Jouke T. Tamsma

Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages

Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation.

Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events.

RATIONALE There is a lack of information on the long-term prognosis of patients with acute pulmonary embolism (PE). OBJECTIVES To assess the long-term risk for adverse events after PE. METHODS Consecutive patients diagnosed with PE between January 2001 and July 2007, and patients in whom PE was ruled out from a previous study were followed until July 2008 for the occurrence of adverse clinical events: mortality, symptomatic recurrent venous thromboembolism, cancer, arterial cardiovascular events and chronic thromboembolic pulmonary hypertension. Hazard ratios (HR) for all endpoints and a combined endpoint were calculated and adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS Three hundred eight patients with unprovoked, 558 with provoked, and 334 without PE were studied with a median follow-up period of 3.3 years. Patients with unprovoked PE had a lower overall risk for mortality than patients with provoked PE (HR, 0.59; 95% confidence interval [CI], 0.43-0.82), but a higher risk for nonmalignancy-related mortality (HR, 1.8; 95% CI, 1.3-2.5), recurrent venous thromboembolism (HR, 2.1; 95% CI, 1.3-3.1), cancer (HR, 4.4; 95% CI, 2.0-10), cardiovascular events (HR, 2.6; 95% CI, 1.5-3.8) and chronic thromboembolic pulmonary hypertension (1.5 vs. 0%). The risk for the combined endpoint did not differ between both groups (HR, 0.98; 95% CI, 0.82-1.1). Patients without PE had similar risks for malignancy and cardiovascular events than patients with provoked PE, but lower risks for the remaining outcomes. The fraction of both patients with provoked and unprovoked PE without events after 1 year was only 70% and decreased to fewer than 60% after 2 years and fewer than 50% after 4 years, whereas this latter was 84% for the control patients. CONCLUSIONS The clinical course of acute PE is complicated by high rates of serious adverse events, which occur in half of the patients within 4 years.

Aspirin in the prevention and treatment of venous thromboembolism

Summary.  This review summarizes available evidence on effects of aspirin on incidence and outcomes of venous thromboembolism (VTE). From a pathophysiological point of view, inhibition of platelet aggregation is associated with an impaired thrombus formation both in an experimental model of venous thrombosis and in vivo. Epidemiological evidence in support of a beneficial effect of acetylsalicylic acid on VTE incidence is provided by the Antiplatelet Trialists’ Collaboration meta‐analysis of studies on the use of antiplatelet agents in cardiovascular risk reduction, showing a significant 25% risk reduction of pulmonary embolism. Moreover, a meta‐analysis on older trials of antiplatelet agents in postsurgical VTE prevention and the large Pulmonary Embolism Prevention trial demonstrate a protective effect of the same magnitude: 25–30%. However, as low‐molecular‐weight heparins (LMWH) and vitamin K antagonists (VKA) have shown a superior efficacy and safety profile, and no direct comparisons have been made between aspirin, LMWH and VKA in prolonged use, the most recent guidelines advise against aspirin monotherapy for thromboprophylaxis in the surgical patient. Currently, there is no evidence to support a role for aspirin in air travel‐related VTE. Regarding prevention of recurrent VTE, studies are ongoing to determine the potential role of aspirin after a first unprovoked VTE.

Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study

BACKGROUND Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. METHODS We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. FINDINGS Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0.44, p=0.04). INTERPRETATION Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals. FUNDING Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).

Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus

Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima–media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of ‘at risk’ patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG.

Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study

OBJECTIVE The purpose of this study was to determine cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after pregnancy. STUDY DESIGN In a multicenter cohort study in The Netherlands from June 2008 through November 2010, cardiovascular risk factors were compared between women with a history of HTP (HTP cohort, n = 306) and women with a history of normotensive pregnancies at term (NTP cohort, n = 99). HTP women had participated in a randomized, longitudinal trial assessing the effectiveness of induction of labor in women with hypertensive pregnancy disorders at term. All women were assessed 2.5 years after pregnancy for blood pressure, anthropometrics, glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and microalbumin and metabolic syndrome. RESULTS After a mean follow-up period of 2.5 years, hypertension (HTP, 34%; NTP, 1%; P < .001) and metabolic syndrome (HTP, 25%; NTP, 5%; P < .001) were more prevalent in HTP women compared with NTP women. HTP women had significantly higher systolic and diastolic blood pressure, higher body mass index, and higher waist circumference. Glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in HTP women. CONCLUSION In women with a history of HTP, hypertension and metabolic syndrome are more common, and they have higher levels of biochemical cardiovascular risk factors 2.5 years after pregnancy.

Bone morphogenetic protein 7: A broad-spectrum growth factor with multiple target therapeutic potency

Bone morphogenetic protein 7 (BMP7) is a member of the transforming growth factor-β (TGF-β) superfamily of growth factors. In recent years, it has become clear that BMP7 is a very pleiotropic growth factor. As described in this review, it plays a pivotal role in the development of bone and kidney, and has only recently been demonstrated to also be crucially involved in differentiation of brown adipose tissue. Because BMP7 thus controls the development and maintenance of many physiological processes in the human body, aberrant expression of BMP7 is associated with a variety of diseases. This review gives a broad overview on the involvement of BMP7 in several pathological conditions, such as incomplete fracture healing, osteoarthritis, the development of bone metastases, renal fibrosis and obesity. Furthermore, the therapeutic potential of BMP7 in these disease states is discussed.

Risk of arterial cardiovascular events in patients after pulmonary embolism

Studies have reported inconsistent evidence for an association between venous thrombosis and arterial cardiovascular events. We further studied the association between both diseases by comparing the occurrence of cardiovascular events in patients diagnosed with acute pulmonary embolism (PE) contrasted to patients with comparable baseline risk characteristics (patients in whom PE was clinically suspected but ruled out). Included were 259 patients with provoked PE, 95 patients with unprovoked PE, and 334 control patients without PE. Patients diagnosed with PE were treated with vitamin K antagonists for 6 months. Median follow-up was 4.2 years. Sixty-three arterial cardiovascular events were registered (incidence, 5.1/100 patient-years). Adjusted hazard ratio was not different between patients with all-cause PE and control patients (1.39, 95% confidence interval [CI], 0.83-2.3) but increased for patients with unprovoked PE versus both patients with provoked PE and control patients without PE (2.18; 95% CI, 1.1-4.5; and 2.62; 95% CI, 1.4-4.9, respectively). This effect was confirmed after redefining the study start date to the moment the vitamin K antagonists were discontinued. Our study underlines the association between unprovoked venous thrombosis and arterial cardiovascular events; however, risk differences between patients with provoked PE and patients in whom PE was clinically suspected but ruled out could not be demonstrated.

Assessment of the carotid artery by MRI at 3T: A study on reproducibility

To examine the reproducibility of carotid artery dimension measurements using 3T MRI.

Association of Aortic Arch Pulse Wave Velocity with Left Ventricular Mass and Lacunar Brain Infarcts in Hypertensive Patients: Assessment with MR Imaging

PURPOSE To assess the possible association between aortic arch stiffness, which may cause hypertensive cardiovascular disease, and cardiac and cerebral end-organ damage in patients with hypertension by using magnetic resonance (MR) imaging. MATERIALS AND METHODS Approval from the local institutional review board was obtained, and patients gave informed consent. Fifty patients with hypertension (31 women and 19 men; mean age +/- standard deviation, 49.2 years +/- 12.7; mean systolic blood pressure, 152.1 mm Hg +/- 22.3; mean diastolic blood pressure, 88.0 mm Hg +/- 13.1), compliant for treatment with antihypertensive medication, were prospectively enrolled for MR examinations of the aorta, heart, and brain with standard pulse sequences. Aortic arch pulse wave velocity (PWV), left ventricular (LV) mass, LV systolic and diastolic function, lacunar brain infarcts, and periventricular and deep white matter hyperintensities (WMHs) were assessed. Univariable and multiple linear and logistic regression analyses were used for statistical analyses. RESULTS Mean aortic arch PWV was 7.3 m/sec +/- 2.5. Aortic arch PWV was statistically significantly associated with LV mass (r = 0.30, P = .03, beta = 1.73); indexes of systolic function, including ejection fraction (r = -0.38, P = .01, beta = -1.12); indexes of diastolic function, including the ratio of early diastolic to atrial contraction peak filling rates (r = -0.44, P < .01, beta = -0.11); lacunar brain infarcts (odds ratio [OR] = 1.8, P < .01); and periventricular (OR = 1.5, P = .01) and deep (OR = 1.6, P = .01) WMHs. Aortic arch PWV was statistically significantly associated with LV mass (r = 0.37, P = .03, beta = 2.11) and lacunar brain infarcts (OR = 1.8, P = .04), independent of age, sex, and hypertension duration, but not with indexes of diastolic and systolic function and WMHs. CONCLUSION Aortic arch stiffness is associated with LV mass and lacunar brain infarcts in hypertensive patients, independent of age, sex, and hypertension duration; these manifestations of end-organ damage may help to risk stratify hypertensive patients.