changes in the heart were ameloriated by exercise in that it led to decreased collagen deposition; decreased TGFβ protein levels; increased active MMPs-1,2,3,14; decreased TIMP-1,2
Czarkowska et al (2009)[33] 59 male normotensive Wistar rats Moderate Treadmill running at 28 m/min for 60 min 5 days/week for 6 weeks No change in myocardial TGFβ mRNA
Fernandes et al (2011)[34] 42 female normotensive Wistar rats Low Swimming Protocol 1 (moderate volume of 60 min 5 days/week for 10 weeks) and Protocol 2 (same as Protocol 1 but high volume week 9 was 60 min x2 and week 10 was 60 min x3 for 5 days those weeks) Decreased Angiotensin, AngI, AngII, and ACE with greater reductions after high volume exercise

According to the animal models described in Table 4 above, aerobic exercise is safe and may produce positive changes in regards to cardiac fibrosis.[32][33][34] Kwak and his colleagues aimed to determine age-related fibrotic changes in the heart and how exercise impacts these changes.[32] Cardiac fibrosis that comes with aging is often due to a reduction in collagen degradation, indicating possible decreased activity of matrix metalloproteinases (MMPs) and increased tissue inhibitors of metalloproteinases (TIMPs), which inhibit MMPs.[32] The authors concluded that treadmill running at 75% maximum aerobic capactiy lessened age-related cardiac fibrosis by decreasing collagen deposition, TGFβ protein levels, TIMPs, while increasing MMP-1, 2, 3, and 14.[32] Despite the decrease in TGFβ in the Kwak et al study, another study showed no change in myocardial TGFβ mRNA after moderate intensity aerobic exercise performed for 6 weeks.[32][33] However TGFβ protein in the heart was not measured in this study.[33] It is important to note that this level of training did not increase TGFβ mRNA, which would contribute to increased fibrosis.[33] The study by Fernandes et al, showed that moderate and high volume, low intensity aerobic exercise led to decreased Angiotensin II (AngII) which has been shown to initiate the fibrotic response in the heart.[34] Therefore, by decreasing AngII levels, it can be concluded that manifestation of cardiac fibrosis is less likely.[34] This article also showed that intensive aerobic exercise if performed at a low intensity is safe to perform in the normal healthy heart in regards to Angiotensin and its family of hormones and enzymes.[34] In conclusion, low to moderate intensity aerobic exercise for 45-60 minutes per day, 5 days per week for 6 to 12 weeks led to beneficial changes in the normal healthy and aging heart.[32][33][34]

Heat Shock Proteins and Gender-Specificity affecting Benefits of Exercise

Cardioprotection (e.g., cellular protection against ischemia-reperfusion injury and subsequent cell integrity degradation) is not exclusively a mechanism of heat shock proteins (HSPs), however, they play a critical role in combating oxidative stress and preventing myocyte death by apoptosis. In order to protect the myocyte from apoptotic-inducing stimuli, HSPs are activated in response to oxidative stress (i.e., increased expression of reactive oxygen species), exercise, and various other cellular stressors. Multiple HSPs, such as HSP10, HSP40, HSP60, HSP70, HSP90, are recognized as protective mechanisms against cardiovascular stress, [35][36] because of their antioxidant effects in response to reactive oxidative species (ROS). However, the exact mechanism that is responsible for the expression of cardiac HSP is still under investigation. Nonetheless, HSP70 has been individually studied due its selective expression. [37] It is thought to play a “cytoprotective role against cardiac protein-damaging stresses” like exercise. [37][38] The increased presence of Hsp70 has also been shown to prevent stress-induced apoptosis in several pro-apoptotic pathways and various pro-inflammatory cytokines.[39]

Interestingly, Paroo et al (2002)[37] was the first to deduce that the HSP response and subsequent protection of the heart appears to have a gender bias.[37] Exercise-induced heart protection has also been shown to be strongly dependent on the hormone estrogen reinforcing the gender-specific model, in favor of male rats even after ischemic injury and ovariectomied female rats. This study[37] found that after only a single bout of exercise HSP70 expression levels doubled in post-ischemic male rats and ovariectomied females (i.e., removing the primary source of estrogen) compared to intact female rats (i.e., ovaries intact - a premenopausal state) and ovariectomized females with estrogen replacements. To delineate a true gender difference, the researchers removed the ovaries in female rats to see if estrogen had any direct implications. Again, their HSP70 levels were similar to male rats. Thus, because estrogen replacement reversed these effects the post-exercise presence of HSP is both gender-mediated and hormone-mediated (e.g. estrogen).[37][40][41] Regardless is estrogen was present or not males still had a better potential for HSP expression and recovered better.[37][42] After an ischemic event exercise improved heart function in both males and ovary-removed females was found which demonstrated a marked presence of HSP70 post-exercise. Thus, the amount of HSP in response to exercise can improve cardiac function, even in a heart that has been damaged.[37] This evidence suggests a cardiac defense mechanism with the absence of estrogen, in addition to attenuated mitochondrial damage and improved function post-injury, and an attenuation of apoptosis.[37] It was also suggested that in females, premenopausal, the increase of Hsp70 in cardiac myocytes appears to be NF-κB and heat transcription factor-1 (HSF-1) dependent.[43] As an aside, HSF-1 binds to the heat shock element of HSP70 and induces an upregulation of HSP70 mRNA.[37] In conjunction with exercise-induced increases in heat shock protein-70 (HSP70) were improvements in LV pressure, the maximal rate of cardiac contraction and relaxation, and reduction in end-diastolic pressure.[37] These effects were not observed in females. Therefore these findings may indicate that exercise is of greater importance in males than females for cardioprotection, as males recovered cardiac function much faster and to a greater degree than females. It is also worth noting that while exercise at low or moderate intensities may not be harmful to females, high-intensity exercise or severe stress may result in ischemic injury due to this phenomenon compared to males. Although estrogen has the ability to relatively maintain homeostasis following moderate exercise, it blunts the body’s adaptive response or defense mechanism against stressors. Therefore, when severe stress occurs, females are at a potentially higher risk for injury compares to males.[37][41]

Also noteworthy is that one study[41] found that the negative effects of estrogen appear to be acute not chronic. In the earlier study by Paroo et al (2002),[37] the rats performed a single bout of exercise so neither the implications for chronic exercise or whether the heart may be further protected due to chronic elevation of heat shock proteins was not deduced. Yet, more recent evidence supports the theory that an advantage exists for premenopausal female in the incidence of CVD (i.e., an upregulation of the cardioprotective Hsp70 by estrogen and progesterone).[41]

Furthermore, the effect of exercise on stress-activated MAPKs was also seen in the cardioprotective heat shock protein (HSP) response invoked by acute exercise. [44][45] Heat shock is a stimulator of the stress-induced MAPK pathways of JNK and p38 that has been shown to promote ventricular recovery following ischemia-reperfusion injury.[46] Exercise has been shown to increase heat shock protein in the heart and subsequently suppress JNK.[44]

Exercise for post-menopausal women thus is more beneficial due to the loss of estrogen production and HSP production, leading to a cardiovascular protective mechanism. Again, exercise may be more important for males than for females in preventing cardiovascular disease and the increased presence of Hsp70 after exercise is a way males can potentially reduce the risk of cardiovascular events. Evidence supports this concept that exercise is of greater importance in males than females for cardioprotection, as males recovered cardiac function much faster and to a greater degree than females.[37][41] While the premenopausal women may be protected against a cardiac event, a preconditioning bout of exercise may be more beneficial to males than females if a negative cardiovascular event does occur. Premenopausal females may require more intense exercise or multiple training sessions to garner the same beneficial adaptations. It is worth noting that while exercise at low or moderate intensities may not be harmful to females, high-intensity exercise or severe stress may result in ischemic injury due to this phenomenon compared to males.[37][41] Although estrogen has the ability to relatively maintain homeostasis following moderate exercise, it blunts the body’s adaptive response or defense mechanism against stressors. Therefore, when severe stress occurs, females are at a potentially higher risk for injury compares to males. More recent research has also supported these findings.[41] But to our knowledge there has yet to be human studies that have tested this premise.

ACSM General Exercise Guidelines

In order to accomplish overall change in health and wellness, it is highly recommended by the Centers for Disease Control (CDC) and American College of Sports Medicine (ACSM) that each adult in the United States engage in at least 30 minutes of physical activity on most days of the week at a moderate intensity level.[1] The prescription of a specific exercise program will vary from person to person based on their overall goal, individual health needs, and individual interest.[1] It will also largely depend on if the person is trying to strictly improve their overall physical fitness level or if they are more focused on reducing their risk for developing various chronic diseases, such as hypertension, hyperlipidemia, type II diabetes, etc.[1] Each exercise prescription should incorporate 5 different elements, which include the type of program, frequency, intensity, duration, and mode.[1] These various elements may be modified and adapted based on the patient’s current health status, current medications, number of risk factors for chronic disease, and personal goals.[1]

In a cardiorespiratory fitness program, the results lead to improved cardiac functioning in that the heart becomes more efficient in delivering oxygen to the working muscles.[1] In order to evaluate if a program is improving the cardiorespiratory fitness level, VO2max testing is completed.[1] Typically, exercise training may result in a 5-30% increase in the person’s VO2max.[1] Dynamic exercises that incorporate large muscle groups for an extended period of time, such as walking, running, swimming, hiking, stair-climbing, and cycling will typically result in the greatest improvements in VO2max.[1] The range of cardiorespiratory intensity from 70-94% heart rate max recommended by the ACSM and CDC, has been shown to be beneficial in improving VO2max in patients that were enrolled in primary and secondary prevention exercise programs when combined with appropriate frequency (3-5 days/week) and duration (20-60 minutes).[1]

A resistance exercise program has also been shown to aid in the reduction of risk for developing numerous chronic diseases such as, osteoporosis, hypertension, type II diabetes, etc.[1] Although resistance training does not significantly improve one’s VO2max, it has been shown improve one’s cardiovascular endurance level by enhancing their muscular strength and endurance, which allows them to sustain their cardiorespiratory activities for a longer duration.[1] The ACSM recommends incorporating resistance training into both primary and secondary prevention programs in combination with cardiorespiratory training.[1]

Table 5. ACSM General Exercise Guidelines[1]

Type of Program Frequency Intensity Duration Mode
Cardiorespiratory Training 3-5 days/week 70-94% heart rate max; 12-16 on Borge RPE Scale 20-60 minutes Dynamic activity incorporating large muscles of the body (i.e. walking, hiking, jogging, swimming, cycling, stair-climbing, etc.)
Resistance Training 2-3 days/week Either to volitional fatigue or about 2-3 repetitions prior to reaching volitional fatigue ≥ 1 set; 3-20 repetitions 8-10 various exercises including each of the main muscle groups


The "Athlete's Heart"

Exercise has been shown to induce positive adaptations that are indicative a stronger heart that functions efficiently. These changes are termed physiological hypertrophy or the “athlete’s heart” and are characterized by increased ventricular wall thickness along with increased chamber size that preserves the ejection fraction.[47],[48]

Myocardial Fibrosis & Lifelong Endurance Exercise

Aerobic exercises have long been prescribed as the cornerstone of cardiac rehabilitation programs. If endurance exercise promotes recovery from cardiovascular pathologies, intuition may allow the assumption that elite endurance athletes have the healthiest hearts. However, recent evidence is challenging this assumption and postulating a more counter-intuitive truth: lifelong ultra-endurance athletes often have significant myocardial fibrosis compared to their less active age-matched peers.

Observations from Human Studies

Due to the relatively small population lifelong, competitive endurance athletes, evidence regarding the prevalence of myocardial fibrosis in this population is fairly low level, observational in nature, and consisting of small sample sizes.

In a 2007 study, Whyte et al.[49] conducted a post-mortem examination of a 57-year-old male with a 20-year history of competitive running who died while running a marathon. Post-mortem examination of the runner’s heart revealed left ventricular hypertrophy, which is an expected characteristic of an athlete’s heart.[49] However, interstitial fibrosis was also found throughout the right and left ventricles, especially in the left ventricle.[49]

Mohlenkamp et al.[50] evaluated a cohort of 108 veteran male marathon runners (the largest sample size revealed in this literature search) for the presence of myocardial fibrosis compared with sedentary age-matched peers. Cardiac magnetic resonance imaging (cMRI) was used to identify myocardial fibrosis after the injection of a gadolinium contrast. Late gadolinium enhancement (LGE) is commonly used as a marker of myocardial fibrosis or impaired perfusion and is inversely associated with left ventricular function.[51] No statistically significant difference in the presence of fibrosis between the cohort of endurance athletes and control group was revealed.[50] However, Mohlenkamp et al.’s inclusion criteria may have led to the selection of runners who were not truly elite lifelong endurance athletes. For example, on average, the cohort of runners began running only 9 years prior to the study.[50] Since the average age of participants was 57 years, most participants probably did not begin running competitively until their fourth decade of life. Lifestyle habits, such as smoking, prior to beginning running would have also impacted the runners’ current heart health. 51.9% of runners in this study were former smokers (4.6% current) and 42.1% of controls were former smokers (28.4% current).[50] The results of this study exposed the need for further research in cohorts of lifelong endurance athletes.

Lindsay and Dunn[52] also sought to investigate the presence of myocardial fibrosis amongst veteran endurance athletes. Their study included 45 males (average age=52 years) who had been participating in competitive marathons for at least 10 years.[52] Biochemical markers that have been implicated in the fibrotic cascade were analyzed, as summarized in the table below. As noted on CELL BIO PAGE, myocardial fibrosis occurs when the ratio of collagen synthesis to collagen degradation is out of balance. The results indicate that all athletes had levels of collagen synthesis and degradation that deviated from baseline levels, but only athletes in later stages of cardiovascular adaptation (who had left ventricular hypertrophy) had significantly elevated TIMP-1, which favors myocardial fibrosis.[52] While veteran endurance athletes in this study displayed signs of myocardial fibrosis, it is worth noting that none of the athletes reported clinical symptoms or demonstrated diastolic dysfunction, which is characteristic of individuals with myocardial fibrosis stemming from pathological stimuli (hyptertension, etc.).[52] The authors postulated that this finding may be due to the different mechanisms of fibrosis initiation between the two populations and diastolic dysfunction may occur much later in the disease process of athletes.[52] Based on these results, it seems evident that myocardial fibrosis is part of the exercise-induced hypertrophic response following long-term endurance exercise, which may explain why ventricular hypertrophy persists after cessation of exercise.[52]

Table 6. Exercise implications of cellular mechanisms in endurance athletes with and without left ventricular hypertrophy (LVH)

Biochemical role Presence in endurance athletes with LVH vs. controls Presence in endurance athletes without LVH vs. controls Results
Tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) Inhibits collagen degradation Significantly elevated Not significantly different
Carboxyterminal telopeptide of collagen type 1 (CITP) Cleaved when collagen type 1 is degraded; marker of collagen degradation Significantly elevated Significantly elevated
Plasma carboxyterminal propeptide of collagen type 1 (PICP) Marker of collagen synthesis and fibrogenesis Significantly elevated Significantly elevated

The most recent publication relating to myocardial fibrosis amongst endurance athletes included 12 individuals (mean age=57 years) who were truly lifelong endurance athletes – having trained and competed at a high level continuously for 35-52 years.[53] Unlike the sample used by Mohlenkamp et al.,[50] the participants in this study did not have concomitant risk factors for cardiovascular dysfunction (only one participant was a previous smoker) and all athletes had trained continuously for the majority of their lives. Two comparison groups were utilized: one group of 20 sedentary age-matched peers and one group of 17 young (mean age=31 years) endurance athletes.[53] Gadolinium-enhanced cardiac magnetic resonance imaging was used to detect the presence of fibrosis. Late gadolinium enhancement was not observed in any young athletes or veteran controls, but 50% of veteran athletes had LGE.[53] The presence of LGE could not be explained by age, height, or weight, but was significantly correlated with training history (number of years spent training, number of competitive marathons and ultra-marathons).[53] These observations provide support for the connection between lifelong endurance exercise and myocardial fibrosis.

Direct Evidence using an Animal Model

To date, one randomized, controlled trial using a rat model has been conducted to investigate myocardial fibrosis resulting from repetitive endurance exercise. Benito et al.[48] randomly assigned rats to either a sedentary or intensive exercise group. The intensive exercise program consisted of 60 minutes of treadmill running at 60 cm/second 5 days per week.[48] Rats in each group were analyzed after 4, 8, and 16 weeks.[48] The human equivalent of this 16-week exercise program is approximately 10 years of daily exercise training at 85% of maximal oxygen uptake at 90% of maximum heart rate.[48] A sample of the rats that completed 16 weeks of the intensive exercise program were assessed for reversibility of exercise-induced effects at 2, 4, or 8 weeks following cessation of exercise.[48] Following 8 weeks of intensive exercise, concentric left ventricular hypertrophy was noted; continuing intensive exercise training for 16 weeks resulted in eccentric hypertrophy and left ventricular diastolic dysfunction.[48] Additionally, increased right ventricle interstitial collagen synthesis was present after 16 weeks of exercise.[48] To isolate and quantify the amount of fibrous tissue, hydroxyproline was measured.[48] Hydroxyproline is a modified amino acid found in collagen.[48] Sixteen weeks of exercise resulted in significant increases in right ventricular hydroxyproline content, with no significant differences in the left ventricles of exercise versus sedentary rats.6 To further quantify myocardial fibrosis, messenger RNA expression of transforming growth factor-β1 (TGF-β1), fibronectin-1, matrix metalloproteinase-2 (MMP-2), TIMP-1, procollagen-I, and procollagen-III were measured, along with subsequent protein expression of each.[48] Significant results after 16 weeks of exercise compared with sedentary controls are as follows:

Table 7. Effects of chronic exercise training on protein expression[48]

mRNA expression Protein expression Results
TGF-β1 Increased in RA, LA, RV Increased in RA, LA, RV
Fibronectin-1 Increased in RA, LA, RV No significant difference
MMP-2 Increased in RA, LA, RV Increased in RA, LA
TIMP-1 Increased in RA No significant change
Procollagen-I (Collagen I) Increased in RA, RV Increased in RA, RV
Procollagen-III (Collagen III) Increased in RA, LA No significant change

Overall, these results suggest extracellular matrix imbalance indicative of interstitial fibrosis in the right ventricle but not the left ventricle.[48] Hydroxyproline content was analyzed throughout the deconditioning period following cessation of exercise to monitor changes in fibrosis.[48] Sixteen weeks after the end of the intensive exercise program, right ventricular hydroproline content was not significantly different than that of sedentary rats.[48] Therefore, reversibility of exercise-induced cardiac remodeling is evident in rat models.[48]

It is currently unknown which mechanisms promote myocardial fibrosis as a result of long-term intensive exercise. It is possible that, as with pathological hypertrophy and fibrosis, initially adaptive responses to excessive and repetitive cardiac overload eventually yield mal-adaptive effects.[48] While human studies have primarily noted left ventricular fibrosis in lifelong endurance athletes, Benito et al.,[48] interestingly, found chamber-specific right ventricular fibrosis. Two potential explanations were postulated: 1) endurance sports have been found to place higher loads on the right ventricle, so fibrotic remodeling is concentrated in the right ventricle; 2) thinner walls make the right ventricle more susceptible to remodeling than the left ventricle.[48]

Another important clinical finding of Benito et al.’s[48] study is the inducibility of cardiac arrhythmias following exercise training. Previously, it had been anecdotally suggested that cardiac fibrosis provides electrical heterogeneity that increases the risk of cardiac arrhythmias.[48] Benito et al.[48] were able to induce sustained ventricular tachyarrhythmias in 42% of rats who completed the 16-week exercise program, compared with only 6% of rats in the sedentary control group.


The benefits of moderate-intensity exercise throughout the aging process have been well-documented. However, recent evidence regarding potentially detrimental effects of chronic high-level endurance exercise on cardiac structure is becoming increasingly available.[53] Several observational studies in human populations have reported increased prevalence of myocardial fibrosis and, thus, arrhythmia susceptibility amongst lifelong endurance athletes.[49],[50],[52],[53] However, experimental studies are limited to date. One randomized, controlled trial using a rat model revealed significant extracellular matrix remodeling indicative of myocardial fibrosis and increased inducibility of arrhythmias following 16 weeks of intensive exercise.[48] The mechanisms involved in the promotion of myocardial fibrosis amongst endurance athletes are not yet understood. However, it seems possible that repetitive bouts of prolonged exercise results in cumulative myocardial damage, which initiates a reparative fibrotic response.[49],[53] Over time, this accumulated fibrosis allows for the development of pathological myocardial fibrosis and susceptibility to arrhythmias.[49],[53]


It has been suggested that left ventricular hypertrophy begins in a prehypertensive state.[54] Therefore, animal models investigating the effects of exercise in spontaneously hypertensive rats (SHR) are reviewed in the following sections to model the lower end of the pathological heart spectrum

Genetics and Sudden Cardiac Death


Sudden cardiac death (SCD) is the unanticipated death of an individual who may or may not present with symptoms of cardiac dysfunction.[55][56] Many of those who experience SCD have no apparent symptoms and may even appear to have optimal health, considering the prevalence of SCD in athletes. With few or no detectable signs leading up to this fatal event, ongoing research is necessary to comprehend the mechanisms behind SCD. Current knowledge of the condition is that it is most often associated with genetic or inherited cardiovascular disorders.[57][58] In general, hypertrophic cardiomyopathy (HCM) is recognized as the most common inherited cardiovascular disease. It affects approximately 1 in every 500 people in the United States.[57] Although there is a variety of possible mechanisms that contribute to SCD, HCM is recognized as the predominant underlying cause.[57][58][56][59][60] SCD is attributed to HCM in approximately one-third of all cases.[57] Approximately half of those HCM-related incidents of SCD occur during physical exertion.[58] Unfortunately, many active individuals are unaware that they have HCM to realize that they are at increased risk for SCD until it is too late.

Athletes under the age of 30 years participating in competitive sports represent the population most affected by SCD.[57][58][56][59] A study conducted in Italy showed that SCD was 2.8 times more likely to occur in athletes compared to non-athletes age 12-35 years.[58][61] It is thought that the chronic, intense training and regular competition that young athletes undergo can lead to excessive cardiac stress and adverse reactions, particularly for those with pre-existing heart conditions. Sports that have elicited the most cases of SCD include basketball, football, and soccer.[59] The increased prevalence is likely due to the high level of intensity sustained for a relatively long duration in competitive play in each of these sports.[59] Also, the athletes are often asymptomatic and therefore may not naturally regulate their levels of exertion as expected with perceived cardiac distress.[56]

Despite the alarming and unexpected nature of the condition, the frequency of SCD in young athletes is relatively low.[57][58] A 12-year survey from Minnesota studying high school athletes in 27 sports reported a frequency of 1:200,000 cases per year of SCD with undiagnosed cardiovascular disease.[59][62] Furthermore, the Minneapolis Heart Institute Foundation reported that 26.4% of SCD occurrences in 387 young athletes were associated with HCM.[57][63] Gender and racial differences exist in the SCD prevalence. The occurrence is more common in males than females, with a 10:1 ratio.[57] It is unclear whether this large difference is due to higher participation of males in competitive sports compared to females or if there is a gender-specific component of SCD.[59] It is also more common in African Americans than Caucasians, with incidences of 0.24% and 0.10%, respectively.[57]


The lack of signs and symptoms leading up to SCD make it difficult to correctly diagnose its predisposing conditions. Furthermore, similarities between physiological hypertrophy in adaptation to exercise and pathological or inherited hypertrophy make it challenging to distinguish the two. One of the main methods of identifying physiological vs. pathological hypertrophy is to assess symptoms and presence of hypertrophy following a period of deconditioning in which an athlete limits physical activity.[57][58][59] The hypertrophic adaptations in response to exercise are typically reversible, whereas inherited hypertrophy would remain even after detraining.[57][58][59] Differentiating between the two types of the condition is also complicated by the theory that there is a point at which the physiological form can progress to pathological hypertrophy. Certain guidelines have been developed to help make the distinction between HCM and physiologic hypertrophy, as presented in Figure 2. Conflicting views exist regarding the safety of physiological hypertrophy and whether it is specific to a certain type or level of training, which is why it is valuable to identify the condition regardless of the form.[59]

Figure 2[59]


Currently, there is not a single inexpensive and efficient clinical test to definitively diagnose HCM.[57][56][59] Genetic testing is one method used to identify mutations in genes indicative of inherited hypertrophy, though it is expensive and may not be as informative as other techniques. Although genetic tests have good specificity, they have poor sensitivity and therefore are not useful in ruling out the condition.[57][56][59] Also, the vast number of potential mutations and genes affected challenge the reliability of detecting the disease trait.[59] Electrophysiologic testing is another method in which the expense and complication of conducting the test may not be justified by the information it provides. It has been suggested that it is no more informative than noninvasive measures of risk for HCM and SCD.[56]

Techniques utilized more often in the assessment of HCM and SCD are electrocardiography and investigating the presence of a number of designated risk factors.[57][58][56][59][64] A 12-lead ECG is typically the recommended setup for electrocardiographic testing to evaluate HCM and risk of SCD.[58] It is not uncommon for trained individuals to present with abnormalities on ECG. Atypical ECG findings are present in approximately 40% of all athletes, with higher prevalence in males compared to females and endurance athletes versus those in other sports.[59] Common abnormalities among the athletic population suggestive of physiological hypertrophy include early repolarization or other repolarization defects, increased QRS-complex and Q-wave amplitudes, and inverted T-wave. These impairments of ventricular conduction and repolarization can trigger irregular heart rhythms, which increases risk of SCD.[64] Arrhythmias often found in athletes include sinus bradycardia, junctional rhythm, and first degree AV block.[59] Common ECG changes observed in general hypertrophy are increased amplitude of ventricular depolarization, premature ventricular contractions, and normal or mildly prolonged QT interval.[64] A main indicator of hypertrophy on ECG are action potentials of prolonged duration, which can contribute to SCD.[64] Atrial fibrillation has been reported as the most common arrhythmia in HCM, experienced by 20-25% of patients.[56]

The following risk factors have been identified for SCD in those with HCM[57][58]:
1) Family history of SCD
2) History of recurrent syncope
3) Left ventricular hypertrophy with a wall thickness of >30mm
4) Abnormal blood pressure response to exercise (SBP increase of ≤25 mmHg or a decline of 15 mmHg from peak SBP)
5) Nonsustained ventricular tachycardia

Having greater than or equal to 2 of these factors significantly increases one’s risk for SCD. This guideline is supported by Elliot et al, who reported that individuals with ≥2 of the risk factors had significantly lower 6-year survival rates compared to those with 0 or 1 of the qualifiers.[58][65] The American College of Cardiology and the AHA have advised that athletes undergo a pre-participation screening every 2 years in high school sports and every 4 years in college.[58] The recommended components of this screening in addition to risk stratification include medical history, family history, and physical exam.[58]

Prevention and Treatment

As mentioned previously, if the hypertrophy is strictly physiological and the individual has 2 or more of the 5 designated risk factors, it may be treatable through activity restriction.[57][58][59] The 36th Bethesda Conference of the American College of Cardiology recommends that athletes diagnosed with HCM should limit participation to low-intensity activities, such as bowling and golfing.[57][66]

A more invasive method to prevent SCD in high-risk individuals with HCM is the use of implantable cardioverter defibrillators (ICDs).[56] This treatment is suggested as an alternative to pharmacological intervention. It is argued that pharmacological treatment is insufficient and impractical in preventing SCD due to side effects, lack of evidence to support it, and possible adverse effects of long-term use in young patients.[56] The ICD works by attempting to return the normal heart rhythm from an episode of ventricular tachycardia or ventricular fibrillation.[56] A large study of 506 patients with HCM across 42 centers in the U.S., Europe, and Australia reported the efficacy of ICDs.[67] Subjects were an average age of 42 years and had mild or absent symptoms of heart failure.[67] Findings showed that in 3.7 years, 20% of patients had their ICD discharge in response to ventricular fibrillation or tachycardia.[67] This represents a 5:1 ratio of those implanted with ICD and those experiencing a life-saving ICD event. It was discovered that the probability of someone incurring an arrhythmia requiring ICD intervention over a 5-year span was 25%.[67] Although the study proved that the device is effective, it also showed it can be flawed in some cases. There was one 21-year old participant that died of SCD due to a mechanical dysfunction of the ICD.[67] Mechanical error causing inappropriate ICD discharge has been reported in up to 25% of patients.[67] ICDs are generally recommended for young, asymptomatic patients with HCM who have normal systolic left ventricular function.[56] Complications that can arise with ICDs include infection, pneumothorax, pocket hematoma, and venous thrombosis.[67]

Hypertrophic Signaling Pathways

Table 8. Effects of exercise on hypertrophic signaling pathways in pathological hearts of human studies.

Author Subject Exercise Intensity Intervention Results
Niebauer et al (2005)[68] Patients with clinically stable heart failure (CHF) for at least 3 months Moderate 8 week home training program: at least 5 day/week; calisthenics and bike ergometer for about 20 minutes at 70-80%maxHR no effect of training on TNFα, TNF-R1 and 2, IL-6, e-selectin (a marker for endothelial inflammation), sICAM (mediates interaction between inflammatory cells and endothelium, sCD14 (receptor for endotoxin complex)
Adamopoulos et al (2002)[69] Patients with stable CHF (class II/III) Moderate 12 week training program: 5 days/week, 30 minutes/day at 60-80%maxHR Significant reduction in plasma levels of TNFα, IL-1, IL-6
Adamopoulos et al (2001)[70] Patients with moderate to severe chronic heart failure (II/III) Moderate 12-week home training program: 5 days/week, bicycle 30 minutes at 70-80%maxHR Decreased inflammatory activation; Improved endothelial function

Table 9. Effects of exercise on hypertrophic signaling pathways in pathological hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Libonati et al (2011)[71] 38 female SHR and 37 normotensive rats Moderate 12 week treadmill program: 5 days/week; speed 25 m/min, 0% grade for 60 minutes Decreased mRNA calcineurin
Serra et al (2010)[72] Male rats Moderate-Intense 13 week aerobic (treadmill) program: 6 days/week for 60 minutes; 18m/min for first 30 minutes and 22/m/min for last 30 minutes Inhibited pro-inflammatory cytokines (e.g., TNFα, IL-6, TGF-β1 mRNA and NF-κB); Increased IL-10; Improved contractility; LV remodeling prevented
Garciarena et al (2009)[73] 22 male SHR and 5 normotensive Wistar rats Low to Moderate Swimming for 90 min 5 days/week for 60 days Decreased Calcineurin A β to levels of normotensive rats; No significant change in PI3K/Akt
Kolwicz et al (2009)[74] 36 female SHR and 18 normotensive rats Moderate Treadmill training for 1 hour 5 days/week for 12 weeks Decreased mRNA calcineurin; no change in Akt mRNA and protein levels
Oliveira et al (2009)[75] Male rats with severe heart failure compared iwth wild type Moderate Treadmill training 5 days/week for 8 weeks at 60% maximum speed & duration Decreased calcineurin-NFAT signaling; anti-remodeling effects (decreased cardiac mass & fetal gene expression)
Leosco et al (2008)[76] Male rats w/ severe, chronic HF Moderate-Intense 10 week aerobic (treadmill) program:5 days/week, 45 min/day; 40-50%VO2max for first 2 weeks then 70-85%VO2max for last 8 weeks at 17m/min. Increased B-adrenergic receptor sensitivity
Kemi et al (2008) [12] 18 mice No exercise intervention Underwent transverse aortic constriction (TAC) for 1 or 8 weeks to mimic the pressure overloaded pathological hypertrophic heart with diminished contractility Deactivation of the PI3K-Akt-mTOR signaling pathway
McMullen et al (2007)[77] Trangenic mouse model: mice with increased or decreased PI3K(p110α) activity to the DCM model, and PI3K(p110α) transgenics to acute pressure overload Moderate-Intense 4 week swim training program until subjects exhibitied signs of heart failure (i.e., labored breathing, fatigue, sedentary behavior) Increased PI3K activity leading to improved cardiac function and lifespan; Reduced PI3K activity reduced lifespan
Lee et al (2006)[78] SHR rats Moderate 12-week aerobic (treadmill) program Decreased mRNA expression of angiotensin converting enzyme and endothelin-1
MacDonnell et al (2005)[79] Female SHRs Low-Moderate 12 week aerobic (treadmill) program: 5 days/week for 60 minutes at 20m/min Increased Beta-adrenergic receptor sensitivity
Miyachi et al (2009)[81] Dahl salt-sensitive hypertensive male rats Low-Moderate Swimming for 1 hour, 5 days/week for 9 weeks Exercise prevented pathological increases in phosphorylated ERK and p38; significantly increased Akt and rapamycin phosphorylation; inhibited the pathological isoform shift of P13K
Saengsirisuwan et al (2001)[17] Female obese Zucker rats Low-Moderate 6 week treadmill training: 3 weeks for 60 minutes/day, 7days/week progressing to 3 weeks for 75 minutes/day, 5 days/week rotating through 15-minute cycles: 24 m/min for 10 min, 26 m/min for 3 min, 28 m/min for 2 min Decreased oxidative stress and improved insulin sensitivity with training

Exercise intolerance is a known characteristic of chronic heart failure. Circulating pro-inflammatory cytokines (i.e., TNFα, IL-1, IL-6, endothelin-1) play a pathological role in patients with heart failure (HF), as well as, may have some relative implications to patient’s exercise intolerance and overall health decline.[69][78] Therefore, studies have focused on determining the ability of exercise to attenuate the activity of pro-inflammatory cytokines and subsequently attenuate pathological signaling pathways. One study[69] found significant reductions in TNFα (TNFα) and interleukin-6 (IL-6) levels after exercise. Thus, exercise training by virtue of its anti-inflammatory effects, may induce beneficial reductions in myocyte and endothelial cell TNFα.[69] This was one of the first studies to demonstrate that exercise training in HF has an immunomodulatory role. Thus, exercise training ameliorates homeostasis, in part, due to a reversal of immune factors associated with CHF (e.g., significant reductions in TNF-alpha, IL-6). Moreover, exercise may partially be beneficial due to its ability to attenuate pro-inflammatory cytokines activity and overall improve activity tolerance.

In pathological hypertension and heart failure, beta-adrenergic activity dysfunction is present compromising the heart's functional capacity. Moreover, the cardioprotection is related to beneficial effects on heart function.[72] Exercise training in the presence of β-adrenergic hyperactivity has the ability to avoid pathologic LV remodeling, inhibit pro-inflammatory cytokines (e.g., TNFα and IL-6), increase interleukin-10 (an anti-inflammatory cytokine),[72] and ameliorate β-adrenergic receptor sensitivity.[79][76] One study[79] found that the improved receptor stimulation was coupled with improved heart contractility quality. Myocardial dysfunction induced by β-adrenergic hyperactivity was prevented.[72] This is previously supported by a study[80] that previously demonstrated that exercise training completely prevents myocardial inflammation. Thus a prolonged exercise program beginning prior to β-adrenergic dysfunction is beneficial, resulting an improvement in the heart's functional capacity, preventing maladaptive LV hypertrophy and remodeling. Exercise training further prevents negative LV remodeling in response to pathological stimuli.[72] Other supportive evidence has shown similar findings using similar exercise training protocols and thus denoted exercise to be the gold standard for attenuation of LV remodeling and heart failure,[82] as well as protecting the heart against β-adrenergic dysregulation. In addition, the enhanced b-adrenergic signaling in the intact myocytes post-injury has lead to a proposed model in which exercise may restore the dysfunctional beta-receptor activity in the intact heart tissue that was previously contributing to LV dysfunction.[76]Although in one study[79] LV wall thickness was increased in response to the exercise stress, it does not appear that it is maladaptive or leads to an attenuation of disease. Unfortunately, the mechanism(s) underlying this exercise-induced cardioprotection against β-adrenergic agonists is incomplete. To our best knowledge, only the study of Frederico et al. (2009)[83] provides evidence for mechanisms contributing to cardioprotection, suggesting that exercise training provides cardioprotection via an attenuation of reactive oxygen species. Nonetheless, exercise training provides protection balancing anti-inflammatory and proinflammatory cytokine activity (as well as by modulation of TGF-β1 signalling in pathological cardiac hypertrophy.)

A study by Wilkins et al.[11] using a mouse model showed that the calcineurin-NFAT circuit is selectively implicated in pathological hypertrophy and not physiological hypertrophy. The mice in this study were subjected to transverse aortic constriction for various lengths of time to produce pressure overload. Cardiac calcineurin-NFAT activity was not increased in the first 24 hours of pressure overload, but, by the second day, NFAT activity was elevated by 2- to 3-fold for up to 8 weeks.[11] These findings suggest that calcineurin-NFAT signaling is a delayed but sustained signal for pathological hypertrophy. A separate cohort of transgenic mice were exposed to exercise for various lengths of time, and significant increases in heart-to-body weight ratios were achieved (physiological hypertrophy). These mice, however, showed no increase in NFAT activity in the heart, and some mice actually demonstrated a decrease in cardiac NFAT activity.Wilkins2004calcineurin These results suggest that physiological growth of the myocardium does not invoke significant calcineurin-NFAT signaling.[11] The investigators postulate that, while exercise produces a temporary alteration in calcium handling that fails to activate calcineurin, pathological hypertrophy stems from continuous stimuli that induce a sustained calcineurin response that mobilizes NFAT factors.[11] Oliveira et al.[75] subjected rats with severe heart failure to a moderate-intensity aerobic exercise program for 8 weeks and observed significant decreases in activity of the calcineurin-NFAT signaling pathway and subsequent maladaptive hypertrophy. This finding implicates moderate-intensity exercise as a possible mechanism to prevent or reverse heart failure.[84]

In the Garciarena et al study, it was found that cardiac remodeling occurred after low to moderate intensity training in SHR from pathological to physiological hypertrophy.[73] Results showed significant decreases in calcineurin but not in PI3K/Akt, which may be due to the fact that calcineurin has been found to only regulate pathological hypertrophy, while the PI3K/Akt pathway is involved in both types of cardiac hypertrophy.[73] Other studies have also shown that moderate intensity training decreases the amount of calcineurin mRNA.[85][74] Furthermore, Kolwicz et al also showed no change in Akt mRNA which is part of the PI3K/Akt pathway in hypertrophic signaling.[74] The cardioprotective role of PI3K may be caused, at least in part, by inhibition of pathological signaling cascades.[77]

Studies[68][69][70] an unsupervised, home exercise program is safe for patients with chronic heart failure. There may be a potential for secondary complications to occur however this study showed that a home program can be both safe and efficacious for an improved exercise capacity. A detrimental increase in pro-inflammatory cytokines does not occur, if exercise is not carried out in acute bouts but chronically.[68] A limitation of the Neibauer (2005) study was exposed by the researchers in that an 8 week program may not long enough to find an improvement in pro-inflammatory cytokines.[68] Based on another study's[70] results, the researchers hypothesized that the active inflammatory process is a contributing factor to exercise intolerance.

In research conducted by Kemi et al [12], the aim of the study was to determine if the PI3K-Akt-mTOR would be activated or deactivated in the physiological and pathological hearts. They concluded that 6 weeks of high intensity interval treadmill training lead to an increase in the activation of IGF, which in turn stimulates the PI3K-Akt-mTOR signaling pathway.[12] The increase in the pathway stimulation therefore leads to accelerated protein synthesis and enhanced contractility/function of the heart.[12] They also determined that the mice that underwent a TAC for 1 or 8 weeks to mimic the pathological hypertrophic heart had the opposite effect on the PI3K-Akt-mTOR signaling pathway.[12] The researchers concluded that the PI3K-Akt-mTOR pathway may be the signaling pathway that determines the division between physiological and pathological cardiac hypertrophy.[12]

Along with this, Miyachi et al. demonstrated that endurance exercise in hypertensive rats induced increased ERK1/2, p38, and Akt phosphorylation levels as well as inhibition of the anti-angiogenic, pathological P13K isoform shift.[81] Hypertension and atherosclerosis, both potential stimulants for cardiac hypertrophy and heart disease in the form of pressure and volume overload, and obesity are associated with skeletal muscle resistance to insulin.[16] There is controversy on whether exercise improves or decreases skeletal muscle insulin sensitivity. A 2001 study[17] showed that 6 weeks of low endurance treadmill training significantly decreased oxidative stress in obese rats and improved insulin sensitivity in skeletal muscle. Thus, endurance training may be protective against oxidative stress by improving skeletal muscle insulin sensitivity and associated cellular responses to stress, and ultimately mitigate the negative effects of hypertension and atherosclerosis by decreasing activation of the hypertrophic MAPK signaling cascades.Thus, endurance training may be protective against oxidative stress by improving skeletal muscle insulin sensitivity and associated cellular responses to stress, and ultimately mitigate the negative effects of hypertension and atherosclerosis by decreasing activation of the hypertrophic MAPK signaling cascades.


Table 10. Effects of exercise on mitochondria in pathological hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Kavazis et al (2009)[86] Rat model Moderate Endurance exercise (treadmill) 5 consecutive days of treadmill exercise for 60 min/day at 30 m/min, 0% grade, and estimated 70%VO2max Decreased mitochondrial oxidant (e.g., MAO-A) production and increased antioxidant enzyme (e.g., PRDX-III) production
Kavazis et al (2008)[87] Rat model Moderate Aerobic (treadmill) training protocol: 5 consecutive days of 60 minutes/day at speed 30 m/min, 0% grade, estimated 70%VO2max Increased mitochondrial antioxidants (e.g., MnSOD and CuZnSOD); Reduced rate of ROS-induced cytochrome c release from mitochondria
Navarro et al (2004)[88] Aging male and female mice Low-Moderate 50 weeks of treadmill training: 5 minutes each at 6, 8, and 12 m/min; once per week Exercise decreased the decline in mitochondrial ETC/antioxidant enzymes seen with aging; males responded better than females
Safdar et al 2011[89] Aging male and female mice Moderate 5-month treadmill training: 3 times/week at 15 m/min for 45 minutes Training induced mitochondrial biogenesis, decreased apoptosis, reduced mtDNA mutations, and decreased aging-induced cardiac hypertrophy and pathology
Goodpaster et al (2003)[90] Obese, non-diabetic men and women Moderate-High 16-week walking program on 4-6 days/week, with weight loss: Weeks 1-4 for ≥30 minutes/session at 60-70% MHR; Weeks 5-8 for 40 minutes at 60-70% MHR; Weeks 9-16 for 40 minutes at 75% MHR 35% increase in resting fat oxidation; 14% increase in energy derived from fat oxidation; improved insulin sensitivity
Burelle et al (2004)[91] Ischemic cardiac injury in trained/sedentary female rats High 10 weeks of treadmill training at 25 m/min and 16% slope for 4 days/wk; duration gradually increased by 15 minutes weekly from 30 to 90 min over 4 weeks Physiologic hypertrophy, increases in FAO (25% greater fraction of glucose oxidation; 50-65% greater palmitate oxidation)and improved cardiac recovery by approximately 50% after ischemic injury
Menshikova et al (2007)[92] Obese, non-diabetic men and women Moderate-High 16-week walking program on 4-6 days/week, with weight loss: Weeks 1-4 for ≥30 minutes/session at 60-70% MHR; Weeks 5-8 for 40 minutes at 60-70% MHR; Weeks 9-16 for 40 minutes at 75% MHR Increased oxidative capacity in skeletal muscle (a 60% increase in cardiolipin), ETC enzyme activity and mitochondrial biogenesis
Chicco et al (2008)[93] Aging female hypertensive rats Low Treadmill training: 14.5 m/min at 10% grade for 45 minutes/day, 3 days/week until development of HF or euthanization due to complications Training induced 21% greater cardiolipin content in cardiac mitochondria

Studies[86][87][94] have supported the model that exercise induces adaptations within cardiac mitochondria that promotes cardioprotection. Due to the mitochondria’s overall role in cellular function and involvement in apoptosis that occurs in cardiac hypertrophy, it only makes sense that it has the potential to be beneficially effected by exercise. Thus, studies[86][87] have proved that exercise training promotes a beneficial mitochondrial phenotype that is cardioprotective even after myocardial injury. One study[86] examined both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of sedentary and exercise-trained rats. The researchers’ confirmed their initial hypothesis that a progressive exercise program provokes changes in protein expression in cardiac mitochondrial proteins involved in energy metabolism, redox regulation, and apoptosis.[87][86] Importantly, IMF mitochondria after exercise had decreased (by a factor of 2) MAO-A protein compared to the sedentary rats, which is significant because as a mitochondrial enzyme it is an important source of reactive oxygen species in the heart.[86] In addition, PRDXIII, a mitochondrial antioxidant that degrades reactive oxygen species, was increased in the subsarcolemmal mitochondria after aerobic exercise.[86] Thus regular endurance exercise beneficially causes mitochondrial adaptations that promote a cardioprotective phenotype. These changes observed in these studies are likely contributors,[86][95] still, the delineation of mechanisms responsible for cardioprotection is under further investigation. However, based on the present research we know that aerobic exercise promotes myocardial recovery even after ischemic injury.

As previously stated, decreased mitochondrial function and fatty acid oxidation are associated with cardiovascular disease, obesity, hypertension, and Type II diabetes, among other conditions.[23][24][25][26][27] After treadmill training for 4 days/week for 10 weeks, trained female rats demonstrated increases in FAO and improved cardiac recovery following ischemic injury compared to untrained rats.[91] It should be noted that training duration was extensive, progressively reaching 90 minutes per day at 16% slope during most weeks. In conclusion, high-intensity exercise seems to reverse the reduction in FAO activity typically seen with cardiac hypertrophy and associated conditions such as cardiovascular disease and heart failure.

Following a 4-month moderate-high intensity walking intervention and weight loss, sedentary obese adults demonstrated increased oxidative capacity in skeletal muscle as evidenced by a 60% increase in cardiolipin, indicating an increase in the surface area of the inner mitochondrial membrane.[92] This response to moderate-intensity exercise translates into more components of the electron transport chain (ETC) and improved mitochondrial function. Increases in ETC enzyme activity and subsequent mitochondrial biogenesis were also seen without increases in skeletal muscle mtDNA. Improved oxidative capacity in obese adults has been associated with improved insulin sensitivity and fatty acid oxidation.[90] Therefore, moderate-intensity exercise is substantial to promote improved muscle oxidative capacity and presumably improve insulin sensitivity and fat oxidation, in obese individuals.

Lastly, in a recent study of induced aging,[89] 5 months of low-intensity endurance exercise led to mitochondrial biogenesis, improved mitochondrial and mtDNA quality and decreased apoptosis in the heart of aging mice, among other tissues. Chronic treadmill training 3 days per week for 45 minutes daily resulted in improved endurance capacity, reduced mtDNA mutations, and alleviated the cardiac hypertrophy and pathology that was present in the aging mice prior to training. Chronic, moderate-intensity exercise significantly attenuated the increase in oxidative stress markers in the brain, heart, liver, and kidney of male and female mice associated with aging.[88] Through “lifelong” treadmill exercise over 50 weeks for 15 minutes once weekly, the decline in mitochondrial ETC and antioxidant enzymes was significantly blunted at middle age but either absent or significantly diluted at old age. These effects from exercise were not only age-specific but gender-mediated; females demonstrated positive responses to a lesser degree than males. Overall, this response subsequently leads to improved mitochondrial function, as more antioxidants are available to ward off free radicals and oxidative stress in the heart, among other organs.

In conclusion, chronic low to moderate-intensity endurance exercise training proves to be an effective approach attenuating the declines in mitochondrial function, quantity and quality in the aging heart. However inconclusive, trends suggest that chronic, moderate to high-intensity aerobic exercise ranging from 12 weeks or longer, ≤ 5 days per week for approximately 1 hour, actually proves more advantageous at improving fatty acid oxidation or mitochondrial oxidative capacity and associated enzymatic activity, mitochondrial content and quantity in the pathological and normal heart. Further research, specifically with human models, is warranted in order to establish a frequency and duration that is most optimal for mitochondrial function.

Energy Metabolism

Among the many processes that are affected by HCM and other heart disease, disruption of energy production, delivery, and utilization is one of them. Energy imbalances develop in heart failure due to increased demand placed on overloaded heart tissue, decreased efficiency of the heart muscle, reduced oxidative capacity, and impaired energy metabolism.[96] Mitochondrial biogenesis is also reduced due to down-regulation of the PGC-1α transcriptional pathway in heart failure.[96] These deficits produce somewhat of a negative cascade of events in that the inefficient muscle fatigues more easily leading to decreased endurance and a decline in exercise tolerance.[96] With decreased available energy, it is difficult for the cardiac cells to produce and maintain strong mechanical activity.[96]

Aerobic exercise is frequently prescribed in heart failure to improve activity tolerance and quality of life as well as to decrease morbidity and mortality.[96] This type of training is generally considered beneficial to improve energy metabolism. It appears to be associated with improved calcium handling, contractility, and oxidative capacity and reduced left ventricular dilation and cellular hypertrophy in patients with heart failure.[97] The cellular mechanisms behind the effects of aerobic exercise on disease status are relatively well established in skeletal muscle, however the processes are not as evident in cardiac muscle.[96] Research in skeletal muscle cannot be directly applied to cardiac tissue due to the fact that the various muscle fiber types are supplied by different energy sources. Fast-twitch skeletal muscle gets energy from PCr and glycogen metabolism, whereas slow-twitch skeletal muscle fibers gain energy from oxidative phosphorylation. Alternatively, cardiac muscle relies predominantly on fatty acid and lactate metabolism for energy production.[96]

Once fatty acid and lactate are converted to ATP in the mitochondria, it must be delivered to its target tissues. Due to the amount of energy necessary for normal heart function, it is vital that ATP be available for quick utilization. The enzyme creatine kinase aides in delivery of energy by transferring ATP from areas where it is produced, glycolytic complexes and mitochondria, to areas where it is utilized, the sarcoplasmic reticulum and myosin ATPases.[96] In heart failure, a reduction in creatine kinase levels is often observed which leads to reduced energy transfer and PCr/ATP ratio.[97] It is necessary to consider the function of each of these components of the metabolic processes when studying the effect of aerobic exercise on cardiac energy metabolism.

More studies of cardiac energy metabolism are warranted, as it is not well established that energy production and transfer adaptations occur in response to endurance training to improve cardiac function.[96] The compensatory adaptation of physiological hypertrophy generally leads to normal production of energy through fatty acid metabolism, but the same outcomes may not be associated with disease-related hypertrophy.[96] The mechanism behind improved energy metabolism is also unclear. Studies show conflicting evidence for improved cardiac function being attributable to increased mitochondrial density and oxidative capacity versus an overall increase in skeletal muscle mass.[96] In addition to mitochondrial density and muscle mass, CK levels have been investigated to better understand changes in energy metabolism. Current evidence has reported that aerobic activity increases total myocardial creatine kinase content in the left ventricle of canines. However, these studies have not been proven to be applicable to the human heart.[96]

While many of the studies in cardiac disease look at the effects of aerobic exercise on one’s current cardiac condition, The effects of aerobic exercise on cardiovascular disease prior to myocardial infarction has also been researched in rat models.[98][99] Endurance training prior to a myocardial infarction in these studies resulted in a reduction in the size of the infarct, improved remodeling, decreased left ventricular hypertrophy, improved systolic function, increased expression of cytochrome oxidase subunits, ventricular ANPs, SR calcium APTase and fatty-acid binding protein, and decreased apoptosis. Additionally, it promoted improved contractility, calcium handling and sensitivity in cardiac cells.[96] These studies suggest that aerobic exercise may be used not only for treatment of heart disease but also as a preventative strategy, helping attenuate the damage incurred during MI.

A study by Kemi et al investigated the effects of aerobic exercise and pharmacological intervention on cardiac function following myocardial infarction.[97] The medication used, Losartan, acts as an antagonist to the angiotensin II type 1 (AT1) receptor.[97] The result of this interaction is improved cardiac afterload and hemodynamics.[97] Subjects were female rats that endured either left coronary artery constriction to simulate myocardial infarction or a sham thoracotomy procedure.[97] At 1 week post-MI, the rats were administered Losartan or a placebo.[97] Four weeks after the MI, the rats started an 8-week exercise program. Rats in the control group began a sedentary lifestyle at that point.[97] Beginning exercise 4 weeks after the injury was to allow for stabilization of the cardiac remodeling process.[97] The exercise protocol used was 5 days per week for 8 weeks, with a 10 minute warm-up on the treadmill followed by 1.5 hours of interval training. Intensities alternated between 8 minutes at 85-90% VO2max and 2 minutes active recovery at 50-60% VO2max.[97] Results revealed VO2max increased 20% in the sedentary group that was administered Losartan. The group that performed exercise and took Losartan had the same increase in VO2max as the exercise group given placebo.[97] Citric synthase (CS), which is associated with mitochondrial density, is decreased in heart failure but was elevated toward normal levels with aerobic exercise.[97] Losartan alone had no effect on CS, but it did have a positive effect on CS when combined with exercise. LDH is decreased in heart failure with exercise alone and with Losartan alone, but it is increased with a combination of Losartan and exercise.[97] Exercise alone and exercise in conjunction with Losartan increased creatine kinase activity. Losartan alone had no effect on creatine kinase activity.[97] The proposed reasoning behind the advantageous combination of exercise and Losartan is that Losartan decreases the load on the heart while aerobic exercise increases the oxidative capacity of cardiac muscle.[97] The production of energy by myocardial enzymes was facilitated most by the combination of exercise and Losartan. Exercise alone also proved beneficial, with elevated energy transfer enzyme activity observed in the study.[97]

Table 11. Effects of exercise on energy metabolism in pathological hearts of animal studies.

Author Subjects Exercise Intensity Intervention Results
Kemi et al (2007)[97] adult female Sprague–Dawley rats who underwent coronary artery ligation or sham procedure High 5d/wk for 8 weeks; 10-minute warm-up, 1.5 hours of exercise alternating between 8 minutes at 85-90% VO2max and 2 minutes active recovery at 50-60% VO2max. Exercise only induced same increase in VO2max as combined losartan and exercise. CS returned to normal levels with exercise and exercise plus losartan but not losartan alone. LDH not increased by exercise alone or losartan alone, but increased with combined exercise and losartan. CK activity increased with exercise alone and exercise plus losartan but not losartan alone.

Cardiac Remodeling

Table 12. Effects of exercise on cardiac remodeling in pathological hearts of animal studies.

Author Subjects Exercise Intensity Intervention Exercise Effects
Kolwicz et al (2009)[74] Female SHRs Moderate 12 weeks aerobic (treadmill) program: 20–25 m/min for 60 min, 5 days/week. Increased LV wall thickness; Increased CSA, both concentrically and eccentrically
Garciarena et al (2009)[73] 22 male SHR and 5 normotensive Wistar rats Low to moderate Swimming for 90 min 5 days/week for 60 days Significant increase in cardiomyocyte CSA; significant decrease in collagen content; increased myocardial capillary density; transformation from concentric to eccentric cardiac hypertrophy
Schultz et al (2007)[106] Female hypertensive rats High 16 months of daily, voluntary wheel running for an average 336 minutes/day at 20.0 m/min with a maximum speed of 74.4 m/min Significant pathological cardiac hypertrophy (thickness, mass, chamber size), decreased ejection fraction and myofilament shortening, increased fibrosis and induction of fetal genes
Emter et al (2005)[101] Male hypertensive rats Low 6 months of treadmill training at 14 m/min for 45 minutes/day on 3 days/week Delayed the onset of HF, reduced mortality, delayed pathological fetal gene shift, and increased cardiomyocyte dimensions
Rossoni et al (2011)[102] Aging hypertensive male rats Low Aerobic exercise training at 50-60% VO2Max for 60 minutes/day, 5 days/week for 13 weeks Decreased blood pressure (11-14%), heart rate, LV hypertrophy (11%), collagen content and myocardial wall thickness; no effects on capillary density or myocyte hypertrophy
Chicco et al (2008)[93] Aging female hypertensive rats Low Treadmill training at 14.5 m/min and 10% grade for 45 minutes/day, 3 days/week until development of HF or euthanization due to complications Significantly delayed onset of HF and mortality due to HF and all causes combined; 21% greater cardiolipin content
Haykowsky et al (2007)[103] Meta-analysis Variable Aerobic exercise, resistance training, aerobic exercised combined with resistance training Aerobic exercise, not strength training, leads to attenuated HF-associated LV remodeling; aerobic exercise results in significant improvements in ejection fraction and LV function, significant increases in VO2Max and decreases in EDV and ESV; results were inconclusive for resistance or combined training
Miyachi et al (2009)[81] Dahl salt-sensitive hypertensive male rats Low-Moderate Aerobic swimming for 1 hour, 5 days/week for 9 weeks Attenuated development of HF (decreased LV concentricity and thickness), decreased mortality, reduced interstitial fibrosis, and increased capillary density without impairments in function
de Waard et al (2007)[104] Male and female mice with large myocardial infarction (MI) Variable 8 week of voluntary exercise (overground cage running) No negative effects on mortality, lesion or LV geometry (diameter or myocyte CSA); enhanced LV myofilament and shortening function by 8-12%; no negative shift of genes from adult to fetal; significantly decreased collagen content (stiffness)
Kemi et al (2011)[105] Healthy rats; rats with pressure-overload LV hypertrophy; rats with post-MI heart failure High 8 weeks of treadmill training for 1 hour/day, 5 days/week at 85-90% VO2Max Exercise in normal rats led to 16% increase in cardiomyocyte volume; exercise in LV hypertrophy rats led to further 8% increase in cardiomyocyte volume without change in transverse tubule (TT) density; exercise in HF reversed pathological hypertrophy by 50% and increased TT density by 40%

In addition to improved beta-adrenergic activity, Leosco et al (2008)[76] found that exercise (10-week treadmill protocol) beneficially improves LV remodeling and contractility in rats with severe chronic HF (post-MI). Angiogensis was also stimulated in areas of the heart that were not affected by the infarction. To our knowledge this is the first study showing that exercise may promote angiogenesis (e.g., capillary growth and capillary arteriolarization) in non-infarcted areas of severely decompensated hearts.[76]

In the Garciarena et al study, it was found that 60 days of low-to-moderate intensity aerobic training transformed pathological, or concentric, to physiolocial, or eccentric, hypertrophy in SHR.[73] Physiological hypertrophy is manifested as a comparative increase in the thickness of the left ventricular wall and the size of the left ventrice in response to volume-overload, as seen in the trained SHR in this study.[73]

Spontaneously hypertensive rats, like many used in these models, develop heart failure in a predictable manner, typically between 18-23 months of age.[106] Excessive high-intensity aerobic exercise has been shown to significantly decrease cardiac function and accelerate the development of decompensated heart failure.[106] Increased cardiac fibrosis or scarring suggests an exercise intensity too extreme for the heart to adapt advantageously. Similarly, results from a study by Emter et al.[101] demonstrated that high-intensity treadmill training (17.5m/min) may result in sudden cardiac death in hypertensive rats. Three subjects exercising at high-intensity terminated shortly after initiating the protocol, thus forcing researchers to decrease intensity to a much lower, tolerable intensity (14 m/min) at which no animals perished. Moderate-intensity aerobic exercise has warranted similar results. Twelve weeks of moderate-intensity treadmill training led to physiologic hypertrophy, decreased apoptosis and increased cell proliferation, ultimately inducing a safe balance between cell death and genesis in the hearts of hypertensive rats.[74]

Results from a 2007 meta-analysis[103] of exercise in heart failure patients showed aerobic exercise was effective at inducing advantageous cardiac remodeling and increasing aerobic capacity (VO2Max), whereas resistance training or a combination of both were not. Although results from this review were not conclusive regarding exercise intensity, aerobic exercise can be interpreted as an effective, safe, and inexpensive treatment option for individuals with heart failure.

A recent study by Kemi et al[105] demonstrated that exercise significantly reverses the characteristic pathological hypertrophy and loss of transverse tubules in rats with decompensated heart failure.[106] This effect correlates with improved cardiac pump function. Similarly, eight weeks of voluntary exercise improves cardiac contractility even without affecting LV dimensions in mice hearts after myocardial infarction with associated hypertrophy.[104]


Table 13. Effects of exercise on apoptosis in pathological hearts in human hearts.

Author Subjects Exercise Intensity Intervention Results
Adamopoulos et al (2002)[69] Patients with stable, moderate to severe heart failure (classII/III) Moderate 12 week home-based program: 5 days/week, 30 minutes/day at 60-80% maxHR Decreased Fas/FasL

Table 14. Effects of exercise on apoptosis in pathological hearts in animal hearts.

Author Subjects Exercise Intensity Intervention Results
Libonati et al (2011)[71] Female rats Moderate 12-week aerobic (treadmill) program: 5 days/week; 60 minutes/day at 25 m/min, 0% grade Decreased capase-3 activity; Decreased Bad phosphorylation;
Kolwicz et al (2009)[74] SHR rat model Moderate 12 week aerobic (treadmill) training program: speed 20–25 m/min for 60 minutes, 5 days/week Attenuation of apoptotic rate
Kavazis et al (2008)[87] Rat model Moderate Aerobic (treadmill) training protocol: 5 consecutive days of 60 minutes/day at speed 30 m/min, 0% grade, estimated 70%VO2max Decreased propensity toward apoptosis (e.g., reduced rate of ROS-induced cytochrome c release from mitochondria and mitochondrial permeability transition pore opening)
Lee et al (2006)[78] SHR rats Moderate 12-week aerobic treadmill program Increased Bcl-2; Decreased Bax; Decreased caspase-3

Apoptosis is a known contributor in cardiac hypertrophy and overtime a progression to heart failure. Research has demonstrated that exercise, particularly chronic, attenuates apoptosis and overall ameliorating myocyte survival.[86][87][71] Studies[74][78][71] reported a lower rate of apoptosis after exercise training in subjects with pathologic hypertrophy. The researchers of a recent study[71] found a decrease the pro-apoptotic mediators Bad and capase-3 compared to the sedentary subjects.[71] In addition, the apoptotic rate progresses toward a more normal balance in hypertension after exercise training. Although apoptosis still occurs, the rate of cell proliferation is greater subsequently improving the amount of functional myocytes.[74] However, this premise is incomplete. One study[107] showed an increased presence of pro-apoptotic cells (e.g., Bax) post-exercise in addition to overall increase in rate of apoptosis, anti-apoptotic proteins (e.g., Bcl-2) and HSP72. Nonetheless, chronic exercise attenuates the apoptotic pathway, specifically the intrinsic, by inhibiting its mediators, the signal transduction pathways secondary to pathological hypertrophy, as well as, improving the regulation of the systolic function.[71][78] Several studies[86][87] have partly linked the ability of exercise to reduce apoptotis to an alteration in mitochondrial phenotype that is cardioprotective.

Additionally, the role of Fas and the Fas ligand (FasL) also acts as an important mediator in apoptosis. These apoptotic-mediators are known to play a pathological role in patients with heart failure (HF), as well as, may have some relative implications to patient’s exercise intolerance and clinical decline.[69] Therefore, studies delineating the role of exercise in patients with HF have found that physical training decreases both apoptotic-mediators Fas, the binding ligand, FasL,[69] and pro-inflammatory cytokines. Thus, exercise training by virtue of its anti-apoptotic effects, may induce beneficial reductions in Fas/FasL expression.[69] This was one of the first studies to demonstrate that exercise training in HF has an immunomodulatory role. Thus, exercise training improves the balance of homeostatic, attenuates apoptosis, partly due to a reversal of immune factors associated with CHF (e.g., significant reductions in TNF-alpha, IL-6, FasL).

As previously discussed, exercise training promotes cardiac mitochondrial adaptations that beneficially promote a resilient phenotype to apoptosis.[87] Post-exercise, mitochondrial antioxidant enzymes in both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria and anti-apoptotic proteins were increased.[87] To our knowledge this is the first article to that concludes exercise has the ability to alter mitochondria activity and protect against apoptosis, hence, supporting the premise of a cardioprotective phenotype. Interestingly, in the IMF mitochondria of the sedentary rats, when exposed to moderate oxidative stress, cytochrome c was released which did not occur in the SS mitochondria, eluding to a different sensitivity between IMF and SS mitochondria to “ROS-induced apoptotic stimuli.”[87] Thus sedentary rats had an overall increased susceptibility to apoptotic stimuli. Additionally after the exercise bout, antioxidants (e.g., HSP 70, catalase, and GPX) were significantly increased in both types of mitochondria decreasing cytochrome c release.[87][108] Overall, these findings are paramount, suggesting that exercise decreases the vulnerability of mitochondria to reactive oxygen species and subsequent detrimental apoptosis.

Calcium Handling & Contractility

Calcium is a key regulator of muscle contractility in cardiac muscle. Calcium binds to troponin and initiates a shortening of the actin-myosin cross-bridge during systole and allows relaxation of cardiomyocytes when it releases from troponin during diastole.[109] Exercise induces positive changes in cardiac contractility; a 10-week high-intensity training program increased cell fractional shortening by 40-50% and rates of contraction-relaxation by 20-40%.[109] These adaptations reverse rapidly upon cessation of regular exercise. Within 4 weeks of detraining, the improvements achieved through 10 weeks of high intensity aerobic training had completely reverted to baseline levels.[109] Rat models of heart failure have offered support for high-intensity aerobic exercise for improving myocardial function; rats with heart failure who exercised regularly achieved fractional shortening equivalent to that of healthy controls.[109] Improved calcium handling is implicated in the functional myocardial improvements among heart failure rats subjected to exercise interventions.[109] The mechanisms through which exercise improves cardiac contractility are not fully understood. Changes in intracellular calcium concentrations during systole or diastole have not been observed, so some researchers have suggested that altered calcium sensitivity is responsible for increased myofilament shortening and contraction-relaxation rates.[109] Table 15 summarizes cardiomyocyte contractility and calcium cycling adaptations to exercise training without heart failure, heart failure, and exercise training with heart failure.[109] As outlined in Table 15, rats with heart failure that participated in regular exercise demonstrated trends in calcium handling similar to rats with healthy hearts.[109]

Table 15. Summary of cardiomyocyte contractility and Ca2+ handling[109]

Exercise training in healthy hearts Heart failure Exercise training in heart failure
Amplitude of shortening Increased Decreased Increased
Rates of contraction-relaxation Increased Decreased Increased
Force-length relationship Increased Decreased Unknown
Power output Increased Decreased Unknown
Peak systolic [Ca2+] Decreased Increased Decreased
Diastolic [Ca2+] Decreased Increased Decreased
[Ca2+] transient amplitude Decreased Decreased Increased
Rates of rise & decay of [Ca2+] transient Increased Decreased Increased
Myofilament Ca2+ sensitivity Increased Inconclusive Inconclusive

Cardiac Fibrosis

As described on the Cardiac Hypertrophy Cell Bio Page, cardiac fibrosis is regulated by many molecules including TGFβ, CTGF, and microRNA (miRNA) and manifests as increased extracellular matrix protein and collagen deposition. Angiotensin II in the heart is also involved in the initiation of cardiac fibrosis, but not necessary to begin hypertrophic signaling pathways.[34] The following table briefly describes studies that have investigated the effects of exercise on cardiac fibrosis and its regulators in animal models.

Table 16. Effects of exercise on fibrosis in pathological hearts in animal models.

Author Subjects Exercise Intensity Intervention Results
Lachance et al (2009)[110] 160 male adult rats; 2 groups with aortic valve regurgitation Moderate Treadmill running for 30 min, 5 days/week for 9 months Significantly less cardiac fibrosis, perivascular fibrosis, and collagen content; reduced overexpression of mRNA TGFβ1 and 2 and CTGF
Zamo et al (2011)[111] Young and old male SHR Low Swimming for 1 hour, 5 days/week for 8 weeks No significant change in cardiac AngII; decreased AngII in blood
Garciarena et al 2009[73] 22 male SHR and 5 normotensive Wistar rats Low to moderate Swimming for 90 min 5 days/week for 60 days Significant decrease in collagen content
Schultz et al (2007)[106] 29 SHHF female rats and 16 Wistar-Furth normotensive rats Moderate to High Running at will on a wheel for 16 months; average speed of 20 m/min up to average maximum speed of 74 m/min for an average of 5.6 hours/day Trained SHHF rats showed 338% increase in interstitial and perivascular collagen compared to sedentary normotensive rats; increased cardiac fibrosis
Xu et al (2008)[112] 8 trained male rats with MI, 8 sedentary rats with MI, sham control rats Moderate Treadmill running at 16 m/min for 50 min 5 days/week for 8 weeks Training in rats with MI resulted in significantly decreased mRNA expression of TIMP-1 and ACE, but insignificant decrease in types I and III collagen and TGFβ compared to sedentary rats with MI. There was no significant change in protein levels of type I and III collagen, TGFβ, and MMP-1 between groups. Trained rats with MI did show significantly decreased protein levels of TIMP-1

Moderate intensity aerobic exercise appears to decrease cardiac fibrosis and involved mRNA expression of TGFβ1 and 2 and CTGF.[110] Low intensity aerobic exercise, on the other hand, did not show a significant effect on cardiac levels of AngII which has been shown to be involved in the triggering of cardiac fibrotic signaling.[111] However, direct measures of cardiac fibrosis, collagen content, and levels of TGFβ and CTGF were not taken in the low-intensity exercise study.[111]

Excessive moderate to high intensity aerobic exercise has been shown to be stressful to the hypertensive, failed heart.[106] The rats with pathological heart condition used in the study by Schultz and colleagues were spontaneously hypertensive heart failure (SHHF) rats.[106] Heart failure occurs with severe and prolonged cardiac hypertrophy and fibrosis and is therefore important to determine the limits of exercise that are safe in this population of people. Limitations of this study include the extended period of time each day (5.6 hours) that the SHHF rats ran on the wheel in their cage, which is not applicable to or realistic in humans.[106] Despite the lack of applicability to humans, this study showed that excessive moderate to high intensity training is not safe in the pathological heart and can increase the progression to heart failure.[106] Although exercise has been shown to be safe and beneficial in individuals with cardiovascular disease, it is important to control for the duration and intensity as to not place a pathological overloading stress on the heart.[1][106]

Another study by Xu et al showed the effects of exercise in rats post-myocardial infarction (MI).[112] Cardiac remodeling, including the fibrotic response, occurs following an MI, and therefore the effects of exercise should be determined.[112] This study found that moderate intensity aerobic training for 8 weeks is safe post-MI and resulted in the prevention of excessive cardiac fibrosis in an animal model.[112]

Special Considerations:

β-blockers and their effects on monitoring exercise intensity

It has been widely accepted to utilize heart rate in order to assess the intensity of exercise at which a person may be performing, as there is a direct relationship between one’s heart rate and their maximal oxygen uptake (VO2max).[113] However, in cardiac patients that may be taking β-blockers, heart rate is not an accurate means of predicting exercise intensity.[113] When analyzing the patient’s heart rate response to exercise, β-blockers blunt this response.[113] This means that patients may be exercising at a very high intensity, but display zero to minimal signs of increased heart rate.[113] Therefore, it is the responsibility of the Physical Therapist to include other means of assessing exercise intensity in their practice, such as the Borg Rating of Perceived Exertion (RPE) scale when treating patients that are taking β-blockers.[113] In a study by Zanettini et al[113], they analyzed the effectiveness of utilizing the 10-point Borg RPE scale with cardiac patients that were currently talking β-blockers.[113] They found that the by incorporating self-regulation into their exercise program at an intensity between 4-5 on the RPE scale, it served as an effective and safe means of determining exercise intensity in the early phases of rehab.[113] However, in the later phases, they found that patients would be exercising at a higher intensity than reported via RPE.[113] Therefore, they concluded that in order to maintain patient safety, the Borg RPE scale should be utilized along with other objective measures such as the percentage of heart rate reserve.[113]


The overwhelming majority of evidence implies that long-term, moderate-intensity aerobic exercise promotes cardioprotection and health. The recommended exercise prescription for individuals with cardiac hypertrophy and fibrosis based on the above findings is:

  • Long-term, moderate-intensity (50-80% max heart rate) aerobic exercise, approximately 60 minutes, 5 days a week. A gradual progression to this exercise tolerance goal is recommended, especially for those individuals previously sedentary.

However, further research is still needed to determine the optimal exercise prescription based on a lack of human models, evidence of gender-specificity, and evidence of negative exercise implications in long-term endurance athletes. It is still unknown the point at which physiologic exercise adaptations convert to pathologic adaptations. In conclusion, evidence promotes exercise as both primary and secondary prevention for myocardial hypertension and heart failure. Incorporating exercise and physical activity into a healthy lifestyle will not only improve the body's ability to mediate the disease process but also improve general health.

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