Oxidative metabolism and cardiac work in different heart failure phenotypes Free

This editorial refers to ‘Myocardial efficiency in patients with different aetiologies and stages of heart failure’, by K.B. Hansen et al., pp. 328–337.

Positron emission tomography (PET) with carbon-11 acetate (¹¹C-acetate) is a non-invasive method for measuring myocardial oxygen consumption.¹ Once taken up by the myocytes, acetate is transformed to ¹¹C-acetyl-CoA that enters the tricarboxylic acid cycle where it is metabolized to carbon dioxide. Because the tricarboxylic acid cycle and oxidative phosphorylation are tightly coupled, the washout rate of ¹¹C activity from the myocardium reflects overall flux in the tricarboxylic acid cycle and thus, oxidative metabolism.

Myocardial external efficiency describes the ability of myocardium to convert energy into external stroke work.¹ Efficiency of the heart can be measured as the ratio of left ventricular external work (product of arterial pressure and stroke volume) and oxygen consumption in the left ventricular myocardium. Measurement of oxygen consumption by ¹¹C-acetate is robust, and therefore, small sample size is sufficient to demonstrate differences in myocardial efficiency provided that left ventricular work can be estimated accurately.^2–4

Decreased myocardial external efficiency is a typical feature of heart failure, where oxygen consumption for a given amount of work is elevated.^5–8 Although myocardial oxygen consumption appears to be similar or even reduced in severe heart failure when compared with healthy controls, it is increased in relation to mechanical work power. Myocardial efficiency is directly associated with ejection parameters and inversely related to afterload in patients with dilated cardiomyopathy.⁵ However, in contrast to the healthy heart, the severely failing heart is not able to respond with an increase in efficiency to increasing ventricular volume.⁵ It has been hypothesized that impaired myocardial energetics is a contributing factor to the progression of heart failure and thus, myocardial external efficiency represents a useful surrogate marker for heart failure trials.⁹ Indeed, assessment of myocardial external efficiency by ¹¹C-acetate PET has been used to support the beneficial effects of various heart failure therapies on myocardial energetics, such as beta-blockers, mineralocorticoids, and cardiac resynchronization therapy.^1,10

In a study published in the current issue of the European Heart Journal Cardiovascular imaging, Hansen et al.¹¹ explored myocardial external efficiency in patients with different aetiologies and phenotypes of heart failure. Study cohort included healthy controls (n = 20), patients with ischaemic or non-ischaemic heart failure with either reduced ejection fraction (HFrEF, n = 25) or mildly reduced ejection fraction (HFmEF, n = 23), and patients with asymptomatic (n = 38) or symptomatic (n = 15) aortic stenosis and preserved ejection fraction. By pooling patients from four previous studies, the authors were able to analyse a large cohort as compared to earlier studies. The study found that compared with controls, myocardial external efficiency was reduced in patients with HFrEF, HFmEF, or symptomatic aortic stenosis. Compared with HFmEF, efficiency was further reduced in patients with HFrEF. Across the whole study population, myocardial external efficiency declined with worsening of left ventricular ejection fraction and left ventricular hypertrophy. Furthermore, female sex, low body mass index, and increasing age were associated with lower myocardial external efficiency.

The study provides some new insights in coupling between cardiac oxidative metabolism and work in patients with heart failure, such as finding of reduced myocardial external efficiency in patients with HFmEF. In heart failure patients, increased wall stress associated with eccentric remodelling was likely to contribute to disproportionally high myocardial oxygen consumption in addition to reduced stroke volume. In HFmEF as well as in patients with symptomatic aortic stenosis, left ventricular hypertrophy also appeared to be a significant contributor to reduced efficiency. Although oxygen consumption per gram of myocardium was similar or even reduced when compared with controls, overall oxygen consumption of the left ventricle increased in parallel with the degree of hypertrophy. This is in line with previous studies showing that in hypertensive patients and in heart failure with preserved ejection fraction, myocardial efficiency is reduced in the presence of significant left ventricular hypertrophy.^12,13 As the authors discuss, the finding of reduced myocardial energetic efficiency can be seen in the context of retrospective analyses from randomized controlled trials suggesting that patients with mildly reduced ejection fraction may benefit from similar therapies to those with ejection fraction ≤40%.¹⁴ In the study of Hanssen, patients were indeed on recommended heart failure therapies. It should be noted, however, that the retrospective cohort represents a subgroup of patients originally recruited in studies focusing on patients with reduced systolic function and it is not known whether the cohort included patients that had originally HFrEF phenotype whose ejection fraction had recovered.

Myocardial external efficiency is complex measure as it is a composite of myocardial oxygen consumption and cardiac work consisting of non-invasive measures of stroke volume, myocardial mass, and arterial pressure. In the study of Hanssen et al., a validated, automated analysis software for measurement of parameters of left ventricular work and oxygen consumption from a single, electrocardiogram-gated ¹¹C-acetate PET scan was used.³ The technique has shown good reproducibility and agreement with the measures of left ventricle work based on cardiac magnetic resonance.^3,4 Other study procedures were also similar across the original studies, and therefore, combining patients into a large cohort was feasible. The study of Hansson et al. identified some potential factors to be considered in studies evaluating the pathophysiological significance of measured myocardial external efficiency in heart failure patients, including sex, age, and body mass index. It is notable, that obesity, a common comorbidity in heart failure, may modify myocardial energetics differently in patients with heart failure than previously described in the absence of heart failure.¹⁵

Increasing availability of cyclotrons to produce ¹¹C-acetate together with standardized analysis tools facilitate the use of myocardial external efficiency as a marker of efficacy of heart failure therapies in clinical trials. The study of Hansson et al. provides evidence that in addition to patients with heart failure and reduced ejection fraction, impaired external efficiency is a pathophysiological mechanism at least in some patients with mildly reduced ejection fraction or aortic stenosis that can be monitored non-invasively.

Funding

The authors acknowledge financial support by grants from the Academy of Finland, the Finnish Foundation for Cardiovascular Research, and State Research Funding of Turku University Hospital.

Conflict of interest: A.S. discloses speaker or consultancy fees from Amgen, Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, and Pfizer. J.K. is director of Turku PET Centre and discloses speaker fees from GE Healthcare, Merck, Lundbeck, Pfizer, Boehringer-Ingelheim and Bayer, and study protocol consultancy fees from GE Healthcare and AstraZeneca.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal - Cardiovascular Imaging or of the European Society of Cardiology.

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