Energetic Adaptations and Stress Reserve In the Obese Heart

The human race is dealing with an epidemic of obesity the likes of which has never been seen on planet earth. In the United States alone, the prevalence of obesity is projected to rise to 50% in just 10 years, a staggering increase from 15% in the mid-1970’s.¹ Obesity is a major risk factor for a number of cardiovascular disorders, including heart failure (HF), and particularly HF with preserved ejection fraction (HFpEF). There are multiple mechanisms by which obesity challenges the cardiovascular system to ultimately produce HFpEF, including renal volume retention, systemic inflammation, excessive cardiac loading, insulin resistance and alterations in cellular metabolism.²

The effects of obesity in the cardiac myocyte are just beginning to come into focus. Prior studies suggested direct toxic effects mediated by lipid accumulation in the heart as promoters of myocardial dysfunction in patients with obesity.³ Increasing body weight is directly correlated with increases in myocardial oxygen consumption and free fatty acid uptake.⁴ This excess fat oxidation promotes energetic inefficiency and may also contribute to generation of lipotoxic and reactive oxygen species. Patients with obesity display impaired myocardial energetics.⁵ This puts the obese heart in an energetically disadvantaged position, especially considering that cardiac workload increases strikingly with obesity, both at rest and with exertion when blood pressure and cardiac output increase.^{2, 6} It is not clear how the obese heart adapts to this energy deficit, or how these adaptation might affect cardiac reserve.

In this issue of Circulation, Rayner and colleagues provide novel and extremely important new insights into the relationships between obesity and myocardial energetics.⁷ The authors performed state of the art MRI and cardiac ³¹P-magnetic resonance spectroscopy (³¹P NMR), together with measures of body composition and aerobic capacity in 45 obese and 35 non-obese volunteers. ³¹P NMR is a good fit for studies of human cardiac energetics because ATP and phosphocreatine are readily detected, and both molecules are substrates for the creatine kinase reaction: ADP + phosphocreatine + H⁺ ⇌ ATP + creatine. The authors used two ³¹P NMR methods. A conventional ³¹P NMR spectrum measured the phosphocreatine/ATP at rest. They also applied a more advanced technique, termed ³¹P saturation transfer. The basic idea is simple and relies on the fact that the phosphate group of phosphocreatine exchanges with the γ-phosphate of ATP via creatine kinase. If one phosphate is magnetically labeled, then the transfer of this magnetic label to the exchanging metabolite can be monitored without disturbing the enzyme-catalyzed equilibrium. In the study by Rayner et al, the γ-phosphate of ATP was tagged and the resulting change in the phosphocreatine signal was related to the kinetics of exchange in the creatine kinase reaction.⁷ This is an elegant demonstration of measuring the activity of a single enzyme-catalyzed reaction, completely noninvasively, in the human heart.

The authors found that phosphocreatine/ATP was lower at rest in obese patients, but total ATP delivery was actually preserved, thanks to a 33% higher k_f^CK as compared to controls (Figure 1A).⁷ In nature, these sorts of adaptations usually come with a price, and to explore this, Rayner and colleagues hypothesized that the capacity to augment ATP delivery with stress might be compromised by this energetic adaptation. To test this hypothesis, the authors then performed repeat MRI/MRS studies during dobutamine infusion to increase cardiac workload, revealing striking differences in cardiac reserve that were not apparent from the resting assessments. In healthy volunteers, both ATP delivery and k_f^CK increased by 80–86% with dobutamine stimulation. In contrast, there was no increase in either ATP delivery or k_f^CK in the obese participants, suggesting that the energetic shuttle was essentially operating at maximal capacity at rest, with no reserve. This was mirrored in a blunted increase in LVEF in the obese participants. Notably, the change in k_f^CK was significantly correlated with aerobic capacity in the cohort, supporting the possibility of a causal relationship.⁷

Figure.

[A] Schematic showing cardiomyocyte ATP generation, transfer and consumption. ATP is generated primarily in mitochondria, illustrated at the left, and is continuously consumed by ion pumping and mechanical processes, illustrated to the right. Flux of high energy phosphates from mitochondria to sites of consumption must increase with exercise in order to enhance both contraction and relaxation. As shown by Rayner and colleagues, there is an ample phosphocreatine (PCr) pool and high PCr/ATP ratio at rest in healthy volunteers (top) that becomes limiting in the setting of obesity (bottom). To compensate for this PCr/ATP deficit, the obese heart adapts through increased ATP flux at rest (thick lines). The “cost” of this adaptation resides in the inability to augment flux during stress, presumably because the system is operating at near-maximal capacity at baseline. High energy phosphates are highlighted in red. [B] Bar graphs showing rest and exercise left ventricular early diastolic annular velocities (LV e’) in controls (top) and obese patients with HFpEF (bottom), showing relative preservation of diastolic function at rest (blue) but limited reserve with stress in obese subjects (red). [C] Even as resting pulmonary capillary pressures are normal at rest (blue), the relaxation deficit in obesity may cause a severe increase in pulmonary capillary pressures with exercise (red). Obese HFpEF patient data was derived from reference 8.

A subset of the obese participants (n=36) then underwent a 6 month dietary weight loss intervention, after which 27 of the participants lost weight (11±5% reduction in body mass).⁷ Weight loss improved insulin sensitivity, reduced LV mass, and decreased visceral fat. This was coupled with an improvement in phosphocreatine/ATP, and corresponding reductions in ATP delivery and k_f^CK to values at rest, which were similar to values in non-obese volunteers. In 6 of the obese participants that lost weight, dobutamine testing was repeated, revealing significant improvements in energetic reserve with exercise, with greater dobutamine-mediated enhancements in ATP delivery and k_f^CK. The authors conclude that myocardial ATP delivery is maintained in obesity through compensatory increases in CK kinetics, but this diminishes the reserve capacity of the heart to augment function with stress, which may provide an energetic mechanism underlying exercise intolerance in obesity.⁷

Creatine kinase serves at least two functions in the heart (Figure 1A). One role is as an energy buffer. If ATP demand outstrips supply, for example during transient ischemia or rapid increase in mechanical load, the high-energy phosphate bond of phosphocreatine is transferred to ADP, to quickly regenerate ATP and maintain critical ATP-dependent processes such as contraction, pumping Ca⁺⁺ into the sarcoplasmic reticulum and maintaining the Na⁺ electrochemical gradient. Since ATP may diffuse relatively slowly in the cytosol, the other role of creatine kinase is to shuttle high energy phosphate bonds from the site of generation in the mitochondria to the site of utilization at the myofibrils. Although Rayner and colleagues emphasized the shuttle role of creatine kinase, studies of some creatine kinase isoenzymes using murine knock-out models do not find substantial effects on cardiac hemodynamics during changes in loading,^{9, 10} perhaps indicating that a significant fraction of ATP delivery to the myofibrils may occur independent of the creatine kinase system. Nevertheless, the key point is that defective creatine kinase activity may impair both temporal and spatial buffering of ATP availability, with deleterious effects.¹¹

The data reported by Rayner et al. provide valuable new insight into the nature of cardiac dysfunction in obesity, with very important implications for HFpEF, perhaps the most common and difficult to treat cardiac sequela of longstanding obesity.² Much like myocardial energetics in the current study volunteers,⁷ ventricular function is often well preserved at rest in patients with HFpEF, but there are marked limitations during exercise (Figure 1B).^{8, 12} These reserve deficits are even more impaired in patients with the obese phenotype of HFpEF,² and are directly related to the hemodynamic abnormalities that develop during stress (Figure 1C).⁸ While reserve limitation is well-documented in HFpEF, its cellular mechanisms are not well-understood. The findings from Rayner and colleagues raise the possibility that energetic abnormalities may also play a role in patients with the obese phenotype of HFpEF.^{2, 12}

In obese patients, cardiac work increased with dobutamine, but ATP delivery and k_f^CK were not augmented to match the heightened demand.⁷ This suggests that energy availability was compromised, and that alternative sources of energy were being called upon with stress, such as with anaerobic glycolysis. By altering intracellular metabolite levels and pH, this too could influence myocyte function. Inadequate ATP supply also may interfere with calcium handling and thick-thin filament interactions, which may further contribute to functional and hemodynamic impairments.

Perhaps the most intriguing finding is the reduced phosphocreatine/ATP ratio in obese subjects under baseline conditions.⁷ As noted above, ADP is a substrate for CK. Any decrease in phosphocreatine/ATP, absent other major changes in the system such as intracellular pH, means that [ADP] must increase under equilibrium conditions. It is generally thought that the control of mitochondrial respiration involves ATP/ADP, free [ADP] or some combination of the substrates for ATP synthesis. Hence the observed decrease in phosphocreatine/ATP indicates disruption of mitochondrial control. The mechanism can only be a matter of speculation since the control of respiration involves the complex interaction of multiple processes: glycolysis, β-oxidation, the Krebs cycle, electron transport, oxidative phosphorylation and numerous transportors. In studies of the isolated heart, it is known that changes in substrates available for oxidation, for example switching exclusively from glucose to pyruvate or fats, may cause marked changes in the phosphocreatine/ATP.^13-15 Such dramatic shifts in substrate oxidation in vivo are unlikely, but these studies do illustrate the intricate interactions between oxidative fuels and energetics.

The authors are to be commended on this landmark study, which has major implications for our understanding of obesity and obesity-related cardiac diseases such as HFpEF. The combination of both cross sectional comparisons and post-weight loss intervention assessments in human patients, with rest and stress-reserve assessments, using sophisticated state of the art measures of energetics are all major strengths.⁷ The modest sample size, lack of invasive hemodynamic data, and variable time of follow up assessment are minor but notable limitations, as acknowledged by the authors.

Although it is unclear why phosphocreatine/ATP is reduced in obese subjects in the first place, it seems most likely that the observed alterations in k_f^CK are simply adaptations to a state of chronic energy deprivation, as suggested by the authors.⁷ The latter finding is ironic considering the surfeit of fuel available to the obese heart, where fat stores are clearly increased, as are free fatty acid uptake and fat oxidation.⁴ This observation emphasizes how the human heart is not built for such excess. In this regard, the authors’ finding that weight loss improved myocyte energy delivery is extremely important.⁷ This raises the question of whether favorable changes in cardiac energetics may partly explain the hemodynamic improvements that occur following weight loss.⁶ Rayner and colleagues provide a valuable contribution that helps us to understand the nature of cardiac dysfunction in obesity. Together with others, these data heighten the importance of further study into the mechanisms of and treatment for cardiac dysfunction in people with excess fat. Perhaps then we may finally be able to stem the rising tide of obesity-related cardiac disorders such as HFpEF.