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      Systemic Arterial Stiffness in New Diagnosed Idiopathic Pulmonary Arterial Hypertension Patients

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          Abstract

          Objective

          We suggested: 1) patients with idiopathic pulmonary hypertension (IPAH) have active factors which could damage not only the pulmonary but systemic arteries too as in arterial hypertensive patients; 2) if these changes were present, they might correlate with other parameters influencing on the prognosis. This study is the first attempt to use cardio-ankle vascular index (CAVI) for the evaluation of systemic arterial stiffness in patients with IPAH.

          Methods

          A total of 112 patients were included in the study: group 1 consisted of 45 patients with new diagnosed IPAH, group 2 included 32 patients with arterial hypertension, and in the control group were 35 healthy persons adjusted by age. Right heart catheterization, ECG, a 6-minute walk test (6MWT), echocardiography, blood pressure (BP) measurement and ambulatory BP monitoring, pulse wave elastic artery stiffness (PWVe; segment carotid-femoral arteries) and muscular artery stiffness (PWVm; segment carotid-radial arteries), CAVI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level were provided. The Spearman correlation, a linear regression and multivariable binary logistic analysis were performed to indicate the predictors associated with PWV and CAVI.

          Results

          The groups were adjusted for principal characteristics influenced on arterial stiffness. IPAH patients had significantly (P<0.001 for all) shorter 6MWT distance and higher Borg dyspnea score than the patients with arterial hypertension (systolic/diastolic BP = 146.1±10.7/94.2±9.8 mmHg) and the control group = 330.2±14.6 vs 523.8±35.3 and 560.9±30.2 m respectively and 6.2±1.8 vs 1.2±2.1 and 0.9±2.8 points. The PWVm and PWVe were the highest in hypertensive patients (10.3±1.5 and 11.42±1.70 m/s). The control group and IPAH did not have significant differences in aorta BP, but PWVm/PWVe values were significantly (P<0.003/0.008) higher in IPAH patients than in the control group (8.1±1.9/8.49±1.92 vs 6.63±1.34/7.29±0.87 m/s). The CAVIs on both sides were significantly lower in the healthy subjects (5.91±0.99/5.98±0.87 right/left side). Patients with IPAH did not differ from the arterial hypertension patients by CAVIs in comparison with the control group (7.40±1.32/7.22±1.32 vs 7.19±0.78/7.2±1.1 PWVe) did not correlate with any parameters except uric acid. PWVm correlated with uric acid (r=0.58, P<0.001), NT-proBNP (r=0.33, P=0.03) and male gender (r=0.37, P=0.013) at Spearman analysis, but not at multifactorial linear regression analysis. The CAVI correlated with age and parameters characterized functional capacity (6MWT distance) and right ventricle function (NT-proBNP, TAPSE) at Spearman analysis and with age and TAPSE at multifactorial linear regression analysis. At binary logistic regression analysis CAVI > 8.0 at right and/or left side had a correlation with age, 6MWT distance, TAPSE, but an independent correlation was only with age (β=1.104, P=0.008, CI 1.026–1.189) and TAPSE (β=0.66, P=0.016, CI 0.474–0.925).

          Conclusion

          In spite of equal and at normal range BP level, the age-adjusted patients with IPAH had significantly stiffer arteries than the healthy persons and they were comparable with the arterial hypertensive patients. Arterial stiffness evaluated by CAVI correlated with age and TAPSE in IPAH patients. Based on our results it is impossible to conclude the pathogenesis of arterial stiffening in IPAH patients, but the discovered changes and correlations suggest new directions for further studies, including pathogenesis and prognosis researches.

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          Most cited references55

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          Pulmonary arterial hypertension: pathogenesis and clinical management

          Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor ( BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.
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            Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function?

            Arterial distensibility measures, generally from pulse-wave velocity (PWV), are widely used with little knowledge of relationships to patient outcome. We tested whether aortic PWV predicts cardiovascular and all-cause mortality in type 2 diabetes and glucose-tolerance-tested (GTT) multiethnic population samples. Participants were randomly sampled from (1) a type 2 diabetes outpatient clinic and (2) primary care population registers, from which nondiabetic control subjects were given a GTT. Brachial blood pressures and Doppler-derived aortic PWV were measured. Mortality data over 10 years' follow-up were obtained. At any level of systolic blood pressure (SBP), aortic PWV was greater in subjects with diabetes than in controls. Mortality risk doubled in subjects with diabetes (hazard ratio 2.34, 95% CI 1.5 to 3.74) and in those with glucose intolerance (2.12, 95% CI 1.11 to 4.0) compared with controls. For all groups combined, age, sex, and SBP predicted mortality; the addition of PWV independently predicted all-cause and cardiovascular mortality (hazard ratio 1.08, 95% CI 1.03 to 1.14 for each 1 m/s increase) but displaced SBP. Glucose tolerance status and smoking were other independent contributors, with African-Caribbeans experiencing reduced mortality risk (hazard ratio 0.41, 95% CI 0.25 to 0.69). Aortic PWV is a powerful independent predictor of mortality in both diabetes and GTT population samples. In displacing SBP as a prognostic factor, aortic PWV is probably further along the causal pathway for arterial disease and may represent a useful integrated index of vascular status and hence cardiovascular risk.
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              A role for uric acid in the progression of renal disease.

              Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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                Author and article information

                Journal
                Vasc Health Risk Manag
                Vasc Health Risk Manag
                VHRM
                vhriskman
                Vascular Health and Risk Management
                Dove
                1176-6344
                1178-2048
                16 January 2020
                2020
                : 16
                : 29-39
                Affiliations
                [1 ]Secondary Hypertension Department, State Institution “National Scientific Center “Institute of Cardiology Named After acad.M.D.Strazhesko” of Ukrainian National Academy of Medical Science , Kyiv, Ukraine
                [2 ]Non-Coronary Heart Disease Department, State Institution “National Scientific Center “Institute of Cardiology Named After acad.M.D.Strazhesko” of Ukrainian National Academy of Medical Science , Kyiv, Ukraine
                Author notes
                Correspondence: GD Radchenko Department of Secondary Hypertension, State Institute “National Scientific Center “Institute of Cardiology n.a.acad. M.D. Strazhesko” of National Academy of Medical Science , Kyiv, UkraineTel +38-0667128405 Email rganna@bigmir.net
                Author information
                http://orcid.org/0000-0002-3651-3014
                http://orcid.org/0000-0002-4091-4910
                Article
                230041
                10.2147/VHRM.S230041
                6971813
                32021226
                8b7cf07c-7503-4c20-afa0-f3236998bbc1
                © 2020 Radchenko et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 06 September 2019
                : 15 November 2019
                Page count
                Tables: 4, References: 73, Pages: 11
                Categories
                Original Research

                Cardiovascular Medicine
                idiopathic pulmonary arterial hypertension,systemic arterial stiffness,functional capacity,pulse wave velocity,cardio-ankle vascular index

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