The impact of cardiovascular comorbidities associated with risk for left heart disease on idiopathic pulmonary arterial hypertension: Data from the Hellenic Pulmonary Hypertension Registry (HOPE).

Whereas younger female patients were diagnosed with idiopathic pulmonary arterial hypertension (IPAH) in 1980s, it is now frequently encountered in elderly patients with cardiovascular comorbidities (CVCs) associated with increased risk for left heart disease. We present data until November 2019 regarding specific features and clinical outcomes of IPAH population from the Hellenic Pulmonary Hypertension Registry (HOPE). Patients were divided into two groups based on the presence of ≥ or <3 CVCs, arterial hypertension, diabetes mellitus, obesity, presence of coronary artery disease, or atrial fibrillation. Overall, 77 patients with IPAH (55.1 [interquartile range, IQR: 24.1] years, 62.8% women) have been recorded. Fifteen patients (19.2%) had ≥3 CVCs, while 25 (32%) were over 65 years old. Patients with ≥3 CVCs were older, presented an almost equal female to male ratio, walked less in 6-min walk test, and had lower mean arterial pulmonary pressure and pulmonary vascular resistance at baseline than patients with less CVCs. Fewer patients with ≥3 CVCs received PAH-specific treatment compared to patients with less comorbidities (n = 11 [73.3%] versus n = 58 [95.5%], p = 0.02). During a median follow-up period of 3.8 (IQR: 2.7) years, 18 patients died (all-cause mortality 24.3%). Male sex and older age were independent predictors of mortality and/or lung transplantation, while CVCs did not have a significant impact on clinical outcomes. In this nationwide, register-based study, the epidemiology of IPAH involves older patients with CVCs, who seem to have less hemodynamic compromise, but worse functional impairment and are treated less aggressively with PAH pharmacotherapy.

Epidemiology and initial management of pulmonary arterial hypertension: real-world data from the Hellenic pulmOnary hyPertension rEgistry (HOPE).

Pulmonary arterial hypertension (PAH) is a heterogenous clinical entity with poor prognosis, despite recent major pharmacological advances. To increase awareness about the pathophysiology, epidemiology, and management of the disease, large national registries are required. The Hellenic pulmOnary hyPertension rEgistry (HOPE) was launched in early 2015 and enrolls patients from all pulmonary hypertension subgroups in Greece. Baseline epidemiologic, diagnostic, and initial treatment data of consecutive patients with PAH are presented in this article. In total, 231 patients with PAH were enrolled from January 2015 until April 2018. At baseline, about half of patients with PAH were in World Health Organization functional class II. The majority of patients with PAH (56.7%) were at intermediate 1-year mortality risk, while more than one-third were low-risk patients, according to an abbreviated risk stratification score. Half of patients with PAH were on monotherapy, 38.9% received combination therapy, while prostanoids were used only in 12.1% of patients. In conclusion, baseline data of the Greek PAH population share common characteristics, but also have some differences with other registries, the most prominent being a better functional capacity. This may reflect earlier diagnosis of PAH that in conjunction with the increased proportion of patients with atypical PAH could partially explain the preference for monotherapy and the limited use of prostanoids in Greece. Nevertheless, early, advanced specific therapy is strongly recommended.

Independent and additive prognostic ability of serum carboxy-terminal telopeptide of collagen type-I in heart failure patients: a multi-marker approach with high-negative predictive value to rule out long-term adverse events.

BACKGROUND: Altered myocardial extracellular matrix turnover has been proposed as a major determinant of myocardial remodelling. Carboxy-terminal telopeptide of collagen type-I (CITP) represents a collagen type-I degradation-derived serum peptide. In this study we examined the independent and additive prognostic value of serum concentrations of CITP compared with well-known mortality predictors such as the N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) patients. METHODS: We studied 196 consecutive patients (126 male, mean age 69 ± 10 years), who were admitted for acute decompensation of the CHF syndrome. The study entry point was determined at the discharge of the patients after achieving a stable compensated status. The primary endpoint was cardiac mortality during a 12-month follow-up. RESULTS: In the multivariate Cox proportional hazard model the levels of CITP remained a predictor of survival (hazards ratio 0.4 95% confidence interval 0.21-0.76, P = 0.005), independent of NT-proBNP levels. The stratified log-rank test (P < 0.001) showed that CHF patients characterized by low levels of both biomarkers had better survival (hazards ratio 0.12 95% confidence interval 0.04-0.35, P < 0.001) compared with patients characterized by high levels of both biomarkers. The negative predictive value of the combined measure for long-term adverse events was 94%. CONCLUSION: Serum levels of CITP were shown to be an independent and strong prognostic marker regarding survival in CHF patients. Furthermore, CITP levels had an additive prognostic value compared with NT-proBNP levels. These findings underline the detrimental role of myocardial fibrosis in the progression of heart failure and suggest a novel multi-marker approach for risk stratification in the CHF syndrome.

Circulating levels of a biomarker of collagen metabolism are associated with health-related quality of life in patients with chronic heart failure.

PURPOSE: Assessment of circulating levels of collagen-derived peptides has been proposed as a useful tool to monitor indirectly myocardial collagen metabolism in chronic heart failure (CHF) patients. The potential link between circulating concentrations of collagen metabolism biomarkers and health-related quality of life (HRQOL) has not been adequately evaluated. With the present study, we investigated the association between serum levels of collagen-derived peptides and HRQOL. METHODS: We studied 280 consecutive outpatients (of mean age 67 ± 10 years, 180 men) with CHF. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP)-a marker of collagen type I degradation-were measured in all patients both at baseline and during a period of 6 months follow-up. HRQOL was assessed by Minnesota living with heart failure questionnaire (MLHFQ). RESULTS: CITP levels were significantly associated with MLHFQ scores both at baseline (r = 0.231, P < 0.001) and at 6 months follow-up (r = 0.145, P = 0.044). CITP levels remained significantly associated with MLHFQ score in multivariable linear regression analysis. Higher CITP levels were observed with higher MLHFQ scores (poor HRQOL) both at baseline (P = 0.001) and at 6 months (P = 0.041). Unadjusted analysis demonstrated a significant relationship between increasing CITP levels during 6 months follow-up and worsening HRQOL (r = 0.204, P = 0.001). The aforementioned correlation remained significant in multivariable linear regression analysis. CONCLUSION: Our findings show that increased CITP levels are associated with poorer HRQOL in patients with CHF. These findings are consistent with a link between a pathophysiologic mechanism, i.e., collagen metabolism and patient self-assessed health status in CHF.

Independent and additive predictive value of total cholesterol content of erythrocyte membranes with regard to coronary artery disease clinical presentation.

BACKGROUND: A new mechanism for clinical instability in coronary artery disease (CAD) has been proposed where erythrocytes could play an active role in atherosclerotic plaque growth and rupture. Clinical studies showed increased total cholesterol levels in the membrane of circulating erythrocytes (CEM) in acute coronary syndrome (ACS) patients compared to patients with chronic stable angina (CSA). We investigated the independent and incremental discriminating value of CEM along with N-terminal propeptide of BNP (NT-proBNP), high sensitivity C-reactive protein (hs CRP), myeloperoxidase (MPO) and apolipoprotein B (apoB) with regard to CAD clinical presentation. METHODS: 519 consecutive angina patients were assessed; 252 had CSA (195 men, 62 ± 9 years) and 267 had ACS (213 men, 62 ± 10 years).CEM levels and serum concentrations of NT-proBNP, hs CRP, MPO and apoB were measured upon study admission. RESULTS: Simple logistic regression models showed that all biomarkers could distinguish ACS, nevertheless CEM with greater potency (OR 9.26 95%CI 6.31-13.59, p<0.001). Multiple logistic regression models after adjustment for all the variables that were different between the 2 groups as well as for other biomarkers showed that CEM continued to be a significant and an independent predictor of ACS (OR 22.27 95%CI 10.63-46.67, p<0.001). An increment of the C-statistic was also shown when CEM levels were incorporated in the predictive model (including traditional vascular risk factors and new well established biomarkers i.e. hs CRP, MPO, apoB and NT-proBNP). CONCLUSIONS: The present study showed that CEM levels are associated with clinical instability in CAD patients in an independent and incremental manner.

Chronic heart failure patients with high collagen type I degradation marker levels benefit more with ACE-inhibitor therapy.

Not all patients respond to angiotensin converting enzyme (ACE)-inhibitor equally. Genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs. With the present study we assessed the prognostic impact of ACE-inhibitor in chronic heart failure patients with different degrees of collagen metabolism as assessed by serum levels of a collagen type I degradation marker (CITP). One hundred ninety-six (126 male, 69+/-10 years) chronic heart failure patients were studied prospectively for 12 months regarding survival. Serum concentrations of CITP were measured at study entry. Chronic heart failure patients were divided into groups according to whether (n=114) or not (n=82) they received ACE-inhibitor as well as to their CITP levels. Survival (52.2%) was significantly lower in ACE-inhibitor naive patients with high CITP levels compared to ACE-inhibitor naive patients with low CITP levels (83.3%, P=0.003), to ACE-inhibitor users with low CITP levels (80%, P=0.006) and to ACE-inhibitor users with high CITP levels (70.4%, P=0.015). ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. CITP levels possibly reflecting an activated status of the renin-angiotensin-aldosterone system, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor.

Statin use is associated with a significant reduction in cholesterol content of erythrocyte membranes. A novel pleiotropic effect?

PURPOSE: High cholesterol content of erythrocyte membranes (CEM) levels is present in patients with acute coronary syndromes (ACS). Intraplaque hemorrhage and erythrocyte lysis contribute to the deposition of cholesterol on the atherosclerotic plaque and to plaque rupture. With the present study we assessed the effect of statin therapy on CEM levels, a novel marker of coronary artery disease (CAD) instability during a 1-year follow-up in CAD patients. METHODS: 212 consecutive eligible (158 men, 62 +/- 10 years) patients undergoing diagnostic coronary angiography for the assessment of angina pectoris were assessed. The study population comprised of 84 chronic stable angina (CSA) patients and 128 ACS patients. All study participants were commenced on statin treatment in equipotent doses and were followed for up to 1 year (at - 1, - 3, - 6 and - 12 months). RESULTS: Repeated measurements analysis of variance after appropriate adjustment showed a significant decrease (p < 0.001) in CEM content during follow up. CEM levels were decreasing at each time point (1 month : 100 microg/mg 95%CI 94.3-105.6, 3 months : 78.1 microg/mg 95%CI 73.2-83, 6 months : 67.2 microg/mg 95%CI 63.1-71.2, 1 year : 45.3 microg/mg 95%CI 42.2-48.3) compared to admission (112.1 microg/mg 95% CI 105.9-118.3) and to all previous measurements. CONCLUSIONS: The present study showed, that use of statins is associated with a reduction in CEM, an emerging marker of clinical instability and plaque vulnerability in CAD patients. The pleiotropic effects of statins at the cell membrane level represent a promising novel direction for research in CAD.

Resolution of symptoms and serum peptides of collagen type I turnover in acute heart failure patients.

OBJECTIVES: Myocardial collagen content as a fundamental component of extracellular matrix, is altered in pathological states including heart failure (HF). Serum peptides related to myocardial collagen synthesis and degregation can be measured and may be used as indices of myocardial collagen turnover. The present study was undertaken to assess the hypothesis that resolution of acute decompensation of chronic HF is associated with changes in serum peptides related to collagen synthesis and degregation. METHODS AND RESULTS: Serum concentrations of the amino-terminal propetide of procollagen type I (PINP) and the carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were determined at the time of admission and discharge in 156 patients (100 men, 68 +/- 10 years) with acute decompensation of chronic HF. A significant decrease (-3.5 ng/ml 95% CI -5.3/-1.6 ng/ml, P < 0.001) of PINP was observed whereas CITP levels were significantly increased (+ 0.04 ng/ml 95% CI 0.01-0.08 ng/ml, P = 0.031) at discharge compared to admission. CONCLUSIONS: Findings of the present study showed that serum indices of myocardial collagen turnover were changed significantly in a short period of time during the improvement of acute decompensation of chronic HF.

Serum levels of collagen type-I degradation markers are associated with vascular stiffness in chronic heart failure patients.

BACKGROUND: Chronic heart failure (CHF) induces peripheral vasoconstriction, endothelial dysfunction and arterial stiffness by activation of various neurohormonal pathways. The abnormal collagen turnover observed in CHF may be attributed not only to myocardial remodelling, but also to vascular remodelling. However, the effect of collagen metabolism on progressive large artery stiffening in the setting of CHF is understudied. AIMS: The present study was undertaken to investigate the association between circulating markers of collagen turnover and vascular stiffness in patients with CHF. METHODS: Eighty patients (mean age 65+/-11 years, 68 men) with stable CHF and in sinus rhythm, were studied. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) and amino-terminal propetide of procollagen type I (PINP), markers of collagen type I degregation and synthesis respectively, were measured in all patients. Pulse wave velocity (PWV) and augmentation index (AIx) of aortic pulse wave form, markers of arterial stiffness, were also determined by applanation tonometry. RESULTS: Peripheral PWV was inversely associated with serum CITP levels (r=-0.585, p<0.001). AIx although weakly was negatively correlated with serum CITP levels (r=-0.285, p=0.01). Multiple regression analysis showed that peripheral PWV remained independently associated with serum CITP levels after adjustment for all confounding variables. CONCLUSIONS: Findings from the present study imply a possible link between altered collagen metabolism and peripheral vascular stiffness in CHF.