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Am J Physiol Heart Circ Physiol 292: H387-H391, 2007. First published September 8, 2006; doi:10.1152/ajpheart.00737.2006
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Altered high-energy phosphate metabolism predicts contractile dysfunction and subsequent ventricular remodeling in pressure-overload hypertrophy mice

M. Y. Maslov,1,2 V. P. Chacko,2 M. Stuber,2 A. L. Moens,1 D. A. Kass,1 H. C. Champion,1 and R. G. Weiss1,2

1Department of Medicine, Cardiology Division, and 2Department of Radiology, Division of Magnetic Resonance Research, The Johns Hopkins Hospital, Baltimore, Maryland

Submitted 10 July 2006 ; accepted in final form 3 September 2006


   ABSTRACT
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To study the role of early energetic abnormalities in the subsequent development of heart failure, we performed serial in vivo combined magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) studies in mice that underwent pressure-overload following transverse aorta constriction (TAC). After 3 wk of TAC, a significant increase in left ventricular (LV) mass (74 ± 4 vs. 140 ± 26 mg, control vs. TAC, respectively; P < 0.000005), size [end-diastolic volume (EDV): 48 ± 3 vs. 61 ± 8 µl; P < 0.005], and contractile dysfunction [ejection fraction (EF): 62 ± 4 vs. 38 ± 10%; P < 0.000005] was observed, as well as depressed cardiac energetics (PCr/ATP: 2.0 ± 0.1 vs. 1.3 ± 0.4, P < 0.0005) measured by combined MRI/MRS. After an additional 3 wk, LV mass (140 ± 26 vs. 167 ± 36 mg; P < 0.01) and cavity size (EDV: 61 ± 8 vs. 76 ± 8 µl; P < 0.001) increased further, but there was no additional decline in PCr/ATP or EF. Cardiac PCr/ATP correlated inversely with end-systolic volume and directly with EF at 6 wk but not at 3 wk, suggesting a role of sustained energetic abnormalities in evolving chamber dysfunction and remodeling. Indeed, reduced cardiac PCr/ATP observed at 3 wk strongly correlated with changes in EDV that developed over the ensuing 3 wk. These data suggest that abnormal energetics due to pressure overload predict subsequent LV remodeling and dysfunction.

high-energy phosphates; magnetic resonance imaging; magnetic resonance spectroscopy

CHRONIC PRESSURE OVERLOAD initiates a process that often results in left ventricular hypertrophy (LVH). Although LVH in the setting of pressure overload is felt to be an initially adaptive process, it can be followed by progressive ventricular dilatation, contractile dysfunction, and, ultimately, heart failure and increased cardiovascular mortality (11, 18). The magnitude of the pressure overload as well as many genetic and phenotypic factors, including neuroendocrine, intracellular signaling cascades, extracellular changes, and mechanical remodeling, all have been shown to contribute to the progression to failure in hypertrophic hearts (10, 20). Increased energy demand underlies many of these contributing factors, and thus an imbalance in metabolic energy supply and demand has been postulated as a central and potentially important factor contributing to heart failure development in LVH (15).

Myocardial energetic demands are met primarily through mitochondrial ATP production via oxidative phosphorylation, following the omnivorous metabolism of carbon substrates including fatty acids, glucose, lactate, and ketone bodies (24). The creatine kinase (CK) reaction serves as the prime cardiac energy reservoir, quickly and reversibly converting adenosine diphosphate and phosphocreatine (PCr) to ATP and creatine (16, 33). The temporal ATP buffering of CK helps meet cyclic energetic demands during cardiac contraction and especially following abruptly increased workloads. The CK reaction also may act as a spatial ATP buffer assisting in the delivery of high-energy phosphate from the mitochondria to the ATP utilization sites, which include myosin ATPase, sarcoplasmic reticular Ca-ATPase, and the Na/K exchanger.

31P magnetic resonance spectroscopy (MRS) is the only noninvasive technique capable of nondestructively measuring the CK metabolites PCr and ATP. The ratio PCr/ATP is one indicator of the energetic state of the myocardium that can be measured by 31P MRS, and this ratio is reduced in animal models of myocardial hypertrophy (21, 36) and in human LVH (9, 17, 26), as well as in chronic heart failure (CHF) (13, 25). Reduced PCr/ATP has been observed in pressure-overload LVH hearts from many species, including rats, dogs, and pigs (31, 36, 37). In mice, thoracic aortic constriction results in pressure-overload hypertrophy with subsequent dilatation and, ultimately, a high mortality (30). Work in our laboratory recently validated noninvasive MRS/MRI techniques that enable the noninvasive quantification of CK metabolites and myocardial anatomy and function in mice (8, 23).

We hypothesized that if reduced CK energy reserve contributes to the contractile dysfunction and ventricular dilatation that occurs as the compensated LVH heart progresses to heart failure, then the energetic abnormalities should occur before or at the same time as functional abnormalities and remodeling, and not after them. Although in vivo open-chest MRS studies have been performed in several LVH animal models, to our knowledge there have been no repeated studies in any species of serial CK energetics in the same animal and therefore none during the progression of pressure-overload LVH to LV dilatation and systolic dysfunction. We combined this new animal model with these noninvasive MRS/MRI techniques to test the hypotheses that a failing CK system contributes to the transition of pressure-overload LVH to CHF in mice and that a reduced PCr/ATP at an early stage predicts the subsequent remodeling process.


   MATERIALS AND METHODS
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Experimental animals. The studies were performed on adult male C57BL6/ mice (weight 20–28 g) as approved by the Institutional Animal Care and Use Committee.

Animal surgery. Pressure-overload nonischemic CHF was created in 12 mice by permanent thoracic aorta constriction (TAC) (29). Briefly, the aorta was approached via a minimal parasternal incision, and a partial ligature was placed around the transverse aorta. Nine animals that did not undergo surgery served as controls.

MRI/MRS study. In vivo MRI/MRS studies were carried out 3 and 6 wk after TAC surgery, as previously described (8, 23). Specifically, mice were positioned on a Plexiglas platform with temperature control (37 ± 1°C). ECG leads, respiratory pad, and thermo couple (SA Instruments) were used to monitor basic vital parameters. Anesthesia was induced by ~1% isoflurane in an air-oxygen mix and was adjusted during the experiment to keep the heart rate ~550–600 beats/min and the respiratory rate 100–120 breaths/min. Global LV function and energetics were studied during the same examination with 1H MRI and image-guided, spatially localized 31P MRS as previously reported (8, 23). The probe set included 22-mm 1H MRI and 11-mm 1P MRS coils. Experiments were carried out on a Bruker Biospec NMR/MRI spectrometer equipped with a 4.7-T/40-cm Oxford magnet and a 12-cm (inner diameter) actively shielded BGA-12 gradient set capable of developing gradient strength of up to 400 mT/m. LV function was quantified from multislice FLASH cine MRI (15 frames, TE = 1.8 ms, TR = 7 ms, flip angle = 30°) by using ECG and respiratory gating. Spatially localized 31P MRS was carried out using a one-dimensional chemical shift imaging sequence, with a 32-mm field of view and 32 phase encoding steps in the direction perpendicular to the plane of the coil, 64 averages per phase encoding step, a modified BIR4 adiabatic excitation pulse of 60° flip angle, and an interpulse delay of 1 s. All mice awoke within ~1 min after the study was over.

1H MR images were analyzed with ImageJ software and 31P MR spectra with in-house custom software (3). The largest and smallest LV volumes were visually identified as end-diastolic (EDV) and end-systolic volumes (ESV). LV mass was the sum of all end-diastolic cross-sectional slices of the LV epicardial and endocardial difference multiplied by 1.05 (cardiac tissue-specific gravity). The LV ejection fraction (EF) was calculated from the relative difference in EDV and ESV. The cardiac PCr/ATP ratio was quantified from the integrated peak areas of PCr and [beta-31P]ATP resonances from voxels intersecting the anterior LV wall and apart from chest skeletal muscle, as identified with 1H MR images as previously described (8, 23). Voxel shifting was performed when necessary to avoid chest muscle contamination (7).

Statistical analysis. Data are expressed as means ± SD. Two-tailed, two-sample unequal variance t-tests were used for comparison of control and TAC animals, and paired t-tests were used for comparison of 3-wk TAC and 6-wk TAC animals. Differences were considered statistically significant at P < 0.05. The correlations between PCr/ATP3 wk and the changes in EDV ({Delta}EDV = EDV6 wk – EDV3 wk), PCr/ATP and EF, and PCr/ATP and ESV at 3 and 6 wk were analyzed with linear regression.


   RESULTS
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A representative typical short-axis 1H MR image of a mouse heart and the corresponding cardiac 31P MR spectrum are shown in Fig. 1. Summary LV functional and high-energy phosphate data from normal hearts are shown in Table 1 and agree with published values (8, 23).


Figure 1
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  		Fig. 1. Left: typical transverse short-axis 1H magnetic resonance (MR) image of a mouse thorax through the mid-left ventricular (LV) slice of the heart at end diastole. Right: 31P spectrum from the anterior cardiac slice is shown with the prominent peaks of creatine phosphate (PCr) and beta-phosphate of ATP ([beta-P]ATP).

 

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  		Table 1. Morphology, function, and energetics in control and TAC mice

 
Three weeks following TAC, LV hypertrophy and dilatation developed as shown by an increase in mean LV mass (74 ± 4 vs. 140 ± 26 mg, control vs. 3-wk TAC, respectively; P < 0.000005; Table 1) and EDV (48 ± 3 vs. 61 ± 8 µl; P < 0.005). Reduced EF (62 ± 4 vs. 38 ± 10%, control vs. 3-wk TAC, respectively; P < 0.000005) and stroke volume (SV: 30 ± 1 vs. 23 ± 6 µl) with increased ESV (18 ± 1 vs. 37 ± 10 µl; P < 0.00003) exemplified the LV contractile dysfunction (Table 1). LVH and systolic abnormalities at 3 wk were accompanied by a 35% fall in the cardiac PCr/ATP ratio compared with that of normal animals (P < 0.0005; Table 1).

After an additional 3 wk (i.e., total 6 wk after TAC), LV mass increased further (140 ± 26 vs. 167 ± 36 mg, 3 wk vs. 6 wk, respectively; P < 0.01). Despite additional increases in EDV and ESV (61 ± 8 vs. 76 ± 8 µl and 37 ± 10 vs. 45 ± 9 µl, respectively; P < 0.001), EF remained at the 3-wk level as SV increased (Table 1). There was no further fall in the cardiac PCr/ATP ratio. Figures 2 and 3 display the relationship between PCr/ATP ratio and EF and ESV, respectively, at the 3- and 6-wk time points. The relations were minimal after 3 wk of TAC but became stronger at 6 wk (EF: r = 0.37 vs. 0.75, 3 wk vs. 6 wk, respectively, Fig. 2; ESV: r = –0.03 vs. –0.77, Fig. 3). Although cardiac PCr/ATP at 3 wk did not correlate with subsequent changes in EF, depressed LV energetics measured at 3 wk after TAC predicted the level of subsequent LV dilatation that evolved between the third and sixth week after TAC (r = –0.79) (Fig. 4).


Figure 2
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  		Fig. 2. Relationship between cardiac PCr/ATP as determined by 31P magnetic resonance spectroscopy (MRS) and ejection fraction (EF) at 3 wk [A; EF = –0.9.14(PCr/ATP) + 26.73, r2 = 0.142, r = 0.37] and 6 wk [B; EF = 29.75(PCr/ATP) +0.43, r2 = 0.56, r = 0.75] after transverse aorta constriction (TAC). The relationship evolves and becomes significant at 6 wk.

 

Figure 3
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  		Fig. 3. Relationship between cardiac PCr/ATP as determined by 31P MRS and end-systolic volume (ESV) at 3 wk [A; ESV = –0.76(PCr/ATP) + 38.78, r2 = 0.0009, r = –0.03] and 6 wk [B; ESV = –34.43(PCr/ATP) +92.08, r2 = 0.59, r = –0.77] after TAC. The correlation is significant at 6 wk.

 

Figure 4
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  		Fig. 4. Relationship between PCr/ATP at 3 wk (PCr/ATP3 wk) and the change in LV end-diastolic volume ({Delta}EDV) from 3 to 6 wk [{Delta}EDV = –20.35(PCr/ATP3 wk) + 41.82, r2 = 0.61, r = –0.79]. Reduced cardiac PCr/ATP at 3 wk predicts subsequent remodeling as indexed by the change in EDV.

 

   DISCUSSION
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There are five major findings in this report. These are the first cardiac MRS studies performed in serial fashion with repeated measures in the same animal as a pathological process evolves. Second, this mouse model of pressure-overload hypertrophy mimics the contractile and energetic abnormalities (reduced PCr/ATP) of human pressure-overload hypertrophy. Third, abnormalities in cardiac energy metabolism occur early in pressure-overload LVH. Fourth, the contemporaneous relationship between altered energetics and contractile function and ventricular geometry is not constant but, in fact, changes over time in pressure-overload LVH and is strongest late in the remodeling process. Fifth, early energetic changes predict the extent of subsequent LV remodeling, consistent with the hypothesis that altered energy metabolism contributes to heart failure progression.

The pathology of LVH has been extensively studied for decades, and abnormalities in CK energy metabolism, as indicated by the cardiac PCr/ATP, were previously reported in larger animal models of chronic pressure-overload and human LVH (1, 4, 17, 31, 37). Although abnormal energetics was consistently found across species, it was not clear whether altered energetics occurred before or as a consequence of LV contractile dysfunction and dilatation.

This serial use of in vivo MRS in the same animals allowed the exploration of changes in energetics, contractile dysfunction, and LV anatomy over time as LVH evolves. These observations not only show that this murine model of pressure-overload LVH mimics the anatomic and energetic changes observed in human LVH (14, 17), but they also provide important insights into the causes and consequences of LVH pathophysiology. Abnormalities in energetics were observed early in the remodeling process. There was no further fall in PCr/ATP from 3 to 6 wk, but the correlation with EF and ESV strengthened over time. This demonstrates that the relationship between cardiac PCr/ATP and contractile function is not constant within a given animal and suggests that impaired energetics may play a role in the transition of LVH to heart failure. This observation also may be important for interpreting apparent inconsistencies in published human cardiac energetic data. Although low PCr/ATP is a consistent finding in human heart failure, some studies have reported a correlation between PCr/ATP and contractile measures (4, 12), whereas other studies have not (13, 25). Although differences among patient groups may explain the differences, these data indicate that the relationship between energetics and function is dynamic during disease evolution and suggest the possibility that differences in disease duration among patient groups may explain, in part, the variability in the relationship between energetics and function.

How could impaired energy metabolism contribute to the progression to heart failure in hypertrophic hearts? LVH is thought to be an adaptive change following chronic pressure-overload that supports pump function according to the circulation demands of the body. Particularly, increased mechanical work causes structural and metabolic remodeling with synthesis of ATP-requiring structural proteins such as actin and myosin. Myocardial contraction and wall stress are the major ATP expenditures, and these too are increased in pressure-overload LVH. Many ion pumps are also energy dependent, such as the Na-K-ATPase and the sarcoplasmic reticulum Ca-ATPase, which may be altered in LVH.

There are several limitations to this work. It is not known whether the energetic response to stress in the mouse is identical to that of larger mammalian species, including humans. Although differences in cardiac energetics have been identified across species (19), the PCr/ATP is commonly studied as an important energetic parameter. It is encouraging that the in vivo PCr/ATP is similar in normal murine and human hearts (8, 22, 34), that the acute response to adrenergic or exercise stress is comparable in murine and larger hearts (2, 23, 27, 34), and that cardiac PCr/ATP is chronically 25–35% lower in pressure-overload LVH hearts from mice through humans (1, 4, 17, 28, 31, 37). Nevertheless, serial studies of energetics in larger animals and especially humans with LVH would be of considerable interest. Although the PCr/ATP is an important energetic parameter, it does not directly reflect ATP flux through CK. The use of in vivo 31P MRS to measure CK flux is now possible (5, 6, 28, 35) but is not yet available in mice. If developed, this capability would allow greater insight into the role of altered energetics in LVH progression in the mouse model. Measures of myocardial creatine content would also be of interest, since creatine loss may be partially responsible for lower PCr/ATP in LVH.

The novel observation that the early reduction in PCr/ATP predicts the degree of subsequent LV dilatation is consistent with the hypothesis that energetic abnormalities contribute to ventricular remodeling and the development of heart failure. This is in line with prior clinical reports that agents with beneficial effects on ventricular remodeling, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, all reduce energetic demand in failing and hypertrophic hearts (20, 32). This observation also suggests that metabolic interventions designed to improve energetics early in the disease may limit subsequent remodeling. However, the current studies do not show cause and effect. Another plausible explanation is that the early fall in PCr/ATP reflects cellular injury due to pressure overload and that subsequent remodeling results from the injury with altered energetics another consequence, and not the cause, of the remodeling. Put another way, it is possible that the sicker or more stressed animals had lower PCr/ATP and were also destined to have more remodeling. To resolve this question, future studies are needed with metabolic interventions to determine whether augmenting myocardial PCr/ATP in this setting improves myocardial function and limits the subsequent remodeling process.


   GRANTS
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-63030 and HL-61912 as well as the David E. Gibbons Grant-in-Aid Award from the Mid-Atlantic Affiliate of the American Heart Association.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. G. Weiss, Carnegie 584, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-6568 (e-mail: rweiss{at}jhmi.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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