The effects of obesity and weight loss in heart failure: imaging the obesity paradox using magnetic resonance imaging and spectroscopy
Keywords: Heart failure
Magnetic resonance spectroscopy
Obesity
Myocardial energetics
Magnetic resonance imaging

Obesity and cardiovascular function are closely linked on a number of different levels, from the impact of the whole-body complications of obesity, to the geometric remodelling inflicted on the heart and vasculature by increased body weight, to the influence of the endocrine state of the body on intracellular signalling cascades, to the very efficiency of energy generation and transfer within the myocyte itself.
Whilst obesity is one of the main contributing risks to the development of number of different cardiovascular diseases, it has a particularly strong relationship with the development of heart failure. However, there is a counterintuitive association with survival in established disease and increasing body mass index, known as the obesity paradox. This underlines the complex relationship between the two conditions, and poses the question as to whether there is a protective physiological mechanism at play within the obese myocardium.
Magnetic resonance imaging is perfectly placed to interrogate this interplay in more detail, being the gold-standard technique for assessing a number of different parameters of cardiovascular structure and function, but also unveiling the potential for investigating cellular physiological parameters using non-invasive spectroscopic techniques.
It is known that inflexibility in substrate selection has an impact on cardiovascular function and that this plays an important role in the development of diabetic cardiomyopathy, as well as potentially the obesity phenotype. In this thesis, I use the popular Very Low Calorie Diet in a healthy obese cohort, both to assess its efficacy in treating obesity-related cardiovascular disease, and also to demonstrate the impact of altering the availability of myocardial substrate on cardiovascular function. While after 8 weeks of dietary intervention, myocardial steatosis and diastolic dysfunction are reversed, there is an interesting early deterioration in function, associated with an increase in circulating fatty acids and deposition of ectopic lipid within the myocardium. This highlights the potential for dietary intervention as a treatment strategy in metabolic cardiac dysfunction, but also the need for caution in a population with pre-existing cardiovascular disease.
While substrate selection is an important factor in determining the efficiency of energy generation, the rate of transfer of ATP from the mitochondrion to the myofibril is also a key step in regulating myocardial energy transduction. This step is catalysed by the creatine kinase enzyme, enabling PCr to act as a buffer maintaining rates of ATP delivery under fluctuating demand. The reaction rate of creatine kinase can be interrogated with sophisticated non-invasive MR spectroscopic techniques, and has been found to be reduced in heart failure. In obesity, however, there is typically preserved systolic function despite reduced PCr/ATP concentrations, which raises the question of whether creatine kinase kinetics compensate to maintain ATP delivery. I investigated this question in obese individuals without additional cardiac disease, and found not only that the reaction rate of creatine kinase was elevated, maintaining ATP delivery at rest, but that the enzyme reaction rate response to catecholamine stress was blunted, yielding no increase in energy delivery despite increased workload. This was linked to whole body exercise capacity, and reversed with intentional weight loss. These results suggest that obesity may have direct effects on the resting energetic state in the myocardium, but that this comes at a cost of reduced reserve to cope with increased demand. This may explain why exertional symptoms are so prevalent in obesity.
To investigate the impact of obesity on myocardial energetics in individuals with established cardiac dysfunction, I examined volunteers either normal weight or obese with dilated cardiomyopathy, measuring myocardial PCr/ATP and creatine kinase kinetics at rest and under dobutamine stress, and interpreting these results in the context of cardiac function and exercise capacity. In obese heart failure, baseline PCr/ATP was lower compared to individuals with normal systolic function, but the creatine kinase rate constant was again elevated compared to those of normal weight. This meant that in obese heart failure, overall ATP delivery was maintained to a similar degree to those without systolic dysfunction. However, the diminished capacity to cope with increased haemodynamic demand was exacerbated, with catecholamine stress leading to a fall in PCr/ATP, blunted response in creatine kinase activity, and an overall fall in ATP delivery. This was in the context of poor exercise capacity, and may be linked to exertional symptoms in obese heart failure.
The impact of intentional weight loss on cardiac function and energetic status in obese heart failure was examined in the final chapter. Volunteers were asked to adhere to a calorie controlled diet for a period of 12 months before comprehensive retesting was performed. The striking finding was an improvement in contractile function, even in volunteers with established heart failure, with a marked improvement in left ventricular ejection fraction with weight loss. Equally exciting was significant cardiac remodelling, with reduction in left ventricular end-diastolic volume and mass. The changes in myocardial energetics were more subtle, with no change in PCr/ATP, creatine kinase activity at rest, or ATP delivery. However, there was a suggestion of restoration of the stress response of enzyme activity, with individuals with successful weight loss seeing an increase in stress creatine kinase kinetics which had not previously been measured. These results raise a number of interesting points; clinically, whether intentional weight loss has the potential to become a therapeutic tool in heart failure, and on a more mechanistic level, how left ventricular contractility can improve despite no measurable change in resting energy delivery.
In summary, this thesis interrogates the mechanisms underpinning the relationship between obesity and cardiac function, demonstrating the importance of substrate selection in determining cardiovascular function, establishing a potentially compensated energetic state in the obese myocardium, and providing the first stage of evidence for intentional weight loss to be used as an additional treatment strategy in obese heart failure.