university of texas at san antonio

Effect of Post-MI Exercise Training on Cardiac Remodeling and Function

Kayla Floyd and Castural Thompson II

11/27/2013

Effect of Post-MI Exercise Training on Cardiac Remodeling and Function

Abstract

Kayla Floyd1 and Castural Thompson II1

1University of Texas at San Antonio

This paper reviews the impact of post myocardial infarction along with physical and

physiological effects that are accompanied with this aliment. Due to the severity of myocardial

infarction, healthy behaviors and lifestyle modifications must be considered before and after the

onset of this type of cardiac event.  Two main categories involved with post myocardial

infarction are cardiac remodeling (duration, intensity, frequency) and function (contractility,

baroreflex sensitivity, gene and protein expression, and ACE). The supported evidence

demonstrates the benefits of exercise training in relation to remodeling and function, but due to

increased variance, there is no guarantee of an enhanced outcome for certain individuals. In

addition, further research in the areas of cardiac stem cell and resistance training research will

allow a multi-faced approach in future treatment and research options to better comprehend

cardiac remodeling and function for infarcted patients.

Chapter I: Introduction

Myocardial infarction (MI), also termed as a heart attack or ischemia, is a blood clot that

obstructs arteries that supply blood to the cardiac muscle leading to compromised cardiac cells.

As the cardiac cells reach a critical threshold point, cellular repair mechanisms that maintain

homeostasis are negatively altered. After the cardiac muscle is deprived of oxygen and

metabolites, the muscle cells die and scar tissue accumulates in the affected areas. Typically, the

site that causes the blockage contains cholesterol or triglyceride plaque accumulation along the

inner wall of the artery (12). This review will include topics covering cardiac remodeling and

cardiac function post-MI associated with the effects of exercise and implications for possible

future studies.

Chapter II: Literature Review

Myocardial infarction is one of the most preventable diseases and leading causes of death

presented in the U.S. and western countries; in addition, MI is the leading cause of morbidity and

mortality worldwide (1, 4, 11, 16). Nearly half a million new cases and 300,000 recurrent cases

of MI occur every year; and of this population, approximately 40% will experience a recurrent

case and die within a year (2, 11).  Some risk factors when dealing with MI include increased

blood pressure, tobacco use, diabetes, elevated cholesterol, gender, and family history. The onset

of MI normally occurs in individuals of 50 years of age and increases each year. Between men

and women 50 years or older, MI is three times more likely to occur in men (17). The hormone

estrogen plays a large role in the protection of heart attacks for women. Its association with

increased blood levels of high density lipoprotein (HDL) and decreased levels of low density

lipoprotein (LDL) decrease the risk of heart attacks (25). MI has multiple ranges of conditions

that can be caused by the sudden decrease in blood flow to the heart artery (acute coronary

syndrome) or can be the result of long-term plaque accumulation (21). MI can be sub-

categorized on the basis of anatomic or diagnostic standpoint (28). The two forms of anatomic

MI are considered to be transmural and non-transmural. Transmural is ischemia due to necrosis

of the wall thickness in the affected muscle portion that can stretch from the endocardium,

through the myocardium, and ending at the epicardium. Non-transmural MI contains necrosis but

does not extend the full thickness of the myocardial wall. This limits the ischemic necrosis

spreading solely to the endocardium or the endocardium and myocardium. The most susceptible

parts of the heart are the endocardial and subendocardial zones at which the wall thickness has

the highest chance of ischemia.  

Effects of Exercise on Cardiac Remodeling

Cardiac Remodeling

The state of the cardiac muscle post-MI causes molecular and chemical mechanisms

which initiate compensatory processes that are debilitating for the weakened heart but can be

attenuated or suppressed by pharmacological or exercise intervention (24). Three main

mechanisms are initiated during remodeling that can have detrimental influences to the heart –

left ventricular hypertrophy, dilation, and collagen accumulation (24, 27, 29, 30). Vaghasiya,

Trivedi and Chorawala (24) claim that the best biological marker of ventricular overload is by

ANF (atrial natriuretic factors) expression because it signals an increase in secretion of peptides.

This cascading effect induces the stimulation of vacuoles and lysosomes within endothelial cells

that cause chromatin abnormalities and distribution of collagen fibers in extracellular matrix of

endothelium (27). Beneficial effects from exercise have shown that training reduces cardiac

hypertrophy in LV and RV weights (29) and blunts LV dilation (10). However, other studies

have shown that the infarcted area does not decrease due to exercise, but that the area gets

attenuated (27, 30). Remodeling is divided into two phases: early and late. Early phase

remodeling is within the first 72 hours of MI and late phases pertain to >72 hours. Studies have

proved that for every 30 minutes in delay of treatment the left ventricle becomes more

susceptible for long term dysfunction at a rate of 8.7% and the risk of death at one year by 7.5%

(15). This study stated that failure to recruit myocytes into the scar tissue by exercise continued

the weakening of the contractile function and progressive dilation forces increased stress upon

the myocardial wall (15). Although exercise training can be negative, a study showed that late

exercise involvement can assist in the recovery of calcium gradient equilibrium which

contributes to myofilament function of cardiomyocytes (18).

Duration

A majority of patients can exercise after MI, but the intensity, duration, and frequency

depend on the severity of one’s heart condition. La Rovere, Bersano, Gnemmi, Specchia and

Schwartz (13) stated that exercise training over periods of time can supplement as an important

non-pharmacological tool in the treatment of cardiac rehabilitation. The authors provided

evidence that aerobic training in patients that have coronary artery complications or ones that do

have infarcted hearts can benefit from exercise. Their study was a meta-analysis consisting of

8940 patients with 48 randomized control trials; one experiment had a duration that lasted for 4

weeks in which the results illustrated that cardiac rehabilitation programs utilizing aerobic

training decreased cardiovascular mortality by 26%. The study also confirmed that a reduction in

total cholesterol, triglycerides, and blood pressure became evident after the 4 weeks for MI

patients.

A recent experiment from Lee, Chen, Hsu, Su, Wu, Chien, Tseng, Chen and Lee (14)

used rabbits with surgically altered coronary artery function. After 4 weeks of aerobic exercise

training, the ventricular function showed a significant improvement due to the changes in

autophagic function (intracellular degradation system); this was seen because the ventricular

function had become less impaired, oxygen consumption, cardiac output, and regional blood

flow became more evident within the exercise subject groups.

Intensity

The intensity of training must also be considered when dealing with myocardial infracted

hearts. Exercise capacity and physical fitness increases when exercise is performed on a daily

basis. Cannistra, Davidoff, Picard and Balady (6) investigated the effects of moderate to high

intensity exercise training programs on left ventricle remolding after MI. This study consisted of

68 patients with first time myocardial infracted hearts for 12 weeks. The measurements of the

infracted heart size for the experimental group changed from 57.95 +/- 13.1cm2/m2 to 57.80 +/-

12.04 cm2/m2. According to the results for this study, slight variation within the experimental

group proved that exercise intensity with smaller infracted hearts does not adversely alter left

ventricle remolding.  However, a study showed MI patients that exercised at increased relative

intensities elicited elevated aerobic capacity and other cardioprotective effects when opposed to

moderate or low exercise intensities (22).

Frequency

Recent studies have compared high and low frequency bouts of exercise training

programs. Nieuwland et al (19) noted that higher frequency of training is more effective in terms

of ventilatory anaerobic threshold (oxygen uptake immediately below the exercise intensity at

which pulmonary ventilation increased disproportionally relative to VO2 and quality of life). This

study consisted of 114 men with the mean age of 52 +/- 9 years that were randomly selected to

perform in a two-hour, 6-week high (ten sessions per week) or low (2 sessions per week)

exercise program. Functional capacity and quality of life were evaluated before and after the

rehabilitation session. Their findings proved that ventilator anaerobic threshold rates increased

more with higher frequency programs. Quality of life and improved subjective physical function

were also associated with high frequency training programs.

Effects of Exercise on Cardiac Function

Contractility – Ca2+ Sensitivity

It has been shown that post-MI patients are susceptible to an increase in the sympathetic

nervous system and a decrease in the parasympathetic system (4, 23). As a result, post-MI

patients are at a higher risk of left ventricular fibrillation (LV) and tachycardia. Schober and

Knollmann (23) conducted a meta-review analysis over the effect of exercise post-MI in

contractility and Ca2+ sensitivity. Within this review, it has been shown that with exercise, there

is an improvement in cell shortening, elevated end-diastolic Ca2+ readings are lowered, and

increased myofilament Ca2+ sensitivity/depressed maximum developed forces that returned to

normal levels. It is hypothesized that these effects are a result of the improvement in β1-

adrenergic signaling and cAMP (9). During further review, Bonilla, Belevych, Sridhar,

Nishijima, Ho, He, Kukielka, Terentyev, Terentyeva and Liu (4) investigated this phenomenon

by using canines in a 10-week aerobic training program to see if exercise could reduce the risk of

antiarrhythmias. Results indicated that exercise could 1) prevent ischemia-induced

tachyarrhythmias, 2) stabilized QTc intervals, 3) reduced action potential duration at 50% and

90% repolarization, and 4) restored Ca2+ spark frequency to levels associated with control. To

further highlight this mechanism, Wisløff, Loennechen, Currie, Smith and Ellingsen (29)

demonstrated that cardiomyocyte shortening was approximately 60% higher in trained-infarcted

rats and peak Ca2+ transients were 18% lower than sedentary-infarcted rats.

Baroflex Sensitivity (BRS)

In a study conducted by Coutsos, Sala-Mercado, Ichinose, Li, Dawe and O'Leary (7),

researchers separately analyzed the effects of prazosin (an α1-adrenergic antagonist) and exercise

in mongrel, female dogs (N = 7). Coustsos et al found that there was minimal studies that

observed the effect of muscle metaboreflex activation (MMA) during exercise did not increase

cardiac output in patients who had heart failure which essentially limits the ability for the left

ventricle to contract adequately; this is due to altered autonomic alterations because of reduced

vagal activity (13). This was in part due to the limitations from coronary blood flow that was

restrained because of coronary vasoconstriction. This mechanism impairs the oxygen delivery

that is needed for the cardiac muscle in order to maintain the workload that compromises

coronary blood flow, coronary vascular conductance, and the maximal rate of left ventricular

pressure change. Exercise showed that cardiac power increased stimulating coronary

vasodilation, but not at the same levels as control. Once the α1-adrenergic drug was introduced,

levels returned to those seen in the control group highlighting the beneficial effects of

pharmacological and exercise intervention. Additionally, another study that utilized humans

showed that exercise-training increased BRS by 26% (13) and that BRS values could predict

long-term cardiovascular mortality (8).

Gene and Protein Expressions

Numerous chemical levels are altered post-MI, however, how and when these

mechanisms are stimulated are relatively unknown. In a study conducted by Bonilla et al (4), it

was mentioned that canines were administered to a 10-week endurance program; within this

study, the authors investigated protein expression for the potassium channel subunit (4). Even

though the results were not as promising to indicate that exercise had an effect on these

expressions to explain current alterations, there were some significant findings: KChIP2 was

significantly reduced in sedentary counterparts compared to control and exercise while there was

no difference with Kv4.3 and DPP6 expression between the groups. In addition, exercise training

showed increased levels of PLN (phospholamban), SERCA2a (sarcoendoplasmic reticulum

calcium ATPase), and RyR2 (ryanodine receptor 2) that were comparable to control, and a

reduction in NCX1 expression (sodium/calcium exchanger). In another study, Western blot

analysis showed that SERCA2a levels increased by 34% in trained-infarcted rats compared to

sedentary-infarcted rats, and that NCX1 increased by 33% (29). Furthermore, this study

indicated that ANP (atrial natriuretic peptide) gene expression attenuated over the course of the

study, t=4 weeks. However, results for SERCA2a levels have been contradicted in other studies

(9) that have shown that there is not a significant difference; this might stem from differences in

experimental design where this study used rats with a large myocardial infarction. Further

analysis over collagen indicators have shown that exercise lowered TIMP-1 levels and

normalized MMP-1/TIMP-1 ratio that contribute to a reduction in myocardial matrix collagen

disruption.

Studies by Wang, Wang, Wier, Zhang, Jiang, Li, Chen, Tian, Li and Yu (27) and de

Waard, van der Velden, Bito, Ozdemir, Biesmans, Boontje, Dekkers, Schoonderwoerd,

Schuurbiers and de Crom (9) provide further insight in regards to vasodilation. eNOS stands for

endothelial nitric oxide synthase that stimulates vasodilation in endothelial cells. Post-MI,

dysfunction in this mechanism causes an increase in oxidative stress and hampers the ability for

this system. Wang et al (27) revealed that MI can inhibit the activation of Akt or PI3K that

decreases the activity of eNOS and NO production in adult male Sprague-Dawley rats. The rats

in this study were subject to an 8-week aerobic exercise program in which the results indicated

exercise increased activation of PI3K, Akt, and eNOS in mesenteric arteries. Furthermore, de

Waard et al (10) conducted a study on three different types of mice – eNOS+/+, eNOS +/-, and

eNOS -/- - for 8-weeks in an exercise training program. They wanted to see the effects of full

allele expression within mice with exercise; the results were that full allele expression is

necessary to abolish interstitial fibrosis and apoptosis in the remote remodeled myocardium,

attenuate global LV systolic dysfunction, and ameliorate pulmonary congestion.

ACE

Post-MI patients are shown to have an increased expression of ACE to provide support to

the weakened heart, but it can eventually lead to deteriorating health risks for the future. Burrell

et al (5) noticed that the new enzyme ACE2 might play an important role in circulating RAAS

which could lead to new ways to overcome chronic heart failure, however, the mechanism as to

how it factors in the RAAS system remains to be elucidated. ACE2 is a protein that is localized

in the heart, testis, and kidney that is believed to degrade Ang II to the vasodilator Ang 1-7. In

their study, the investigators took 56 Sprague-Dawley rats and stimulated a MI by ligation of left

coronary artery and used five male patients who had heart failure. To examine the activity levels

for ACE and ACE2 at days 1, 3, and 28, only the hearts from the rats were used; human hearts

were later used after extrapolation from transplant surgery to make comparisons. At day 3, ACE

mRNA was elevated only in border/infarct zone compared to MI-viable area; at day 28 ACE

mRNA was elevated in MI-viable myocardium. There was increased ACE2 expression in

border/infarct zone of MI rats at day 3 compared to MI-viable area and changes persisted at day

28; at day 28, ACE2 mRNA was elevated 3x in the MI-viable myocardium. ACE2 protein was

present in viable myocardium, border zone, and infarct region; ACE2 was localized to the

endothelium of small to large arteries and sporadically within the smooth muscle of vessels and

associated to myocytes. In the human hearts, ACE and ACE2 immunoreactivity was

predonminately localized in the vascular endothelium, smooth muscle, and in cardiomyoctes.

This study showed ACE2 might have a role in counter-regulatory mechanisms by increasing

vasodilators Ang 1-7.

A study by Wan, Powers, Li, Ji, Erikson and Zhang (26) analyzed the effect of aerobic

exercise training on post-MI male rats that were 7-weeks old associated with circulating RAAS.

The study was conducted for 8 weeks with six experimental groups: 1Wk-Sham, 1Wk-MI-Sed,

1Wk-MI-Ex, 6Wk-Sham, 6Wk-MI-Sed, and 6Wk-MI-Ex. Results from this study showed that

time was insignificant at manipulating the effects of exercise; plasma renin activity and

aldosterone levels were significantly decreased for the exercise groups compared to sedentary,

and even reached levels to sham counterparts.

Chapter 3: Conclusion

Exercise has shown to improve cardiac mechanisms, however, identifying the

physiological functions for improvement are still vague that require more studies to elucidate the

cardiac functions that benefit the body post-MI.

In sight of the physiological benefits from post-MI training regimens, training modalities

for endurance and resistance exercise training should be further considered. One avenue could be

resistance training at high and low intensities that supplement aerobic exercise. This type of

training is associated with left ventricle wall thickening, increased exercise capacity, muscular

strength, and basal metabolic rates. We suspect that resistance training will promote

improvement in cardiac function along with weight control, person independence, increase in

health-related quality of life, and avoid supplemental stress for musculoskeletal system (2, 3).

Promising studies have demonstrated that embryonic cells might help reconstruct

damaged cardiac cells. As mentioned above, MI comprises the transportation of oxygenated

blood to the heart that will limit the maintenance and physiological function of the myocardium.

In a matter of seconds damage to the heart will occur and in minutes an alarming amount of

destruction will commence where regeneration of the heart is infeasible by drugs or exercise; as

stated in Zimmerman et al (2007), approximately 1 billion cardiomyoctes are destroyed during

myocardial infarction (31). In order to compensate for the compromised heart, scar tissue will

accumulate at the infarcted zones to provide support for the debilitating heart. Embryonic stem

cells can originate from bone marrow, blood, fat, skeletal muscle, or other sites in humans that

can be used in areas of need (31). However, the risk, monetary challenges, molecular foundation,

and ethics behind stem cells affect the feasibility for this area of research. For example, the heart

is made up of cardiac myocytes by 30% and endothelial cells, smooth muscle cells, and

fibroblasts by 70% that could potentially cause a proinflammatory responses (31). However, a

study from 2004 illustrated that by injecting autologous bone marrow mononuclear cells at the

site of infarction might improve exercise capacity and perfusion for human patients at 6 and 12

months; this sample size was small and 2 patients died from the treatment group, but elicits

promising evidence for individuals at end-stage heart failure who can no longer receive benefits

from exercise or drugs (20).

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