SummaryAdipose tissue secretes bioactive peptides, termed 'adipokines' , which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-α and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

In hypertensive subjects, the metabolic syndrome amplifies cardiovascular risk associated with high BP, independent of the effect of several traditional cardiovascular risk factors.

Short-term blood pressure (BP) variability predicts cardiovascular complications in hypertension, but its association with large-artery stiffness is poorly understood and confounded by methodologic issues related to the assessment of BP variations over 24 hours. Carotid-femoral pulse wave velocity (cfPWV) and 24-hour ambulatory BP were measured in 911 untreated, nondiabetic patients with uncomplicated hypertension (learning population) and in 2089 mostly treated hypertensive patients (83% treated, 25% diabetics; test population). Short-term systolic BP (SBP) variability was calculated as the following: (1) SD of 24-hour, daytime, or nighttime SBP; (2) weighted SD of 24-hour SBP; and (3) average real variability (ARV), that is, the average of the absolute differences between consecutive SBP measurements over 24 hours. In the learning population, all of the measures of SBP variability showed a direct correlation with cfPWV (SD of 24-hour, daytime, and nighttime SBP, r=0.17/0.19/0.13; weighted SD of 24-hour SBP, r=0.21; ARV, r=0.26; all P<0.001). The relationship between cfPWV and ARV was stronger than that with 24-hour, daytime, or nighttime SBP (all P<0.05) and similar to that with weighted SD of 24-hour SBP. In the test population, ARV and weighted SD of 24-hour SBP had stronger relationships with cfPWV than SD of 24-hour, daytime, or nighttime SBP. In both populations, SBP variability indices independently predicted cfPWV along with age, 24-hour SBP, and other factors. We conclude that short-term variability of 24-hour SBP shows an independent, although moderate, relation to aortic stiffness in hypertension. This relationship is stronger with measures of BP variability focusing on short-term changes, such as ARV and weighted 24-hour SD.