Myocardial triglycerides : magnetic resonance spectroscopy in health and diabetes

Hammer, S. (2008)

Doctoral Thesis

In this thesis we focused on the functional and metabolic consequences of myocardial triglyceride (TG) accumulation in healthy subjects and in patients with diabetes mellitus. Ectopic accumulation of TGs is associated with organ dysfunction in metabolic disease in experimental animal studies. These organs include the heart, the liver and skeletal muscle. For the heart,translational studies in humans are scarce, mainly due to the difficulty of the assessment of myocardial TG content in humans, in vivo. Therefore, it remains unclear to what extent the observations in animal experiments can be extended to humans. Furthermore, the physiological and pathophysiological relevance of myocardial TG accumulation for myocardial function is unknown. In Chapter 2 we describe a non-invasive method, using hydrogen 1 magnetic resonance spectroscopy (1HMRS), to accurately and reproducibly measure myocardial TG content in humans, in vivo. We observed improved spectral resolution and an improved intraclass correlation coefficient for the assessment of myocardial TG content when spectroscopic measurements were performed with respiratory motion correction compared to spectra obtained without respiratory motion compensation. Diabetes mellitus and obesity are associated with increased plasma non-esterified fatty acid (NEFA) levels, myocardial TG accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a short-term VLCD on myocardial TG content and cardiac function in healthy subjects in Chapter 3. We found increased myocardial TG content and a decrease in left ventricular diastolic function. Moreover, hepatic TG content decreased, indicating organ-specific effects of a VLCD. In animal studies high plasma levels of NEFAs are associated with increased myocardial TG stores and impaired myocardial function. Caloric restriction increases the delivery of fatty acids to the myocardium. We have therefore evaluated the effects of progressive caloric restriction in healthy subjects in Chapter 4. Upon progressive caloric restriction we documented a dose-dependent increase in plasma levels of NEFAs and myocardial TG content, and a dose-dependent decrease in left ventricular diastolic function. Short-term high-fat diets increase TG content in skeletal muscle. Moreover, a high-fat diet induces myocardial TG accumulation and myocardial dysfunction in animal models. We studied the effects of a short-term high-fat diet in healthy individuals in Chapter 5. We found no changes in myocardial TG content and no effects on left ventricular function. However, hepatic TG content increased. The data document physiological and organ-specific adaptation of TG content during a high-fat diet. Myocardial metabolism in patients with type 2 diabetes mellitus (DM2) is heavily dependent on fatty acids. Furthermore, in animals and in humans this increased fatty acid reliability has been associated with structural changes in the diabetic myocardium and with myocardial dysfunction. Therefore we have evaluated the effects of a short-term VLCD in patients with DM2 in Chapter 6, to test the myocardial flexibility in these patients. We have shown that myocardial TGs increase after a VLCD, associated with a decrease in left ventricular diastolic function. Furthermore, anti-lipolytic therapy with acipimox during the VLCD prevented these changes in myocardial TG stores and myocardial function. Hepatic TG content was unchanged after both the interventions. The study illustrates the flexibility of myocardial TG stores and myocardial function in patients with DM2. Moreover, the data implicate the relevance of plasma NEFAs as mediators of the cardiac effects of a VLCD in patients with DM2. In Chapter 7 we evaluated the effects of therapeutic weight loss in obese, insulin-treated patients with DM2. Obesity and DM2 are major risk factors for cardiovascular disease, and prolonged caloric restriction has shown to induce weight loss and improve glycemic control. In this study we evaluated the effects of prolonged caloric restriction on myocardial and hepatic TG content and on myocardial function. Upon substantial weight loss there were considerable metabolic improvements in glucose and fat metabolism, associated with decreased myocardial TG content and a decrease in hepatic TG stores. Furthermore, myocardial diastolic function improved. The data show that in these obese patients with DM2, myocardial TG stores are flexible and amendable to therapeutic intervention by caloric restriction. Patients with type 1 diabetes mellitus (DM1) suffer from frequent episodes of hyperglycemic dysregulation, due to imperfections in exogenous insulin treatment, which mimics endogenous insulin secretion. These episodes of hyperglycemia are accompanied by perturbations in lipid metabolism as well. We have therefore evaluated the effects of controlled, short-term hyperglycemia in patients with DM1 in Chapter 8. Despite hyperglycemic dysregulation by partial insulin deprivation and the increase in plasma NEFA levels, myocardial TG content and myocardial function did not change. Apparently, the heart is protected from short-term metabolic effects of partial insulin deprivation in patients with DM1. In conclusion, myocardial TGs can be accurately measured in humans with 1HMRS. Myocardial TG stores are flexible in healthy subjects and in patients with DM2 upon differences in dietary nutritional intake. Changes in myocardial TG content are associated with changes in left ventricular function. Myocardial TGs reflect the discrepancy between fatty acid uptake and fatty acid oxidation and most likely reflect increased intracellular availability of fatty acid derivatives, which alter structure and function of the myocardium. Redistribution of TGs is tissue-specific, since TGs in the heart and the liver do not always show the same responses to physiological interventions. In patients with DM1, the heart is protected from short-term metabolic effects of hyperglycemic dysregulation, with respect to myocardial TG accumulation and alterations in myocardial function.

• Cardiovascular complications
• Diabetes mellitus
• Diastolic function
• Magnetic resonance
• Magnetic resonance spectroscopy
• Triglycerides

• All authors: Hammer, S.
• Supervisor: Smit, J.W.A.; Romijn, J.A.; Roos, A. de
• Co-supervisor: Lamb, H.J.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2008-11-20
• ISBN (print): 9789085594093
• Sponsorship: Financial support by the Netherlands Heart Foundation and the Dutch Diabetes Foundation for the publication of this thesis is gratefully acknowledged. Additional financial support is provided by The J.E. Jurriaanse Foundation, Foundation Imago (Oegstgeest), Foundation of Image Processing, Philips BV, Astra Zeneca BV, GlaxoSmithKline BV,Medis medical imaging systems BV, Bristol-Myers-Squibb BV, Merck Sharp & Dohme BV, Solvay Pharmaceuticals BV, Guerbet Nederland BV, Sanofi-Aventis BV and Novo Nordisk BV.