The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O
-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently ...discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O
-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.
Background Psoriasis is associated with higher incidence of atherosclerotic comorbidities. Sustained arterial wall inflammation mediated by common cytokines of psoriasis and atherogenesis precedes ...atherosclerotic plaque development. Increased intima-media thickness (IMT) is an accepted indicator of subclinical atherosclerosis and has been reported in severe psoriasis. Objective This pilot study aimed to clarify whether effective long-term tumor necrosis factor-alfa inhibition decreases IMT in psoriasis. Methods In 16 patients with severe psoriasis, the Psoriasis Area and Severity Index score was calculated before therapy (etanercept, infliximab, adalimumab) and after 6-month treatment. Simultaneously, carotid and brachial IMT was measured by high-resolution, B-mode ultrasonography. Difference between initial and 6-month IMT values was determined for monitored arteries collectively and separately in carotid and brachial arteries. Results All of 16 patients achieved Psoriasis Area and Severity Index 75, and 14 of 16 achieved Psoriasis Area and Severity Index 90 improvement. In the group of patients without initial calcified atherosclerotic plaques (13 of 16) significant IMT decrease was detected when arteries were measured collectively ( P = .0002). Initial and follow-up data differed significantly also at individual analysis of carotid ( P = .011) and brachial ( P = .006) arteries. Eleven of 13 patients had initial carotid IMT exceeding age-adjusted normal values. The other group (3 of 16) with initial manifest plaques showed increasing IMT tendency. Their baseline ultrasonography revealed carotid IMT above the upper limit of healthy adults’ age-adjusted values. Limitations Study limitation involves small patient numbers, self-controlled study design, and lack of patients’ stratification according to common cardiovascular risk factors. Conclusion In our pilot study effective tumor necrosis factor-alfa inhibition was found to decrease IMT in psoriatic patients without irreversible atherosclerotic plaques. Further analysis is recommended to confirm and complete our primary observations.
Pulmonary arterial hypertension (PAH; World Heath Organization WHO Group 1) is associated with increased pulmonary arterial pressure and resistance, with pulmonary vascular remodelling. The vascular ...anatomy of the systemic arteries has been less well studied.
Nineteen (19) patients with PAH, confirmed by right heart catheterisation (RHC), 14 patients with left ventricular heart failure with reduced ejection fraction (LVrEF), and 30 healthy subjects were enrolled. Common carotid artery (CCA) intima thickness, intima/media (I/M) thickness ratio, and intima-media thickness (IMT) were assessed using non-invasive ultrasound (22 MHz centre frequency).
The CCA intima thickness was correlated with several RHC variables (all p<0.05). The intima was 56% thicker (+0.05 mm; 95% CI 0.03, 0.06; p<0.0001) and the I/M thickness ratio was 128% greater (+0.21; 95% CI 0.13, 0.28; p<0.0001) in patients with PAH than healthy subjects. These values were also significantly higher than in patients with LVrEF. In ROC curve analysis, the c-values for CCA intima thickness (0.92) and I/M ratio (0.87), but not for IMT, correctly indicated which individuals belonged to the PAH or healthy control groups. The CCA IMT showed no corresponding significant group differences or associations and was of no use according to receiver operating curve analysis.
Patients with PAH displayed signs of peripheral vascular remodelling, challenging the common opinion that vascular changes in PAH are restricted to the lung vasculature. Correlations with cardiopulmonary variables from RHC support peripheral vascular coupling and the association with vascular ageing. Results from this pilot study warrant further confirmation.
Smooth muscle cells (SMCs) form the thickened intimal layer in atherosclerosis-prone arteries in early life, and provide the initial site for retention and uptake of atherogenic lipoproteins. Here we ...review current knowledge regarding the importance of SMCs in the deposition of cholesterol in atherosclerotic plaque.
SMCs were found to comprise at least 50% of total foam cells in human coronary artery atherosclerosis, and exhibit a selective loss of expression of the cholesterol efflux promoter ATP-binding cassette transporter A1. Cholesterol loading induced a loss of SMC gene expression and an increase in macrophage and proinflammatory marker expression by cultured mouse and human arterial SMCs, with reversal of these effects upon removal of the excess cholesterol. Mice engineered to track all cells of SMC lineage indicated that, at most, SMCs make up about one-third of total cells in atherosclerotic plaque in these animals.
SMCs appear to be the origin of the majority of foam cells in human atherosclerotic plaque. Recent studies suggest a renaissance of research on the role of SMCs in atherosclerosis is needed to make the next leap forward in the prevention and treatment of this disease.
Preliminary findings suggest that very-high resolution ultrasound (VHRU, 55 MHz) could differentiate arterial intima layer thickness (IT) non-invasively in vivo. We aimed to validate ...ultrasound-derived IT measurements and describe a four-line pattern consistent with intimal thickening. VHRU was applied to temporal arteries of 37 patients with suspected giant cell arteritis without inflammation on histology. Anatomically matched ultrasound-derived measurements of arterial layer thickness with the leading-edge method was compared to histology. Intimal thickening (IT >0.06 mm on histology) was identified as a four-line pattern in VHRU with a sensitivity of 96.3% and a specificity of 100%. Histologic and VHRU IT measurement agreement was excellent (mean difference 0.007 mm; 95% limits of agreement, -0.043 to 0.057) and intra-class coefficient (ICC) 0.923 (95% confidence interval CI, 0.833-0.964). Intra- and inter-observer agreements for VHRU IT were high: ICC 0.946 (95% CI, 0.877-0.976) and 0.872 (95% CI, 0.773-0.943). VHRU utilizing the leading-to-leading edge method allows accurate and reliable measurements of arterial IT in patients with IT >0.06 mm. Measurements of IT will provide the opportunity to explore early subclinical structural intimal changes in the arterial wall increasing with age.
The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed ...the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM.
This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period.
Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (-0.5 ± 1.0% vs. -0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (-0.029 SE 0.013 vs. 0.024 0.013 mm P = 0.005; -0.065 0.027 vs. 0.022 0.026 mm P = 0.021; -0.007 0.031 vs. 0.027 0.031 mm P = 0.45, respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline.
Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.
Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute ...cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes.
Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of ...liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.
PDF
