Acute versus chronic exercise-induced left-ventricular remodeling

Abstract

Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients.

Keywords::

• athlete’s heart
• exercise
• left ventricular remodeling
• longitudinal study
• myocardial function

Observations of cardiac enlargement in trained athletes date back to the late 1890s. At that time, the Swedish clinician Henschen used the physical examination skills of percussion and auscultation to quantify cardiac dimensions in elite Nordic skiers [1], while Eugene Darling of Harvard University made similar observations in competitive university rowers [2]. Since the days of Henschen and Darling, our understanding of exercise-induced cardiac remodeling (EICR) has paralleled advances in diagnostic technology. The introduction of chest radiography in the 1950s facilitated definitive documentation of cardiomegaly among trained athletes [3], and the advent of 12-lead electrocardiography in the 1960s and 1970s helped to define the electrical properties of the athlete’s heart [4]. Most recently and perhaps most powerfully, non-invasive cardiovascular imaging has lead to numerous advances in our understanding of how the heart responds to exercise. The use of complementary imaging techniques including echocardiography and magnetic resonance imaging have enabled precise quantification of cardiac structure, definitive documentation of sport/physiology-specific EICR, and some initial insights into the functional myocardial mechanics of EICR. Despite these advances, many properties of EICR remain incompletely understood. Examples of unresolved mediators of EICR include athlete age, interactions between physiologic stress and underlying genetics, and the relative contributions of exercise volume and intensity to the process of EICR. This review will address one cardinal issue of uncertainty, the temporal nature or ‘time course’ of EICR, with an emphasis on the potential differences between ‘acute’ and ‘chronic’ adaptations.

EICR is the process by which the heart adapts to the physiologic stress of exercise. Although a comprehensive description of EICR is beyond the scope of this document, several key points deserve mention. The physiology underlying most common forms of exercise training can be broadly dichotomized into isotonic/dynamic and isometric/static stress. Isotonic stress, the physiology inherent in endurance activities, imparts a volume challenge on the heart which has been associated with left ventricular dilation and eccentric hypertrophy. In contrast, isometric stress, the physiologic hallmark of strength-based activity, imparts a pressure challenge on the left ventricle which has been associated with wall thickening in the form of concentric hypertrophy. The notion of sport specific EICR was first proposed in the 1970s [5] and has been confirmed by more recent studies [6,7]. Additional structural aspects of EICR including right ventricular chamber enlargement [8], atrial dilation [9], and mild aortic remodeling [10] have been described. Application of advanced imaging techniques including speckle-tracking echocardiography and cardiac magnetic resonance have more recently begun to elucidate key functional aspects of EICR including changes in diastolic function and cardiac twist mechanics [11].

The vast majority of the above advances in our understanding of EICR have been derived from cross-sectional studies. Cross sectional study designs rely on measurements made at a single time point within a specific population. This approach is popular due to the fact that it can be completed with relative logistic ease and minimal resource investment. However, cross-sectional data are descriptive and must be considered at best, hypothesis generating with respect to cause and effect to the observations they detail. Recognition of the limitations of the cross sectional approach with respect to advancing our understanding of EICR has lead to increasing enthusiasm for the use of longitudinal, repeated measure studies. The longitudinal approach provides a powerful opportunity to clarify cause and effect as subjects can be studied both before and after a specified exercise intervention. Several longitudinal studies of EICR have recently been completed and have established with certainty, a mechanistic link between exercise exposure and sport/physiology-specific EICR. To date, the few longitudinal studies that have been completed and published have involved relatively short duration exercise exposure.

Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. Among common forms of pathologic hemodynamic stress (i.e., systemic arterial hypertension), myocardial remodeling occurs in a phase-dependent or ‘staged’ manner. For example, the structural and functional characteristics of hypertensive heart disease progress through various disease stages which include early compensatory remodeling followed by subsequent decompensated disease [12]. Other common cardiovascular diseases, including heart valve conditions such as mitral regurgitation [13] and aortic stenosis [14], have also been characterized across a time course of progressive changes in left ventricular (LV) structure and function. In these clinical disease states, identifying the proper stage of myocardial remodeling/ dysfunction has important prognostic and therapeutic implications.

The fact that myocardial remodeling occurs in phases in the setting of pathologic volume and pressure challenges, leads to the logical hypothesis that the volume (isotonic) and/or pressure (isometric) stimuli inherent in exercise training may generate a staged myocardial response. This question has not been well studied due to the lack of long-term longitudinal studies of EICR in athletes. Comprehensive understanding of the time course for EICR development will be a critical step in further defining the myocardial response to sustained exercise training and may help distinguish the boundary between physiology and pathology in athletic patients.

To our knowledge, the published longitudinal studies examining exercise-induced LV remodeling are relatively short in duration. Our group has championed this model of investigation through numerous studies conducted within the Harvard Athlete Initiative. Our basic study design has involved the examination of competitive athletes before and after a 90-day period of collegiate team based exercise training. Our work has largely been confined to the study of university athletes who we deliberately choose to study during their initial collegiate training experience, a time period characterized by a dramatic increase in exercise training load and thus marked corollary cardiac plasticity. In this context, we have compared the impact of endurance and strength based training on LV structure and function [6], and begun to clarify changes in myocardial mechanical parameters such as strain [15] and rotation/twist [11]. More recently, other groups have begun to perform longitudinal-based studies as well, although the longest is a 6 month study that showed increased LV twist in male athletes participating in an incremental endurance exercise training program [16]. Another recent study involving elite female athletes evaluated atrial remodeling and found biatrial enlargement and low atrial stiffness in athletes after a 4-month period of exercise training [17]. Finally, a longitudinal 6-month magnetic resonance imaging study investigated EICR in endurance and strength based athletes and found that endurance training resulted in more pronounced LV remodeling response to exercise training [18]. These studies are valuable in that they establish a cause and effect relationship between exercise and cardiac remodeling. The inherent limitations of this body of work, specifically the short time periods of study, do not facilitate any definitive conclusions about whether EICR develops in a stepwise or staged fashion.

The challenges inherent in the long-term study of athletes largely explain the paucity of such studies. Successful long-term longitudinal efforts require an infrastructure that permits repeated measurements, facilitates careful prescription or observational recording of exercise training load, and permits the necessary data capture to control for confounding variables such as dietary intake, medication use, changes in body mass, and the development of unrelated cardiovascular pathology. Such infrastructures can and should be developed but will require significant financial resources and long-term commitment by dedicated investigative teams. Investigators who choose to embark on this approach will need to consider several key study design factors. First, prescription or observational documentation of exercise training stimuli that are sufficient enough to stimulate EICR while conservative enough to be maintained by study subjects over long periods of time must be delineated. Second, deliberate scheduling of measurement time points must be established to account for the fluctuations in training load that are prescribed or that occur naturally in the context of an athletic career. Third, a priori planning for subject attrition due to musculoskeletal injury or sport career termination must be considered. Finally, careful choice of study subjects with respect to age, gender, ethnic background, and underlying cardiovascular disease or risk factors must be considered.

The challenges outlined above should not be viewed as prohibitive as the performance of carefully conducted longitudinal studies of EICR hold important scientific and clinical value. Long term studies of cardiac remodeling in athletes are required to resolve current discrepancies in the EICR literature that have arisen from the comparison of cross sectional and short duration longitudinal studies. A specific example involves the response of LV twist mechanics to endurance exercise training. Several cross sectional reports describe normal or reduced values of resting LV twist in endurance athlete groups such as cyclists [19] or soccer players [20] while short duration longitudinal studies suggest that endurance training results in increased LV apical rotation and LV twist [11,16]. This apparent paradox is likely to be explained by accounting for the athletes’ ‘stage of training’ with cross-sectional studies having captured more ‘seasoned’ athletes at advanced levels of training (i.e., chronic adaptations) and the available longitudinal studies focused on younger athletes exposed to more acute adaptation. Further studies that engage individuals during both proposed periods of exercise exposure will be required to resolve this area of uncertainty.

Long-term longitudinal studies will also be required to address the recently proposed concept that high volume exercise over long periods of time may facilitate the development of pathologic remodeling [21] and a clinically relevant form of cardiomyopathy characterized by myocardial fibrosis and resultant malignant arrhythmias [22]. This phenotype has recently been described among small cohorts of elite endurance athletes and has been proposed to develop as a direct response to high volume, perhaps excessive, levels of sustained exercise [22]. This intriguing hypothesis will remain a hypothesis until definitive long-term work that includes appropriate control groups and directed attempts to control for alternative causes of cardiomyopathic fibrosis including sporadic cases of myocarditis and occult hypertension is conducted. The public health impacts of establishing with certainty that individuals exposed to very high intensity/high volume exercise may develop related cardiac pathology are substantial, in both athletes and patients with cardiovascular disease [23]. This is particularly important given recent evidence that only small amounts of exercise may be necessary to reduce cardiovascular mortality risk [24]. Additionally, a related area involves the potential increased risk of atrial fibrillation in endurance athletes (i.e., cross country skiers) [25] and long-term studies of atrial remodeling may provide mechanistic insights into the phenomenon.

Another area in which long-term longitudinal study will have value is in the assessment of the impact of exercise cessation (removal of the exercise stimulus) on cardiac structure and function. Also known as prescribed ‘detraining’, this intervention has been proposed for clinical use for the specific purpose of distinguishing pathologic myocardial disease (i.e., hypertrophic cardiomyopathy) from physiologic EICR [26]. At present, there is a relatively limited literature defining the degree and timing of EICR regression after exercise cessation among trained athletes [27]. In addition, we are unaware of any studies which examine cardiac structure and function among athletic patients with newly diagnosed definitive structural heart disease who are counseled to abstain from exercise and to comply with these recommendations. At present, it is therefore challenging to apply this technique to clinical practice with any quantitative certainty. Long-term longitudinal studies of EICR regression in healthy athletes and in athletic patients diagnosed with definitive heart disease will be required to clarify the role of prescribed detraining.

In summary, understanding of exercise-induced LV remodeling has advanced significantly since the days of Henschen and Darling. Sport-specific changes in LV structure and function have been described, although the majority of data stems from cross-sectional and short-duration longitudinal study. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages, similar to that observed in cardiovascular disease. Examination of prolonged exposures to exercise training will be necessary to determine normative values across the age and training spectrums of athletic patients. This information, coupled with the impact of detraining, will be help to more clearly distinguish the boundary between physiology and pathology in athletic patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.