Abstract 17272: Frequency of Acute Vasodilator Response in Incident and Prevalent Patients With Pulmonary Arterial Hypertension (Group 1): Results From the Pulmonary Vascular Disease Omics (PVDOMICS) Study

Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is reported to be around 12% in incident patients with idiopathic PAH (IPAH). The prevalence of AVR, however, is reportedly lower in other disease-associated PAH in Group 1, such as connective tissue disease (CTD). Furthermore, the prevalence of AVR for combined inhaled NO and oxygen, and in patients on PAH therapy (prevalent cohort), is less known. Hypothesis: We hypothesized there would be differences in the prevalence of AVR in PAH subgroups in the large PVDOMICS cohort of incident and prevalent patients. Methods: Group 1 PAH patients enrolled in PVDOMICS underwent right heart catheterization for baseline measurements. AVR was then measured in response to 100% inhaled oxygen (O 2 ) and 100% O 2 plus NO at 40 ppm (O 2 +NO) for 5 min each before hemodynamic measurements. Details of the PVDOMICS methodology and core adjudication of hemodynamic measurements were reported previously. Rates of AVR to 100% O 2 and 100% O 2 +NO were compared between incident and prevalent patients in each PAH subgroup. Results: 351 patients, mostly female (73%), average age of 52.9 years, with mostly prevalent disease (87%) and an average of 4 years from PAH diagnosis, underwent AVR assessment. A positive AVR was found in 0.6% of patients in response to 100% oxygen and 6% of patients in response to 100%+NO for the overall cohort. AVR was similar in incident and prevalent IPAH patients (6 and 6.9%, respectively). It was, however, 0% and 6.9%, in incident vs. prevalent CTD-PAH patients, respectively. There were no responders to either challenge in any other PAH subgroup. Conclusions: The prevalence of AVR is relatively rare in IPAH and CTD-PAH (~ 6%) and absent in other subgroups. There was no response to 100% O2 alone, suggesting specificity of AVR to NO in PAH. AVR is more common than previously reported in CTD-PAH, but only in prevalent disease. Whether the latter is related to long-term PAH therapy affecting pulmonary vasomotor response and/or vascular remodeling in these patients would warrant further studies.

Dysregulated adipokine secretory profile is associated with endothelial dysfunction in human obesity

Adipokines have been postulated as the potential mediators of the relationship between excess adiposity and vascular dysfunction. In obese patients, vascular dysfunction, characterized by impaired vasodilator responsiveness and/or increased endothelin (ET)-1-dependent vasoconstriction, is, in turn, a predominant abnormality in the atherogenic process. We hypothesized, therefore, that in human obesity vascular dysfunction could be associated with changes in circulating concentrations of adipokines. To test this hypothesis, we compared plasma levels of a panel of adipokines (Luminex assay) in lean subjects (n=42) and obese patients (n=134), and tested their relationship with the forearm flow response (strain-gauge plethysmography) to intra-arterial infusion of endothelium-dependent (acetylcholine; ACh) and -independent (sodium nitroprusside; SNP) vasodilators or ETA receptor antagonism (BQ-123, 10 nmol/min). Compared to lean subjects (n=42), obese patients (n=134) had higher plasma levels of chemerin (4.0±0.1 vs. 2.9±0.2 ng/ml; P<0.001), adipsin (2.1±0.1 vs. 2.7±0.1 μg/ml; P<0.001), leptin (8.1±0.4 vs. 24.4±1.8 ng/ml; P<0.001), and visfatin (7.4±0.8 vs. 8.3±0.3 ng/ml; P=0.015); by contrast, no group difference was observed in circulating levels of adiponectin (3.3±0.3 vs. 3.3±0.1 μg/ml; P=0.78) and retinol-binding protein 4 (57.5±2.5 vs. 64.0±4.1 μg/ml; P=0.13). The forearm flow responses to both ACh and SNP were significantly lower in obese patients (12.6±0.6 ml/min/dl and 11.7±0.3 ml/min/dl, respectively) than in lean controls (18.8±1.4 ml/min/dl and 15.1±0.7 ml/min/dl, respectively; all P<0.001). The vasodilator response to BQ-123, by contrast, was higher in obese (53.7±4.5% increase from baseline) than in lean subjects (18.5±7.3%; P<0.001). Similarly, plasma insulin levels were higher in obese (14.9±0.8 μU/ml) than in lean subjects (6.8±0.7 μU/ml; P<0.001). At the linear regression analyses, a significant inverse correlation was found between circulating levels of visfatin and the vasodilator response to ACh (R=0.22; P=0.03); no linear association, however, was observed between the response to ACh and the other measured adipokines (all P>0.05); similarly, no correlation was seen between plasma adipokines and the vasodilator response to SNP (all P>0.05). On the other hand, a significant linear relationship was observed between the vasodilation elicited by B-123 and plasma levels of chemerin (R=0.30, P=0.012) and adipsin (R=0.38, P<0.001), but not those of the other adipokines (all P>0.05). In conclusion, circulating concentrations of selected adipokines, such as visfatin, chemerin and adipsin, are variably associated with obesity-related decrease in endothelium-dependent vasodilation and increase in ET-1-dependent vasoconstriction. These findings are consistent with the notion that adipokines may influence vascular dysfunction and make these molecules promising targets for prevention. Funding Acknowledgement Type of funding source: None

Abstract P095: Aerobic Exercise Training Reduces Endothelin-1-mediated Vasoconstriction In Postmenopausal Women

Endothelin-1 (ET-1)-mediated vasoconstrictor tone is elevated in postmenopausal women (PMW), contributing to their increased cardiovascular risk. Although aerobic exercise is beneficial in reducing ET-1 system activity in men, it is unknown whether this favorable vascular effect is conferred in women. In fact, contrary to men, it is uncertain whether aerobic exercise training improves endothelial dysfunction in PMW. We tested the hypothesis that aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. We further hypothesized reductions in ET-1 vasoconstrictor tone underly exercise-induced improvements in endothelium-dependent vasodilatation in PMW. Methods: Forearm blood flow (FBF) responses to intra-arterial infusion of selective ET A receptor blockade (BQ-123, 100 nmol/min for 60 min), acetylcholine (4.0, 8.0 and 16.0 μg/100 mL tissue/min) in the absence and presence of ET A receptor blockade and sodium nitroprusside (1.0, 2.0 and 4.0 μg/100 mL tissue/min) were determined before and after a 12-week aerobic exercise training intervention in 20 healthy, sedentary PMW (56 + 1 yr). Results: All 20 PMW completed the exercise intervention, walking an average of 4.9 + 0.1 d/wk for 50 + 2 min/d at 71 + 1% of maximal heart rate. After the exercise intervention, BQ-123 elicited no significant change in resting FBF in the previously sedentary PMW compared with significant vasodilation (~25%) before exercise. FBF responses to acetylcholine were markedly higher (~25%; P<0.05) after (from 4.3 + 0.3 to 13.8 + 0.8 mL/100 ml tissue/min) vs before (from 4.1 + 0.2 to 11.3 + 0.8 mL/100 ml tissue/min) exercise training. Moreover, before exercise training the co-infusion of BQ-123 with acetylcholine enhanced (~25%; P<0.05) the vasodilator response (from 4.3 + 0.3 to 13.7 + 0.7 mL/100 mL tissue/min) compared with acetylcholine alone; after exercise training, the presence of BQ-123 did not significantly affect the vasodilator response to acetylcholine. Conclusions: These data demonstrate that aerobic exercise training reduces ET-1-mediated vasoconstriction in PMW. Furthermore, decreased ET-1-mediated vasoconstriction is an important mechanism underlying aerobic exercise-induced improvement in endothelium-dependent vasodilation in PMW.

Long-term clinical prognosis predictors in patients with chronic heart failure and reduced left ventricular ejection fraction

The aim – to identify prognostic factors for the development of adverse cardiovascular events (death and hospitalization) in patients with chronic heart failure (CHF) and left ventricular ejection fraction (LVEF) ≤ 35 % after long-term observation. Materials and methods. 120 stable patients with CHF, aged 18–75, II–IV functional classes according to NYHA, with LVEF ≤ 35 % were examined. Using multiple logistic regression according to the Cox method, we analyzed independent factors that affect the long-term prognosis of patients with heart failure. Results and discussion. During the observation period, out of 120 patients, 61 patients reached combined critical point (CCР). In the univariate regression model, predictors of CCР reaching were NYHA functional class, weigh loss of ≥ 6 % over the past 6 months, systolic and diastolic blood pressure, patient’s history of myocardial infarction, angina pectoris, anemia, number of hospitalizations over the past year and parameters reflecting the functional state of the patient (6-minute walk distance, number of extensions of the lower limb). The risk of CCP developing is significantly higher in patients with lower body mass index, shoulder circumference of a tense and unstressed arm, hip, thickness of the skin-fat fold over biceps and triceps, estimated percentage of body fat. Рredictors CCP reaching are higher levels of uric acid and C-reactive protein. Echocardiographic predictors of CCP onset were LVEF, size of the left atrium, TAPSE score, as well as its ratio to systolic pressure in the pulmonary artery, index of final diastolic pressure in the left ventricle. Also, the risk of CCP reaching is greater at lower values of the flow-dependent vasodilator response. Independent predictors of CCP onset were the circumference of the shoulder of an unstressed arm, the level of C-reactive protein in the blood, and the rate of flow-dependent vasodilator response. When analyzing the indices in 77 patients, who underwent densitometry, it was revealed that the E/E´ index, the index of muscle tissue of the extremities, the index of fat mass, and the ratio of fat mass to growth affect CCP reaching. In a multivariate analysis, taking into account densitometry indices, independent predictors of CCP onset were the size of the left atrium, the index of muscle mass of the extremities, the rate of flow-dependent vasodilator response and the presence of myocardial infarction in anamnesis. Conclusions. Independent predictors of CCP reaching in patients with CHF and LVEF ≤ 35 % are myocardial infarction in anamnesis, lower arm circumference of the arm, limb muscle mass index, flow-dependent vasodilator response, higher levels of C-reactive protein, sizes of the left atrium.

PREDICTORS OF WEIGHT LOSS IN PATIENTS WITH CHRONIC HEART FAILURE AND REDUSED LEFT VENTRICULAR EJECTION FRACTION

Chronic heart failure (CHF) is a heterogeneous syndrome with a poor prognosis. Aim of the work – to define predictors of body weight (BW) loss in patients with CHF and a reduced left ventricular ejection fraction (LVEF). Materials and methods. 120 patients with stable CHF and LVEF ≤35 %, II-IV NYHA class were examined. Patients were divided into two groups according to the value of BW loss for 6 months: the first group - loss of BW <6 %, the second - ≥ 6 %. Results. Out of the 120 patients who were studied, a BW loss of ≥ 6 % occurred in 59 (49.2 %) patients. According to the results of binary logistic regression, predictors of BW loss of ≥6 % in patients with CHF and LVEF ≤ 35 % were: age, coronary heart disease, anaemia, and the number of hospitalizations over the last year. People with poorer quality of life, bigger number of points on the Beck depression scale and DEFS, with lower levels of physical activity and worse endothelium-dependent vasodilator response; higher sizes of the right atrium, right ventricle, and pulmonary artery systolic pressure, E / E '. Higher levels of C-reactive protein (CRP), uric acid are associated with a risk of losing BW≥6 %. Conclusions. Weight loss ≥ 6 % is observed in 49.2 % of patients with CHF and LVEF≤35 %. According to multivariate analysis, independent predictors of BW loss of ≥6 % in patients with CHF and LVEF≤35 % are age, CRP level, III-IV NYHA class, lower cholesterol levels, as well as lower rates of flow-dependent vasodilator response and hip circumference.