AIMS\nWe sought to examine the interrelationship between statin use, inflammation, and outcome of high-risk patients with advanced atherosclerosis.\n\n\nMETHODS AND RESULTS\nWe prospectively studied 515 patients with severe peripheral artery disease (median age 70 years, 296 males). The cardiovascular risk profile and laboratory parameters of inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid A [SAA], fibrinogen, serum albumin, neutrophil counts) were obtained, and patients were followed for a median of 21 months (interquartile range 12-25) for the occurrence of myocardial infarction (MI) and death. We observed 19 MIs (5 fatal and 14 nonfatal) and 65 deaths. Cumulative survival and event-free survival rates (freedom from death and MI) at 6, 12, and 24 months were 97%, 95%, and 89%, and 96%, 93% and 87%, respectively. Patients receiving statin therapy (n=269, 52%) had a lower level of inflammation (hs-CRP p<0.001, SAA p=0.001, fibrinogen p=0.007, albumin p<0.001, neutrophils p=0.049) and better survival (adjusted hazard ratio [HR] 0.52, p=0.022) and event-free survival rates (adjusted HR 0.48, p=0.004) than patients not treated with statins. However, patients with low inflammatory activity (hs-CRP < or =0.42 mg/dl) had no significant benefit from statin therapy (p=0.74 for survival; p=0.83 for event-free survival), whereas in patients with high hs-CRP (>0.42 mg/dl) statin therapy was associated with a significantly reduced risk for mortality (adjusted HR 0.58, p=0.046) and the composite of myocardial infarction and death (adjusted HR 0.46, p=0.016).\n\n\nCONCLUSION\nStatin therapy is associated with a substantially improved intermediate-term survival of patients with severe peripheral artery disease and a high inflammatory activity, whereas in patients with low hs-CRP no survival benefit was observed.

Statin therapy improves cardiovascular outcome of patients with peripheral artery disease

The heart is uniquely responsible for providing its own blood supply through the coronary circulation. Regulation of coronary blood flow is quite complex and, after over 100 years of dedicated research, is understood to be dictated through multiple mechanisms that include extravascular compressive forces (tissue pressure), coronary perfusion pressure, myogenic, local metabolic, endothelial as well as neural and hormonal influences. While each of these determinants can have profound influence over myocardial perfusion, largely through effects on end-effector ion channels, these mechanisms collectively modulate coronary vascular resistance and act to ensure that the myocardial requirements for oxygen and substrates are adequately provided by the coronary circulation. The purpose of this series of Comprehensive Physiology is to highlight current knowledge regarding the physiologic regulation of coronary blood flow, with emphasis on functional anatomy and the interplay between the physical and biological determinants of myocardial oxygen delivery. © 2017 American Physiological Society. Compr Physiol 7:321-382, 2017.

Regulation of Coronary Blood Flow

Peroxisome proliferator-activated receptors (PPARs) a, d (b) and g are ligand-activated transcription factors that belong to the nuclear receptor family. PPARa has been shown to bind and be activated by leukotriene B4 and the hypolipidemic drugs of the fibrate class, whereas prostaglandin J2 derivatives and the antidiabetic glitazones are respectively natural and synthetic ligands for PPARg. PPARa and PPARg function as important regulators of lipid and lipoprotein metabolism, cellular differentiation and glucose homeostasis. Recently, detailed studies of PPARs expression in different immunological and vascular wall cell types have pointed out the roles that these receptors play in inflammation control and apoptosis. Taken together, these observations suggest a modulatory role for PPARs in the control of inflammatory response and in inflammation-related processes, such as atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation

Background Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. Objective We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. Study Design A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025). Results We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker ( P R 2  = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 ( P P  = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation. Conclusion Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies.

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

Background The main aim of this study was to evaluate the additional utility of C-reactive protein (CRP) over traditional cardiovascular risk factors in risk prediction of cardiovascular outcomes. Methods In a nested case-control study, 207 cardiovascular events among participants over 30 years of the Tehran Lipid and Glucose Study (TLGS) were documented during 3 years of follow-up. Those cases that were free of cardiovascular disease at baseline (126 subjects) were matched to 259 controls for age and sex. High sensitivity CRP and traditional cardiovascular risk factors were measured at baseline. Results Modest correlation was found between CRP and body mass index ( r =0.34), waist-to-hip ratio ( r =0.22), total cholesterol ( r =0.24) and calculated 10-year Framingham coronary risk score (FRS) ( r =0.27) (all P values P =0.006). After additional adjustment for traditional cardiovascular risk factors the odds ratio decreased to non-significant levels (0.8, 95% CI=0.3–1.9). Addition of CRP did not improve the area under receiver operating characteristic curve of risk functions that was based on traditional cardiovascular risk factors or FRS. Conclusion It seems that for short-term prediction of cardiovascular disease outcomes in the Iranian population, measurement of CRP has no additional value when traditional cardiovascular risk factors are known.

H Franklin

Papers

Atherosclerosis â An Inflammatory Disease