Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD... Show moreCardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women. Show less
Giorgi, N. di; Michelucci, E.; Smit, J.M.; Scholte, A.J.H.A.; Mahdiui, M. el; Knuuti, J.; ... ; Rocchiccioli, S. 2021
Background and aims: Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) define a specific lipid profile associated with residual coronary artery disease (CAD) risk... Show moreBackground and aims: Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) define a specific lipid profile associated with residual coronary artery disease (CAD) risk independently of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Aim of the present study was to assess whether TG/ HDL-C ratio, coronary atherosclerosis and their change over time are characterized by a specific lipidomic profiling in stable patients with chronic coronary syndrome (CCS). Methods: TG/HDL-C ratio was calculated in 193 patients (57.8 +/- 7.6 years, 115 males) with CCS characterized by clinical, bio-humoral profiles and cardiac imaging. Patient-specific plasma targeted lipidomics was defined through a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) strategy. Patients underwent coronary computed tomography angiography (CTA) and an individual CTA risk score, combining extent, severity, composition, and location of plaques, was calculated. All patients entered a follow-up (6.39 +/- 1.17 years), including clinical, lipidomics and coronary CTA assessments. Results: Patients were divided in groups according to baseline TG/HDL-C quartiles: IQ (<1.391), IIQ (1.392-2.000), IIIQ (2.001-3.286), and IVQ (>= 3.287). A specific pattern of altered lipids, characterized by reduced plasma levels of cholesterol esters, phosphatidylcholines and sphingomyelins, was associated with higher TG/HDL-C both at baseline and follow-up (IVQ vs IQ). The CTA risk score increased over time and this lipid signature was also associated with higher CTA score at follow-up. Conclusions: In stable CCS, a specific lipidomic signature identifies those patients with higher TG/HDL- C ratio and higher CTA score over time, suggesting possible molecular pathways of residual CAD risk not tackled by current optimal medical treatments. Show less
Obesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat... Show moreObesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat adiposity and related disorders, because of its capacity to combust nutrients and increase energy expenditure. To develop novel BAT activating methods, a better understanding of the pathophysiology of diet-induced obesity on BAT function and whole-body metabolism is required. Studies described in this thesis have increased our understanding of nutrient handling by brown adipocytes. We also generated immortalized brown adipocytes which can be used for future research. Furthermore, we gained more insight into the development of diet-induced obesity; feeding a high fat diet (HFD) rapidly made BAT insulin resistant and less active. In addition, HFD feeding increased synthesis of so-called endocannabinoids in both white and brown adipose tissue. Because endocannabinoids regulate both energy intake and expenditure, future research should determine whether inhibiting endocannabinoid signaling specifically in adipose tissue is a worthwhile strategy to pursue in combating obesity. Finally, quercetin, which naturally occurs in fruits and vegetables, induced ‘browning’ of white adipose tissue and thereby improved blood lipid levels. These studies pave the road for further development of BAT-activating strategies! Show less
Berg, R. van den; Kooijman, S.; Noordam, R.; Ramkisoensing, A.; Abreu-Vieira, G.; Tambyrajah, L.L.; ... ; Rensen, P.C.N. 2018
Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show... Show moreMany favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity. Show less
Dam, A.D. van; Boon, M.R.; Berbee, J.F.P.; Rensen, P.C.N.; Harmelen, V. van 2017
This thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described... Show moreThis thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described the role of two hormones, insulin and glucagon-like peptide-1, in the production and clearance of triglycerides. We showed that insulin stimulates the uptake of (triglyceride-derived) fatty acids and that the brain plays an essential role in this process. Additionally, we showed that the glucagon-like peptide-1 receptor analogue exendin-4 decreases triglyceride production by the liver, albeit that the brain does not seem to be involved in this effect. Furthermore, we unraveled the mechanism underlying the effects of metformin, the first-line drug used to treat Type 2 Diabetes, on triglyceride metabolism. We showed that metformin lowers plasma triglyceride levels by stimulating the uptake and subsequent oxidation of triglycerides by the brown adipose tissue, and herewith provided new therapeutical opportunities for this drug. Finally, we showed that apolipoprotein A5, a stimulator of triglyceride hydrolysis and subsequent clearance from the plasma, plays a role in the central regulation of food intake, and herewith described a novel function for this apolipoprotein. Show less
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... Show moreIn 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. Show less
The aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus.... Show moreThe aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus. Therefore we developed a reproducible proton magnetic resonance (MR) spectroscopic technique with respiratory motion compensation to study myocardial steatosis. Using these technique, combined with MR imaging to study myocardial function, correlations between myocardial steatosis and left ventricular function were shown in several (patho)physiological conditions. Furthermore, we showed that myocardial triglyceride content is increased in patients with type 2 diabetes mellitus and is an independent predictor of left ventricular diastolic dysfunction. In addition, differential, tissue-specific partitioning of triglycerides and/or fatty acids among non-adipose organs during various diets was shown. Given the obesity and type 2 diabetes mellitus pandemic and the increasing evidence indicating that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, therapeutic strategies that target reduction of cardiac lipid overexposure might be beneficial to prevent diabetic cardiomyopathy. Show less
This thesis contributes to a better understanding of the roles of apoCI, LPL, and CETP in lipoprotein metabolism. Our data illustrate that the activity of LPL, and thereby the level of plasma TG,... Show moreThis thesis contributes to a better understanding of the roles of apoCI, LPL, and CETP in lipoprotein metabolism. Our data illustrate that the activity of LPL, and thereby the level of plasma TG, is crucially determined by the relative abundance of apolipoproteins. In addition, we showed that LPL is an important determinant in remnant-particle clearance in the absence of the three main apoE-recognizing receptors. Finally, we demonstrated that CETP presents a pro-atherogenic factor in mice resembling a human lipid distribution over lipoproteins and that atorvastatin and fenofibrate treatment influence HDL-metabolism via inhibition of CETP, which may thus add to their therapeutic benefit. Since there were initial concerns that inhibition of CETP would reduce the flux of cholesteryl esters from the periphery back to the liver, thereby possibly increasing the risk for atherosclerosis, it is of interest that we found that fenofibrate-mediated inhibition of CETP did not hamper the total flux of HDL-cholesteryl esters. This holds promise for therapies based on CETP inhibition. Show less
In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between... Show moreIn this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism underlying this association remains unclear. Recently, attention has focused on the role of excessive accumulation of triglycerides (TG) in the liver (hepatic steatosis) in this association. Hepatic steatosis was considered a benign condition until it was discovered that a nonalcoholic fatty liver is associated with many cardiovascular risk factors. Subsequently, many studies have shown a strong association between hepatic TG content and hepatic insulin resistance. The studies in this thesis show that hepatic steatosis is actively and passively involved in the metabolic disturbances in the glucose and lipid metabolism. The prevalence of hepatic steatosis in western countries is high and will certainly increase with the epidemics of obesity and diabetes. This will put an increasing number of subjects at risk for disturbances in the glucose and lipid metabolism and concomitantly for cardiovascular disease. Show less
