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Ann Thorac Surg 2003;75:S678-S684
© 2003 The Society of Thoracic Surgeons

I: Pathophysiology of ischemic-reperfusion injury

Increased susceptibility of hypertrophied hearts to ischemic injury

Ingeborg Friehs, MDa, Pedro J. del Nido, MDa*

a Department of Cardiac Surgery, Children‘s Hospital and Harvard Medical School, Boston, Massachusetts, USA

* Address reprint requests to Dr del Nido, Department of Cardiac Surgery, Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
e-mail: pedro.delnido{at}tch.harvard.edu

Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Cardiac hypertrophy is an adaptive response that compensates for increased workload by normalizing wall stress and preserving cardiac contractile function. In advanced stages, however, clinical and experimental studies have shown that when the high workload is maintained, hypertrophy progresses to ventricular dilatation, contractile dysfunction, and decreased tolerance to ischemia/reperfusion. Development of hypertrophy is accompanied by distinct qualitative and quantitative changes in contractile protein expression and isoform switching, cytosolic calcium regulation, and substrate delivery and use. We have focused our investigations on changes in substrate delivery and capillary density in pressure overload hypertrophy and on the effects that these changes have on tolerance to ischemia/reperfusion. This report summarizes our work in this area using a model of aortic banding in 10-day-old rabbits, which exhibits the same pattern of concentric hypertrophy early, followed by ventricular dilatation and contractile dysfunction that is clinically apparent.

Clinical observational studies have shown that ventricular hypertrophy from pressure overload such as aortic valve stenosis, when untreated, is associated with progressive ventricular dilatation, contractile dysfunction, and increased vulnerability to ischemia/reperfusion injury, and is a well-recognized risk factor in cardiac surgery. The notion that hypertrophied hearts exhibit an increased sensitivity to ischemic injury emerged in the clinical literature during the 1960s and 1970s with the first descriptions of the so-called "stone heart" after cardiac surgery [1, 2]. In the pediatric literature during the same period, similar reports ascribed nearly half of the surgical deaths to increased susceptibility of pediatric myocardium to ischemic injury [3]. In these cases, myocardial hypertrophy (right or left ventricle) was a common finding. Current results with surgery for congenital heart defects have improved significantly due in part to better myocardial protection and in part to early diagnosis and treatment, before the onset of severe hypertrophy. Despite these advances and improved surgical techniques, however, myocardial dysfunction, particularly in children with ventricular hypertrophy, remains a significant cause of postoperative morbidity and mortality [4, 5]. In adults, data from the Framingham Heart Study identify left ventricular hypertrophy as the single most important contributor to cardiovascular morbidity and mortality [6, 7]. This is particularly important in cardiac surgery, as left ventricular hypertrophy is frequently associated with postischemic contractile dysfunction [8, 9].

The mechanism responsible for the decreased tolerance of hypertrophied hearts to ischemia is likely to be a complex array of interactive events. During myocardial ischemia, hypertrophied hearts exhibit accelerated loss of high-energy nucleotides, greater accumulation of tissue lactate and hydrogen ions, earlier onset of ischemic contracture, and accelerated calcium overload during early reperfusion [10, 11]. In several aspects, hypertrophied hearts are similar to hearts during early development. Onset of ischemic contracture due to development of rigor complexes and depletion of high-energy phosphates occurs earlier in neonatal hearts compared to nonhypertrophied adult hearts as well [12, 13]. A number of morphologic, metabolic, and physiologic adaptive changes in the hypertrophied myocardium contribute to increased susceptibility to ischemic injury [14–16].

Changes in substrate metabolism in hypertrophied myocardium

Fatty acid oxidation, which provides most of the energy in normal myocardium, has been shown to be impaired in hypertrophied hearts [17, 18]. Glucose metabolism takes on a more important role in energy metabolism in hypertrophied myocardium, which represents a shift back toward reinduction of the fetal isoforms of the glycolytic enzymes [19, 20]. Hypertrophied hearts have increased rates of glycolysis under aerobic conditions [17]; they use exogenous carbohydrates, such as glucose and lactate, and also glucose from endogenous glycogen stores [17, 21]. It has been argued that the increase in glycolytic potential of the hypertrophied heart is an attempt to normalize energy production due to decreased adenosine triphosphate (ATP) supply from fatty acid oxidation [17]. Glucose is metabolized by either glycolysis to lactate (anaerobic) or by mitochondrial oxidation [22]. Glucose uptake and glycolysis in the myocardium is regulated by several factors including cardiac work, ischemia, hypoxia, and insulin [23]. During ischemia, anaerobic glycolysis is the only potential source of ATP, inasmuch as oxidative phosphorylation is rapidly inhibited by lack of oxygen and accumulation of reduced nicotinamide adenine dinucleotide (NADH) in the mitochondria.

Because hypertrophied hearts are more adapted to use glucose for energy production due to expression of fetal isoforms of many glycolytic enzymes, similar to neonatal hearts [19, 20, 24], in theory this may provide an advantage over nonhypertrophied adult hearts with respect to tolerance to ischemic injury. However, in experimental studies in a model of pressure-overload hypertrophy [25, 26], we have shown that hypertrophied hearts have more injury with ischemia and decreased anaerobic glycolytic potential as compared to nonhypertrophied myocardium. The explanation for this unexpected finding lies in the complexity of glucose metabolism in cardiac myocytes. Glucose metabolism is regulated at several steps including glucose uptake, phosphorylation, glycolysis to pyruvate, glucose oxidation, and glycogen metabolism [22]. In mammalian cells, glucose is not freely permeable across the plasma membrane but depends upon a concentration gradient and is facilitated by specific transport proteins, GLUT-1 and GLUT-4 [27]. In the heart, GLUT-1 is present in low levels and is responsible for "basal" glucose uptake [28]. GLUT-4, the insulin-regulated transporter, is expressed only in cells that require rapid increase of glucose transport, such as skeletal and cardiac myocytes, and adipocytes [29]. We have previously reported that the predominant transporter in adult myocardium is the insulin-sensitive transporter GLUT-4 [30]. Glucose transport across the plasma membrane is the initial step in myocardial glucose metabolism, and the amount and activity of facilitative glucose transporter proteins present in the sarcolemma determine, in great part, the rate of glucose uptake. Under physiologic conditions, glucose entry into the cell is rate limiting for glycolysis [27]. Under basal conditions, GLUT-4 protein is stored in intracellular vesicles and, upon stimulation by insulin, ischemia, hypoxia, or cardiac work, is translocated to the plasma membrane, resulting in an increase of the membrane capacity for glucose transport [22, 23, 29, 31, 32].

Model of left ventricular hypertrophy from pressure overload

To study the role of glucose transporters in hypertrophied myocardium, we developed a model of left ventricular hypertrophy in immature New Zealand White rabbits. Pressure-overload hypertrophy was achieved by banding the descending aorta in 10-day-old rabbits [25, 26, 33, 34]. Implanting a fixed constriction in a young animal and allowing it to grow induced pressure-overload hypertrophy beginning at 3 weeks of age in this model. Measurements of left ventricular mass to left ventricular volume ratio by serial transthoracic echocardiography were used as an index for progression of hypertrophy. We have shown that progression of left ventricular hypertrophy reaches a plateau by 4 weeks of age. After this early "compensated" phase of hypertrophy, increase in ventricular muscle mass can no longer compensate to reduce peak systolic stress and progressive left ventricular dilatation occurs, indicated by a fall in left ventricular mass to left ventricular volume ratio (Fig 1A). Concomitant with this change, myocardial contractile dysfunction develops, as shown by a decline in shortening fraction (Fig 1B). This experimental model of left ventricular hypertrophy also demonstrated increased susceptibility to ischemic injury and depressed postischemic recovery of myocardial function compared to nonhypertrophied age-matched control hearts [25, 26, 34].



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  		Fig 1. (A) Left ventricular mass–to–cavity volume measurement as an indicator of progression of hypertrophy (black circles). After an initial peak at 4 weeks of age in animals with hypertrophied hearts, there is a gradual decline indicative of ventricular dilation (n = 6/group). *p <= 0.05 vs control (empty circles). (B) Measurement of contractility, depicted as shortening fraction, indicates that myocardial function deteriorates as hypertrophy (black circles) progresses into failure (n = 6/group). *p <= 0.05 vs control (empty circles).

 
To determine whether the greater susceptibility of hypertrophied hearts to ischemic injury was due to impaired glucose availability to the myocytes for energy production during ischemia, we measured glucose uptake in normal and hypertrophied hearts at various stages of hypertrophy. For determination of glucose uptake, we used two complementary methods, 31P-nuclear magnetic resonance (31P-NMR) spectroscopy and [2-3H] glucose metabolism in isolated perfused hearts [33]. In 31P-NMR spectroscopy experiments, glucose was partly replaced with 2-deoxyglucose (2-DG) as substrate. 2-DG is transported into the cell by the sarcolemmal glucose transporters (GLUT-1 and GLUT-4) and phosphorylated by hexokinase to yield 2-deoxyglucose-6-phosphate (2-DG-6-P), which is cleared very slowly in the heart. 2-DG-6-P gives a distinct resonance peak, and the rise of this peak over time is proportional to 2-DG uptake and phosphorylation by the cell. Thus, the rate of 2-DG-6-P accumulation is proportional to glucose transport and phosphorylation [35]. Our findings indicated that there was a significant difference between hypertrophied and normal myocardium with a lower rate of glucose uptake in the former. We also found that the impairment in glucose uptake was closely associated with onset of ventricular dilation, eg, failure, in aorta-banded animals (Fig 2). This defect in glucose metabolism occurred before the well described changes in calcium regulation and sarcoplasmic reticulum Ca-ATPase seen in severe hypertrophy and failure [26, 33]. To determine whether these observations made in isolated perfused hearts were also detectable in vivo, we used 3H-O-methyl-glucose infused into the whole animal. 3H-O-methyl-glucose is metabolized in a similar manner as 2-DG, is transported into the cell by means of glucose transporters and phosphorylated by hexokinase but is further metabolized only very slowly. In the in vivo experiments, 3H-O-methyl-glucose was infused into anesthetized rabbits that had undergone aortic banding and into age-matched control animals. After euthanasia, the hearts were excised, the myocardial tissue further processed to isolate the cytosolic fraction and 3H content was determined in a scintillation counter. Our results confirmed the in vitro studies with isolated perfused hearts (Fig 3). These experiments provided further evidence that glucose transport capacity was decreased in the hypertrophied myocardium. In subsequent studies, we sought to determine whether there were differences in glucose transporter expression (eg, glucose transporter protein content) in hypertrophied myocardium versus control hearts (Fig 4). We found that there was no significant difference in GLUT-1 or GLUT-4 levels in whole heart homogenates analyzed by Western immunoblotting, between hypertrophied obtained from aortic banded animals at 6 weeks of age and control hearts. These findings have been confirmed by other investigators [33, 36]. Based on these results, we concluded that the alteration in glucose uptake and metabolism in hypertrophied myocardium is likely due to either a dysregulation of glucose transporter trafficking from the inner membrane stores in the cell to the outer membrane (impaired insulin signaling) or that there was impaired delivery of substrates to the myocytes, probably due to decreased capillary density resulting in greater diffusion distance between capillaries and myocytes.



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  		Fig 2. Glucose uptake was measured as accumulation of 2-deoxyglucose-6-phosphate (2-DG) by 31P–nuclear magnetic resonance spectroscopy over a 30-minute period in isolated perfused hearts. There is significantly impaired glucose uptake in hypertrophied (black circles) hearts (n = 6/group). *p <= 0.05 vs control (empty circles).

 


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  		Fig 3. Myocardial 3H-O-methyl glucose uptake was determined in 6-week-old control and aortic-banded rabbits (n = 6/group). Glucose uptake is significantly decreased in hypertrophied (black rectangle) hearts in vivo. *p <= 0.05 vs control (empty rectangle).

 


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  		Fig 4. Representative Western immunoblot of GLUT-1 (top row) and GLUT-4 (bottom row) expression. There was no significant difference in protein levels in hypertrophied versus nonhypertrophied, age-matched control hearts.

 
Therapeutic strategies for normalizing glucose uptake in hypertrophied hearts

The type and amount of energy-providing substrates available to the heart has been shown to be a major determinant of functional recovery in the postischemic, reperfused heart. In normal hearts, the transition from aerobic to anaerobic glycolysis leads to a 20-fold increase in glycolytic flux [37]. This response is thought to increase substrate availability for glycolysis [38] during ischemia and early reperfusion, thereby facilitating production of high-energy phosphates. GLUT-4 can rapidly increase glucose uptake in response to insulin. In type II diabetes it is known that insulin insensitivity is responsible for impaired glucose uptake in the myocardium, and this defect is even more pronounced during ischemia [39]. Left ventricular hypertrophy has been found to be associated with insulin dysregulation (eg, hyperinsulinemia) and a slower rate of glucose entry into the myocytes [36, 40]. Relative insensitivity to insulin has been reported to occur in other hypertrophy models [36, 40]. A decline in insulin-mediated glucose uptake and nonoxidative glucose metabolism has also been shown in patients with myocardial hypertrophy [41, 42]. It is therefore reasonable to speculate that the underlying defect responsible for impaired glucose transport in hypertrophied myocardium is a failure of insulin-regulated recruitment of the glucose transporter GLUT-4 from intracellular storage vesicles to the sarcolemma, or a defect in the insulin-signaling cascade in cardiomyocytes. In our model, after 15 minutes reperfusion, glucose uptake rates recovered to preischemic values but remained below normal in hypertrophied hearts (Fig 5). The lower glucose uptake rate in the hypertrophied hearts may in part explain the accelerated loss of high-energy phosphates during ischemia and impaired recovery during reperfusion [43, 44]. Rapid recovery of glucose use has been shown to be necessary for optimal recovery of myocardial function during reperfusion [45, 46].



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  		Fig 5. Glucose uptake after 30 minutes of normothermic ischemia, returned to preischemic levels 15 minutes into reperfusion and remained significantly lower in hypertrophied (black circles) hearts (n = 6/group). *p <= 0.05 vs control (empty circles). 2-DG = 2-deoxyglucose-6-phosphate.

 
To investigate whether therapeutic strategies aimed at bypassing the initial steps in the insulin signaling cascade could normalize glucose uptake in the hypertrophied heart, we studied the effects of insulin-like growth factor–1 (IGF-1) in our model. IGF-1, which has been used in patients with type II diabetes, has been proved to reduce insulin resistance and to stimulate glucose uptake in peripheral tissues including skeletal muscle [47–50]. In fact, IGF-1 has structural similarities to insulin but interacts with its own specific cell surface receptor, and cardiac myocytes have been shown to contain receptors for insulin and IGF-1. In subsequent experiments, in an isolated heart preparation with hypertrophied and control hearts exposed to global normothermic ischemia for 30 minutes followed by reperfusion, IGF-1 was added to the perfusate and cardioplegia in the presence of maximal insulin concentration. Addition of IGF-1 normalized glucose uptake in hypertrophied myocardium and improved postischemic recovery of contractile function to levels not significantly different from those of nonhypertrophied hearts [34]. Based on these studies, we concluded that the defect in glucose uptake seen in hypertrophied myocardium could be overcome by therapeutic strategies aimed at bypassing the early steps in the insulin–insulin receptor signaling cascade.

Substrate delivery to hypertrophied cardiac myocytes

An alternative or, perhaps, additional mechanism for impaired substrate availability to the myocytes is morphologic alteration due to the remodeling process during progression of hypertrophy. Alterations in the structure and composition of the left ventricular collagen matrix have been reported in several disease states and are seen uniformly in pathologic forms of hypertrophy [51–54]. Thickening of the collagen layer around myocytes and increased collagen fiber cross-linking has been reported in pressure-overload hypertrophy resulting in increased cardiac stiffness [54]. An increase in diffusion distance between vessels and myocytes has been described [55]. Structural and functional alteration in the coronary circulation of the hypertrophied heart such as a decrease in myocardial capillary density of up to 20% to 30% [56] and impaired coronary flow reserve [57, 58] have also been demonstrated. During development of myocardial hypertrophy, myocytes enlarge and there may not be concomitant microvascular growth [59]. Capillary density and distribution greatly influence the exchange processes between blood and tissue [60, 61]. When the area of myocardial tissue supplied by one capillary increases, delivery of oxygen as well as other nutrients is potentially impaired [60, 62].

To determine whether, in our model of pressure-overload hypertrophy, inadequate capillary growth diminishes myocardial perfusion capacity, left ventricular cross-sections were obtained from hypertrophied hearts and nonhypertrophied, age-matched controls and stained with CD-31, an endothelial cell specific antibody, and a red fluorescently labeled secondary antibody (Fig 6A). Endothelial cells were also labeled with a fluorescein (FITC) tagged Lycopersicon esculentum lectin infused into isolated perfused rabbit hearts (Fig 6B). Lectin binds selectively to the surface of the endothelial cells and allows detailed histologic evaluation of the vascular architecture [63]. As seen in Figure 6, we found a significant decrease in microvascular density in hypertrophied hearts compared to controls. This decrease was temporally associated with the decline in contractility seen as myocardial hypertrophy progressed from compensated to uncompensated. Diminished microvascular supply was also associated with increased vulnerability to ischemia/reperfusion injury. These results indicate that the impaired glucose uptake and, potentially, impairment of all substrate available to hypertrophied myocardium is due at least in part to decreased microvascular density [64].



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  		Fig 6. (A) Representative sections of hearts from aorta-banded and control animals stained with CD-31 as primary antibody and a fluorescent secondary antibody. Number of microvessels detected is lower in hypertrophied myocardium. (B) FITC-labeled, lectin-stained cross sections showed lower numbers of microvessels in hypertrophied hearts than in controls. (Left panels = control; right panels = hypertrophy.)

 
Recent studies have established the feasibility of using angiogenesis promoting growth factors for treatment of perfusion deficits in limb ischemia, and myocardial ischemia induced by coronary artery stenosis in animal models [65, 66] and clinical studies [67–69]. Although these studies have focused on promoting collateral blood supply around a large vessel occlusion, it is certainly possible that therapeutic stimulation of angiogenesis may have a place in promoting capillary growth and, specifically, may normalize capillary density in hypertrophied myocardium, thereby improving substrate delivery. Current work in our laboratory is aimed at evaluating one of these growth factors, vascular endothelial growth factor [70], an endothelial specific mitogen, in our model of left ventricular hypertrophy from pressure overload. Initial results indicate that vascular endothelial growth factor is effective in stimulating capillary growth in pressure-overload hypertrophy and is effective in preserving postischemic contractile function. This is probably due to improved substrate availability to the hypertrophying myocytes, although the exact mechanism of action is still undetermined [64].

In conclusion, myocardial hypertrophy in response to pressure overload results in a number of alterations in myocardial tissue composition and architecture, as well as adaptive changes in cardiac myocyte expression of contractile proteins, enzymes involved in substrate metabolism, and response to exogenous hormones such as insulin. Progression of hypertrophy from compensated to uncompensated with ventricular dilatation is associated with a decline in contractility and tolerance to ischemia. Impaired glucose delivery and uptake into the myocytes also occurs in association with this transition. Therapeutic interventions aimed at normalizing glucose uptake and/or delivery provide substantial improvement in contractile function and tolerance to ischemia.

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