Number 26, 2005
Cardiovascular effects of exercise

Adaptive and maladaptive cardiac hypertrophy

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Michael F. Allard
The James Hogg i Capture Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia – St Paul's Hospital, Vancouver, Canada
Correspondence: Dr Michael F. Allard, The James Hogg iCapture Centre for Cardiovascular and Pulmonary Research, Room 166, St Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Tel: +16048069292, fax: +16048069247, e-mail: mallard@mrl.ubc.ca

Introduction
Prolonged increases in hemodynamic workload lead to cardiac hypertrophy. This response is generally viewed as adaptive because it enables the heart to maintain function [1,2] and normalizes myocardial oxygen consumption [3], all in the presence of elevated hemodynamic workload. However, when consideration is given to the longer term outcome of the hypertrophic response as well as to the functional outcome of the hypertrophied heart after a subsequent acute metabolic stress, it becomes clear that viewing this response as entirely adaptive is too simplistic.
It is well recognized that cardiac hypertrophy occurs in response to prolonged pressure- or volume-overload due to pathologic stimuli such as hypertension or valvular heart disease [4]. As compared to non-hypertrophied hearts, cardiac hypertrophy due to pathologic stimuli is known to be associated with an enhanced risk of sudden death and with the development of heart failure [4]. In addition, such hearts develop larger myocardial infarctions [4] and suffer greater dysfunction following ischemia and reperfusion [5–7]. This latter observation is of importance because cardiac hypertrophy and coronary artery disease are both highly prevalent conditions that commonly co-exist [8]. When the hypertrophic response to pathologic stimuli is considered in this way, so-called pathologic cardiac hypertrophy may be viewed as maladaptive.
Cardiac hypertrophy also develops in response to physiologic stimuli such as endurance exercise training [9–11]. Cardiac functional performance is enhanced in hearts hypertrophied in response to physiologic stimuli and this form of cardiac hypertrophy (ie, physiologic cardiac hypertrophy) is not associated with detrimental long-term outcomes [10,12,13]. The response of physiologically hypertrophied hearts to an acute metabolic stress such as ischemia and reperfusion differs from those hypertrophied by pathologic stimuli. Specifically, post-ischemic recovery of these hearts is enhanced relative to that of non-hypertrophied hearts [11,14]. When these observations are taken into account, the hypertrophic response to physiologic stimuli may be considered truly adaptive in nature.
In addition to enlargement of cardiac myocytes, the hypertrophic response, whether due to pathologic or physiologic stimuli, is accompanied by qualitative changes within the cardiac myocytes. Energy metabolism is one aspect of cardiac myocyte biology that is well recognized as being altered during the hypertrophic response in both pathologically and physiologically hypertrophied hearts [11,15–17]. Of importance, these changes in energy metabolism are considered to be key determinants as to whether the hypertrophic response is adaptive or maladaptive [1,2,7,11,18]. As such, I will review what is known about the way in which energy metabolism is altered in hearts hypertrophied by physiologic or pathologic stimuli with particular emphasis on how changes in energy metabolism may influence the outcome from ischemia and reperusion, this being an indicator of the adaptive or maladaptive nature of the hypertrophic response. Before embarking on this discussion, a brief overview of energy metabolism in the myocardium will be provided.

Myocardial energy metabolism
Circulating fatty acids, glucose, lactate, amino acids, and ketone bodies as well as intracellular glycogen and triacylglerol can be used by the heart to produce energy [19–21]. However, catabolism of carbohydrates, such as glucose and lactate, and long-chain fatty acids produce most of the energy with the majority coming from fatty acid catabolism (Figure 1). After entering the cardiac myocyte through glucose transporters in the sarcolemma, glucose may be incorporated into glycogen or may be degraded to pyruvate in a step-wise manner via glycolysis [20,22,23]. Rates of glycolysis in the heart are determined in large part by the extent of glucose transport and flux rates through reactions catalyzed by hexokinase and phosphofructokinase-1 [22–23]. The pyruvate produced by glycolysis is then either oxidized in the mitochondria or converted to lactate [20,22,23]. The extent of mitochondrial oxidation of pyruvate, which can be derived from lactate or from glycogen, is determined mainly by the activity of the mitochondrial pyruvate dehydrogenase complex [23].

Energy metabolism in cardiac hypertrophy

Glycolysis and glucose oxidation
Rates of glycolysis are accelerated in hearts hypertrophied by pathologic stimuli before and after ischemia [15–17] (Figure 2). Interestingly, rates of glucose oxidation are not correspondingly increased [7,15–17]. Glucose oxidation can, in fact, actually be lower in pathologically hypertrophied hearts than in non-hypertrophied hearts [7]. A corollary of these alterations in glucose catabolism is that the fraction of glucose passing through glycolysis that is oxidized is lower in these hypertrophied hearts. The alterations in glucose catabolism in hearts hypertrophied in response to endurance exercise training stand in stark contrast. Specifically, glycolysis is reduced and glucose oxidation is increased in physiologically hypertrophied hearts compared to non-hypertrophied hearts (Figure 2). Correspondingly, fractional oxidation rates of glucose are higher in these hearts.

Fatty acid oxidation
As compared to non-hypertrophied hearts, long-chain fatty acid oxidation is reduced in pathologically hypertrophied hearts [15–17] (Figure 2). The substrate utilization profile that develops as part of the hypertrophic response to pathologic stimuli is similar to that in a fetal heart [25], a change considered to reflect the reoccurrence of a fetal phenotype in response to chronically altered cardiac workloads [1,26]. This particular catabolic profile for energy substrates has been observed in a number of different pathologic settings including hearts hypertrophied by pressure overload [16] or volume overload [15], and in hearts hypertrophied of spontaneously hypertensive rats [17], as well as in patients with hypertrophied-failing hearts [27].
As with glucose catabolism, the alteration in fatty acid oxidation in hearts hypertrophied by endurance exercise training [11] differs from that in their pathologic counterpart. Specifically, long-chain fatty acid oxidation rates are accelerated as compared to non-hypertrophied hearts (Figure 2). That the profile of energy substrate catabolism differs dramatically between hearts hypertrophied by pathologic stimuli as compared to those hypertrophied by physiologic stimuli indicates that alterations in metabolism induced by prolonged changes in hemodynamic workload are influenced by the nature of the stimulus leading to cardiac hypertrophy.

Adaptive and maladaptive alterations in energy metabolism in cardiac hypertrophy
As mentioned, the hypertrophic response enables the heart to meet the demands of a chronically elevated hemodynamic workload and, in this sense, has been viewed as adaptive in nature. However, it has been suggested that the alterations in the heart that occur as part of this response, including changes in substrate catabolism, have an impact upon the functional outcome of the heart when faced with a subsequent acute metabolic stress which occurs in the setting of myocardial ischemia and reperfusion, for instance [28]. The functional outcome after ischemia and reperfusion can, therefore, be used as a means to determine if the changes induced as part of the hypertrophic response are adaptive or maladaptive.
Based upon results from a variety of sources, post-ischemic functional outcome of hearts hypertrophied in response to physiologic stimuli is greater [11,14], while that of hearts hypertrophied in response to pathologic stimuli is lower than that of non-hypertrophied hearts [5–7] (Figure 3). With the preceding comments in mind, the hypertrophic response to physiologic stimuli can be considered adaptive, but the response to pathologic stimuli can be considered maladaptive. The dramatically different functional outcomes in these two forms of hypertrophy (Figure 3) are associated with equally dramatic differences in catabolic profiles for energy substrates (Figure 2). Given the well recognized link between function and metabolism in the heart [1], it is logical to consider the possibility that alterations in energy substrate catabolism contribute to the adaptive or maladaptive nature of the hypertrophic response, particularly when the hypertrophied heart is exposed to an acute metabolic stress.

Conclusions
The substrate utilization profile of the heart is altered during the hypertrophic response to both pathologic and physiologic stimuli. The alterations in substrate catabolism that occur as part of the hypertrophic response are dependent upon the nature of the stimulus leading to cardiac hypertrophy and, as such, differ significantly in pathologic and physiologic forms of cardiac hypertrophy. These alterations in substrate catabolism can be considered adaptive, as in physiologic cardiac hypertrophy, or maladaptive, as in pathologic cardiac hypertrophy, depending upon how they influence functional outcome of the heart after an acute metabolic stress.

Acknowledgement
This work was supported by operating grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of British Columbia and Yukon.?

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REFERENCES

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