Myocardial Steatosis and Left Ventricular Function in Type 2 Diabetes Mellitus : Assessed with Magnetic Resonance Imaging and
Spectroscopy
Meer, R.W. van der
Citation
Meer, R. W. van der. (2008, November 20). Myocardial Steatosis and Left Ventricular Function in Type 2 Diabetes Mellitus : Assessed with Magnetic Resonance Imaging and Spectroscopy. Retrieved from https://hdl.handle.net/1887/13290
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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General introduction and outline 1
11 General introduction and outline
CHAPTER 1
T
he global epidemic of type 2 diabetes mellitus (T2DM) is strongly associated with the increasing prevalence of obesity due to changing lifestyles, such as the consump- tion of more calorie-rich food and a sedentary lifestyle. T2DM is a major risk factor for cardiovascular disease, in particular coronary artery disease and congestive heart failure, and for early death. However, even in the absence of coronary artery disease or hypertension, cardiac functional and structural changes occur in asymptomatic subjects with T2DM.1,2 These abnormalities have been ascribed to diabetic cardiomyopathy.Although the pathophysiology underlying diabetic cardiomyopathy is complex and the exact mechanisms of disease have not been completely clarified, micro-angiopathy, autonomic neuropathy, increased collagen accumulation, and metabolic abnormalities have been proposed.
Increasing evidence is emerging indicating that lipid oversupply to cardiomyocytes, which may lead to lipotoxic injury, plays a role in the development of diabetic cardio- myopathy.3-5 Increased fluxes of non-esterified fatty acids arising from the disproportion- ate amount of insulin resistant (visceral) adipose tissue lead to excessive delivery and uptake of non-esterified fatty acids by the heart. This uptake of non-esterified fatty acids exceeds the oxidative capacity of the organ giving rise to accumulation of myocardial triglycerides. Neutral triglycerides are probably inert and harmless to cells and may ini- tially even provide a protective buffer by diverting fatty acids from deleterious pathways.6 Eventually, however, excessive triglyceride stores enter a continuous cycle of hydrolysis and fatty acid re-esterification, yielding cardiotoxic intermediates, such as ceramide and diacylglycerol, which seems to be an important route leading to myocardial dysfunc- tion, at least in animal models. Evidence exists that accumulation of these fatty acid intermediates causes mitochondrial dysfunction and reactive oxygen species, leading to myocardial dysfunction either directly through cell-damage and apoptosis or indirectly through the induction of inflammatory cascades.7-10
Some of the earliest descriptions of fatty degeneration of myocytes originate from the 19th century.11,12 However, it took more than a century until lipid cardiomyopathy was identified in the hypertrophied hearts of obese mice.13 Thereafter, the deleterious effect of fatty acids on myocytes has been well documented in animal models. In ZDF fa/fa rats, evidence of increased non-ß-oxidative fatty acid metabolism in the myocardium is reflected by elevations in myocardial triglyceride and ceramide content 10 and by in- creased myocardial oxidative stress.14 Furthermore, there is echocardiographic evidence of reduced myocardial contractility attributed to loss of functioning myocytes through apoptosis. Therapeutic interventions aiming at reduction of myocardial triglyceride ac- cumulation due to disturbed fatty acid metabolism have been shown to have beneficial effects on myocardial function.10
Despite the evidence mentioned above that fatty acids and ceramide may damage cardiomyocytes, myocardial lipotoxicity is not currently recognized as a clinical entity.
Chapter 1
12
Nonetheless, a reduction in the number of cardiomyocytes through apoptosis is a rec- ognized cause of heart failure,15 and lipotoxicity could well be an important cause of apoptosis.10,16 Furthermore, in explanted hearts of obese and T2DM patients with end- stage heart failure, lipid staining was a common finding.4
Magnetic resonance is one of the most versatile imaging modalities that allows as- sessment of myocardial morphology, biochemistry and function on the same instrument.
Developments in proton magnetic resonance spectroscopy (1H-MRS) and magnetic resonance imaging (MRI), enable us to investigate myocardial triglyceride accumulation and myocardial function non-invasively. Since the introduction of human myocardial 1H- MRS, it has been recognized as a promising tool for in vivo assessment of intracellular triglyceride content.17 Major problems concerning myocardial and respiratory motions which greatly influence spectral quality and reproducibility were solved by applying a combination of cardiac and respiratory triggering.181H-MRS can thus provide important contributions to the elucidation of the role of fat accumulation in the human heart in health and disease. In addition, MRI is an established tool to evaluate cardiac function. Systolic function can reproducibly be calculated by assessing myocardial volumes. In addition, flow velocity encoded MRI across the mitral valve gives insight in left ventricular filling dynamics, representing diastolic function.
OUTLINE OF THIS THESIS
The purpose of the studies described in this thesis is to provide more insight into the influence of myocardial triglyceride accumulation on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus.
In chapter 2, cardiovascular metabolic MR techniques such as 1H-MRS are discussed and some examples of their clinical use are shown. In chapter 3, reproducibility of the assessment of myocardial triglyceride content by 1H-MRS with the use of respiratory motion compensation based on navigator echoes is evaluated. Chapter 4 evaluates the influence of a short-term very low calorie diet on myocardial and hepatic triglyceride accumulation and on myocardial function in healthy subjects. In chapter 5, the findings of chapter 4 are extended by assessing the influence of complete caloric restriction on myocardial and hepatic triglyceride accumulation and on myocardial function. To further elucidate the influence on ectopic triglyceride depositions of different dietary calorie and fat intake, chapter 6 describes the adaptations of the liver and the heart to a high-fat, high-energy diet in healthy volunteers. Chapter 7 uses MR imaging and spectroscopy to study the association between physiological ageing, myocardial triglyceride content, and heart function.
13 General introduction and outline
CHAPTER 1
In chapter 8, the influence of adding acipimox to a very low calorie diet in patients with T2DM is investigated. In chapter 9, cardiovascular function in patients with uncom- plicated T2DM is compared to age- and body mass index matched healthy subjects.
Chapter 10 describes myocardial triglyceride accumulation and function in the diabetic heart, and finally, chapter 11 evaluates the effects of pioglitazone treatment in patients with uncomplicated T2DM on myocardial metabolism and function.
Chapter 1
14
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