When Does Too Much Energy Become a Danger to the Heart?

Gabor Czibik; Thomas d'Humières; Geneviève Derumeaux


Eur Heart J. 2022;43(9):878-880. 

Graphical Abstract: Myocardial energetics in lean, obese and obese after weight loss patients with dilated cardiomyopathy versus controls.

Obesity cardiomyopathy was described as a collection of cardiac structural and functional abnormalities that could arise even in the absence of increased afterload and underlying organic heart disease.[1] However, co-existing systemic hypertension, diabetes mellitus, and sleep apnoea syndrome were recognized as aggravating factors. Intriguingly, whilst in patients with chronic heart failure obesity may be protective ('obesity paradox'),[1,2] weight reduction was proposed to improve obesity-related cardiovascular disease and premature atherosclerosis.[3] Recent data suggest that obesity cardiomyopathy may be related not only to body mass index, but also to alterations of the visceral adipose tissue, in particular the epicardial adipose tissue, which undergoes a profibrotic and proinflammatory phenotypic change.[4] Integrating adipose tissue properties with our knowledge may help reconcile the variable impact of obesity on cardiomyopathy, offering crucial diagnostic and therapeutic implications.

Despite a plethora of observational studies in human subjects and the use of established rodent models, our understanding of obesity cardiomyopathy is still incomplete. Importantly, in this issue of the European Heart Journal, Rayner and colleagues provide exciting novel insight into the underlying myocardial energetic processes in human patients.[5] These authors subjected patients with dilated cardiomyopathy (DCM) with normal weight or obesity to a combination of cardiac magnetic resonance imaging (MRI) and 31P spectroscopy and compared them with normal weight healthy control subjects.

First, Rayner and colleagues confirmed that DCM patients with normal weight had a reduced phosphocreatine to ATP (PCr/ATP) ratio and creatinine kinase (CK) flux[6,7] (i.e. ATP delivery from the mitochondria to the cytoplasm, where most intracellular energy gets utilized by the contractile apparatus and ion channels) compared with normal weight control patients. In contrast, obese DCM patients displayed a CK flux twice as high as that of DCM patients with normal weight (at comparable PCr/ATP ratios), indistinguishable from normal weight control subjects. The finding that ejection fraction (reflecting the stroke work carried out by the left ventricle) was not different between the two DCM groups led Rayner and colleagues to propose that hearts of obese DCM patients experience an inefficient myocardial energy utilization.[5]

In normal weight control subjects infused with dobutamine, myocardial CK flux doubled, whilst it remained unchanged in DCM patients with normal weight and even decreased in obese DCM patients. Most interestingly, voluntary weight loss in obese DCM patients was associated with improved left ventriculat (LV) structure, reduced LV end-diastolic volume, and increased LV ejection fraction coincident with a fall in ATP delivery rate.[5] Collectively, these observations support a scenario in which myocardial energy handling in obese patients with DCM is not only different from that of the rest of dilated cardiomyopathy cases in this study but may also be amenable to therapeutic correction through weight loss.

These novel observations made by Rayner et al. may implicate downstream abnormalities. Increased resting CK flux (relative to the stroke work carried out) in obese DCM patients suggests elevated steady-state levels of intracellular ATP, resulting in a relatively high energy state. Based on CK flux, we might therefore speculate that cardiac impairment is inversely proportional to the extent of excess energy delivery in obese DCM patients (Graphical Abstract). Yet, myocardial phosphocreatine and ATP levels are tightly regulated: in states of energy deprivation, ATP-producing mechanisms are turned on, whereas, in energy-replete conditions, ATP overproduction is prevented by feedback inhibition of upstream catabolic enzymes, primarily occurring via allosteric regulation. With a relative increase in ATP delivery in obesity cardiomyopathy compared with the stroke work performed by normal weight DCM patients, excess energy needs to be utilized to avoid inhibition of upstream substrate breakdown and becoming a danger signal to cardiomyocytes.[8] Therefore, the question is where the excess energy dissipates to in the specific context of obese DCM patients. We may propose a few possibilities. First, energy in obese DCM may be mopped up by adverse processes, acting as a 'steal' phenomenon, ultimately limiting the available pool of ATP to be used for normal cellular maintenance and function. Alternatively, unused ATP may catalyse abnormal ATP-dependent enzymatic reactions. In both scenarios, downstream mechanisms must act as buffers to absorb ATP. It follows that ideal suspects may be enzymes with a low Km value for ATP.

Either way, what Rayner et al. referred to as myocardial inefficiency of energy utilization in obese DCM patients may be mechanistically linked to pathological characteristics previously reported. With limited access to human myocardial samples, most of our knowledge comes from studies conducted in rodent models mimicking human caloric overload. For example, in a murine diet-induced model of obesity, increased rates of myocardial apoptosis, a well-known ATP-dependent process, were reported.[9] Indeed, ATP levels are critical to determine how a cell dies when exposed to inducers of cell death: low intracellular ATP levels promote necrosis, whilst high ATP levels induce apoptosis.[10,11] Thus, a relatively high cellular energy content in the heart, especially if energy inefficiently translates to contractility, may favour apoptotic cell death.

Due to its low frequency, apoptosis[1] per se is unlikely to have a significant functional impact in obesity cardiomyopathy, yet its increased occurrence may draw our attention to other ATP-dependent mechanisms. Specifically, hearts of obese rodents manifest oxidative stress,[9,12] and generation of reactive oxygen species (ROS)—virtually or literally—requires energy. Although the healthy myocardium is a metabolic omnivore, flexibly selecting substrates based on momentary availability, obesity cardiomyopathy is characterized by an inflexible shift towards fatty acid oxidation (FAO).[13] Compared with glucose utilization, FAO is less efficient in terms of cardiac work per molecular oxygen consumed, which may be aggravated by increased electron leakage (hence enhancing mitochondrial ROS production). Moreover, NADPH oxidases and uncoupled nitric oxide synthases use NADPH to produce ROS. NADPH production costs ATP compared with the maximal ATP production (i.e. glucose used to make NADPH in the pentose phosphate pathway could alternatively be catabolized through glycolysis and oxidative phosphorylation to generate ATP). Another cellular source of ROS is xanthine oxidase, a key enzyme in oxidative purine catabolism. Xanthine oxidase's involvement in the pathogenesis of obesity cardiomyopathy is suggested by the observation that Western diet-induced cardiomyocyte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired relaxation are alleviated by the xanthine oxidase inhibitor allopurinol.[12]

Furthermore, in a murine diet-induced obesity model, excess ATP has been recently shown to aggravate adipose tissue dysfunction by inducing senescence and a profibrotic secretome in visceral fat, associated with cardiac dysfunction and fibrosis.[9,14] Indeed, low xanthine oxidase expression/activity in pre-adipocytes derived from visceral adipose tissue displayed prolonged intracellular elevation of ATP with slower ATP breakdown after intracellular delivery of ATP.[14] Another novel way of reducing intracellular ATP levels is to release ATP to the extracellular space. Intriguingly, a channel-mediated extracellular ATP release has been reported in skeletal muscle of diet-induced obese mice resulting in increased inflammation and insulin resistance.[15] Albeit these observations were made in non-cardiac cells, similar mechanisms may apply to cardiac cells with relatively high energy content.

The present study by Rayner et al. provides much needed, valuable insight into human obesity DCM, a highly prevalent disease burden in our society, yet it leaves some important questions unanswered. Despite the importance of the myocardial PCr/ATP ratio and CK flux, alone they cannot explain the complex pathophysiology underlying the concept of the obesity paradox in DCM. Indeed, many confounding factors, such as secretory function of adipose tissue and the functional status of other metabolic organs (liver and skeletal muscle), may play important roles in the pathogenesis and progression of DCM. In addition, it is not yet clear whether the myocardial PCr/ATP ratio and CK flux are sufficient to decide on an optimal treatment strategy. There is a long way ahead to better define patient groups before the key observations of this elegant study by Rayner and colleagues can be translated into clinical recommendations. These caveats notwithstanding, the authors are to be congratulated on their inspired achievement and drawing the attention of clinicians to the importance of the myocardial energetic phenotype in metabolic disorders.