Lysed Erythrocyte Membranes Promote Vascular Calcification.

BACKGROUND: Intraplaque hemorrhage promotes atherosclerosis progression, and erythrocytes may contribute to this process. In this study we examined the effects of red blood cells on smooth muscle cell mineralization and vascular calcification and the possible mechanisms involved. METHODS: Erythrocytes were isolated from human and murine whole blood. Intact and lysed erythrocytes and their membrane fraction or specific erythrocyte components were examined in vitro using diverse calcification assays, ex vivo by using the murine aortic ring calcification model, and in vivo after murine erythrocyte membrane injection into neointimal lesions of hypercholesterolemic apolipoprotein E-deficient mice. Vascular tissues (aortic valves, atherosclerotic carotid artery specimens, abdominal aortic aneurysms) were obtained from patients undergoing surgery. RESULTS: The membrane fraction of lysed, but not intact human erythrocytes promoted mineralization of human arterial smooth muscle cells in culture, as shown by Alizarin red and van Kossa stain and increased alkaline phosphatase activity, and by increased expression of osteoblast-specific transcription factors (eg, runt-related transcription factor 2, osterix) and differentiation markers (eg, osteopontin, osteocalcin, and osterix). Erythrocyte membranes dose-dependently enhanced calcification in murine aortic rings, and extravasated CD235a-positive erythrocytes or Perl iron-positive signals colocalized with calcified areas or osteoblast-like cells in human vascular lesions. Mechanistically, the osteoinductive activity of lysed erythrocytes was localized to their membrane fraction, did not involve membrane lipids, heme, or iron, and was enhanced after removal of the nitric oxide (NO) scavenger hemoglobin. Lysed erythrocyte membranes enhanced calcification to a similar extent as the NO donor diethylenetriamine-NO, and their osteoinductive effects could be further augmented by arginase-1 inhibition (indirectly increasing NO bioavailability). However, the osteoinductive effects of erythrocyte membranes were reduced in human arterial smooth muscle cells treated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide or following inhibition of NO synthase or the NO receptor soluble guanylate cyclase. Erythrocytes isolated from endothelial NO synthase-deficient mice exhibited a reduced potency to promote calcification in the aortic ring assay and after injection into murine vascular lesions. CONCLUSIONS: Our findings in cells, genetically modified mice, and human vascular specimens suggest that intraplaque hemorrhage with erythrocyte extravasation and lysis promotes osteoblastic differentiation of smooth muscle cells and vascular lesion calcification, and also support a role for erythrocyte-derived NO.

Contrast-Induced Acute Kidney Injury: An Update.

Contrast-induced acute kidney injury (CI-AKI) is defined as an abrupt deterioration in renal function associated with the administration of iodinated contrast media. This type of acute kidney injury is frequently encountered as a complication of percutaneous coronary intervention (PCI) and is associated with adverse short- and long-term outcomes including mainly mortality, cardiovascular morbidity and prolongation of hospitalization. The incidence of CI-AKI after PCI ranges from 2 to 20 % according to baseline kidney function. It may also range according to the clinical setting, being higher after emergency PCI. The primary manifestation is a small decline in kidney function, occurring 1 to 3 days after the procedure. Kidney function usually returns to preexisting levels within 7 days. Incidence of acute renal failure requiring dialysis following PCI is rare (<1 %). The present article aims to review up-to-date published data concerning diagnosis, definition, epidemiology and prognosis of this novel in-hospital epidemic.

Prevention of Contrast-Induced Acute Kidney Injury: an Update.

Contrast-induced acute kidney injury (CI-AKI) is a common complication of intravascular administration of contrast media used in coronary angiography, percutaneous coronary intervention and other diagnostic and interventional procedures. This review article aims at summarizing the published literature regarding the prevention of CI-AKI, by focusing on available high-quality meta-analyses addressing this matter. Apart from adequate hydration, a number of pharmacologic agents have been proposed as potential candidates to be included in the routine preparation, prior to the patient's arrival in the cardiac catheterization laboratory. Among them, statins and N-acetylcysteine appear to be the most extensively studied ones. Throughout this article we present the available data on CI-AKI prevention and provide a critical clinical appraisal, as well as a summary of currently available guidelines.

Circulating microRNAs and DNA Methylation as Regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation and Key Elements for the Identification of the Mechanism of Action (miR-CRAFT): Study Design and Patient Enrolment.

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment.

Artificial intelligence-based mining of electronic health record data to accelerate the digital transformation of the national cardiovascular ecosystem: design protocol of the CardioMining study.

INTRODUCTION: Mining of electronic health record (EHRs) data is increasingly being implemented all over the world but mainly focuses on structured data. The capabilities of artificial intelligence (AI) could reverse the underusage of unstructured EHR data and enhance the quality of medical research and clinical care. This study aims to develop an AI-based model to transform unstructured EHR data into an organised, interpretable dataset and form a national dataset of cardiac patients. METHODS AND ANALYSIS: CardioMining is a retrospective, multicentre study based on large, longitudinal data obtained from unstructured EHRs of the largest tertiary hospitals in Greece. Demographics, hospital administrative data, medical history, medications, laboratory examinations, imaging reports, therapeutic interventions, in-hospital management and postdischarge instructions will be collected, coupled with structured prognostic data from the National Institute of Health. The target number of included patients is 100 000. Natural language processing techniques will facilitate data mining from the unstructured EHRs. The accuracy of the automated model will be compared with the manual data extraction by study investigators. Machine learning tools will provide data analytics. CardioMining aims to cultivate the digital transformation of the national cardiovascular system and fill the gap in medical recording and big data analysis using validated AI techniques. ETHICS AND DISSEMINATION: This study will be conducted in keeping with the International Conference on Harmonisation Good Clinical Practice guidelines, the Declaration of Helsinki, the Data Protection Code of the European Data Protection Authority and the European General Data Protection Regulation. The Research Ethics Committee of the Aristotle University of Thessaloniki and Scientific and Ethics Council of the AHEPA University Hospital have approved this study. Study findings will be disseminated through peer-reviewed medical journals and international conferences. International collaborations with other cardiovascular registries will be attempted. TRIAL REGISTRATION NUMBER: NCT05176769.

Rationale and Design of Heart Failure Prevalence and Evolution of Heart Failure in Diabetes Mellitus Type II Patients at High Risk (HF-LanDMark Study).

(1) Background: Patients with diabetes mellitus (DM) are at increased risk for heart failure (HF). Accurate data regarding the prevalence of HF stages among diabetics in Greece are scarce. (2) Aim: The present study will examine the prevalence and evolution of HF stages among patients with type II DM (T2DM) diagnosed in the past 10 years, with no previous history of HF and at high CV risk, in Greece, as well as will explore the potential determinants of the development of symptomatic HF in these patients. (3) Methods: Through a non-interventional, epidemiological, single-country, multi-center, prospective cohort study design, a sample of 300 consecutive patients will be enrolled in 11 cardiology departments that are HF centers of excellence. Patients will be either self-referred or referred by primary or secondary care physicians and will be followed for up to 24 months. Demographic, clinical, echocardiography, electrocardiography, cardiac biomarkers (troponin, NT-proBNP) and health-related quality of life questionnaire data will be recorded as well as clinical events, including mortality, HF hospitalizations and HF-related healthcare resource utilization. The primary outcomes are the proportion of patients diagnosed with symptomatic HF (ACC/AHA Stage C) at enrolment in the overall study population and the proportions of patients with HF stages A, B and C, as well as by NYHA functional classification in the overall study population. (4) Conclusions: The HF-LanDMark study is the first epidemiological study that will assess the prevalence of HF among T2DM patients in Greece that could potentially enhance prompt therapeutic interventions shown to delay the development of HF in the T2DM patient population (HF-LanDMark, Clinical Trials.gov number, NCT04482283).

Statin-induced immunomodulation alters peripheral invariant natural killer T-cell prevalence in hyperlipidemic patients.

PURPOSE: To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. METHODS: A total of 77 hyperlipidemic individuals (54 ± 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. RESULTS: Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 ± 0.04% vs 0.39 ± 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 ± 0.04% to 0.28 ± 0.11%, p = 0.03) but not with ezetimibe (from 0.16 ± 0.05% to 0.17 ± 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r(2) = 0.009, p = 0.76) or LDL cholesterol (r(2) = 0.008, p = 0.78) reached by simvastatin. CONCLUSIONS: Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe.

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.

Renal artery revascularization is a controversial treatment strategy for renal artery stenosis: A case series and a brief review of the current literature.

Renal artery stenosis (RAS) may cause secondary hypertension, progressive decline in renal function, and cardiac destabilization syndromes including "flash" pulmonary edema, recurrent congestive heart failure, and cerebro-cardiovascular disease. Atherosclerotic lesions, fibromuscular dysplasia, and vasculitides are the pathophysiological basis of the disease. Common therapeutic pathways for RAS include medical therapy and revascularization with or without stenting. Randomized controlled trials evaluating renal revascularization have not reported any advantages of revascularization over medical therapy alone in terms of renal function improvement or prevention of cardiovascular events. However, mounting clinical experience suggests that the best strategy in RAS management is to identify which patients are most likely to benefit from renal artery stenting and to optimize the safety and durability of the procedure. This review presents 3 cases of patients who have undergone renal revascularization and discusses the available clinical evidence for the identification of RAS patients who will potentially respond well to revascularization.

Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

Atherosclerosis is an inflammatory disease. The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development. Chemokines are crucial mediators in every step of this process. Additionally, cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions. However, until recently data were mostly focusing on leukocytes and platelets. Erythrocytes were considered unreceptive bystanders and limited data supported their importance in the progression and destabilization of the atherosclerotic plaque. Recently erythrocytes, through their Duffy antigen receptor for chemokines (DARC), have been proposed as appealing regulators of chemokine-induced pathways. Dissimilar to every other chemokine receptor DARC possesses high affinity for several ligands from both CC and CXC chemokine sub-families. Moreover, DARC is not coupled to a G-protein or any other intracellular signalling system; thus it is incapable of generating second messages. The exact biochemical role of erythrocyte DARC remains to be determined. It is however challenging the fact that DARC is a regulator of almost every CC and CXC chemokine ligand and therefore DARC antagonism could effectively block the complex pre-inflammatory chemokine network. In the present review we intent to provide recent evidence supporting the role of erythrocytes in atherosclerosis focusing on the erythrocyte-chemokine interaction through the Duffy antigen system.

Plasma leptin and adiponectin concentrations in healthy, non-obese children.

BACKGROUND: Alterations in plasma leptin and adiponectin concentrations are associated with an adverse metabolic profile in obese children. OBJECTIVE: To simultaneously assess multiple factors with possible effects on plasma leptin and adiponectin concentrations in healthy, non-obese children. SUBJECTS: We studied 170 healthy non-obese children (86 males, age 10+1.5 years), with available medical records from birth. METHODS: Plasma leptin and adiponectin concentrations were assessed by immunoassay. The ratio of current weight/birth weight (WBWR) was used as an index of children growth from birth. Children's intensity of physical activity and parental characteristics were also assessed. RESULTS: Leptin was positively associated with WBWR (p<0.0001); parental smoking (analysis of variance, ANOVA; p-=0.03) and parental obesity (ANOVA; p<0.001) were negatively associated with breastfeeding (p<0.01) and children's access to exercise (p<0.0001). Adiponectin was negatively associated with WBWR (p<0.0001) and parental smoking (p=0.04), with an additive negative effect of parental smoking status and parental obesity on children's adiponectin levels (ANOVA; p=0.02). CONCLUSIONS: Children's and parental factors are related and could possibly influence leptin and adiponectin concentrations in healthy non-obese children. Early preventive strategies that target both children and parents could improve the profile of adipocytokine in these children.

Colocalization of Erythrocytes and Vascular Calcification in Human Atherosclerosis: A Systematic Histomorphometric Analysis.

Background Intimal calcification typically develops in advanced atherosclerosis, and microcalcification may promote plaque progression and instability. Conversely, intraplaque hemorrhage and erythrocyte extravasation may stimulate osteoblastic differentiation and intralesional calcium phosphate deposition. The presence of erythrocytes and their main cellular components (membranes, hemoglobin, and iron) and colocalization with calcification has never been systematically studied. Methods and Results We examined three types of diseased vascular tissue specimens, namely, degenerative aortic valve stenosis ( n = 46), atherosclerotic carotid artery plaques ( n = 9), and abdominal aortic aneurysms ( n = 14). Biomaterial was obtained from symptomatic patients undergoing elective aortic valve replacement, carotid artery endatherectomy, or aortic aneurysm repair, respectively. Serial sections were stained using Masson-Goldner trichrome, Alizarin red S, and Perl's iron stain to visualize erythrocytes, extracelluar matrix and osteoid, calcium phosphate deposition, or the presence of iron and hemosiderin, respectively. Immunohistochemistry was employed to detect erythrocyte membranes (CD235a), hemoglobin or the hemoglobin scavenger receptor (CD163), endothelial cells (CD31), myofibroblasts (SMA), mesenchymal cells (osteopontin), or osteoblasts (periostin). Our analyses revealed a varying degree of intraplaque hemorrhage and that the majority of extravasated erythrocytes were lysed. Osteoid and calcifications also were frequently present, and erythrocyte membranes were significantly more prevalent in areas with calcification. Areas with extravasated erythrocytes frequently contained CD163-positive cells, although calcification also occurred in areas without CD163 immunosignals. Conclusion Our findings underline the presence of extravasated erythrocytes and their membranes in different types of vascular lesions, and their association with areas of calcification suggests an active role of erythrocytes in vascular disease processes.

HEllenic Registry on Myocarditis SyndromES on behalf of Hellenic Heart Failure Association: The HERMES-HF Registry.

AIMS: Despite the existence of many studies, there are still limited data about the characteristics of myocarditis in Greece. This led to the creation of the Greek Myocarditis Registry aiming to document the different symptoms and treatment of myocarditis, assess possible prognostic factors, and find similarities and differences to what is already published in literature. This paper is a preliminary descriptive analysis of this Registry. METHODS AND RESULTS: We analysed data for the hospitalization period of all patients included in the Registry from December 2015 until November 2017. Statistics are reported as frequency (%) or median and inter-quartile range (IQR) as appropriate. In total, 146 patients were included; 83.3% of the patients reported an infection during the last 3 months. The most common symptom, regardless of the underlying infection, was chest pain (82.2%) followed by dyspnoea (18.5%), while the most common finding in clinical examination was tachycardia (26.7%). Presentation was more frequent in the winter months. ECG findings were not specific, with the repolarization abnormalities being the most frequent (60.3%). Atrial fibrillation was observed in two patients, both of whom presented with a reduced ventricular systolic function. Left ventricular ejection fraction changed significantly during the hospitalization [55% (IQR: 50-60%) on admission vs. 60% (IQR: 55-60%) on discharge, P = 0.0026]. Cardiac magnetic resonance was performed in 88 patients (61%), revealing mainly subepicardial and midcardial involvement of the lateral wall. Late gadolinium enhancement was present in all patients, while oedema was found in 39 of them. Only 11 patients underwent endomyocardial biopsy. Discharge medication consisted mainly of beta-blockers (71.9%) and angiotensin-converting enzyme inhibitors (41.8%), while 39.7% of the patients were prescribed both. CONCLUSIONS: This preliminary analysis describes the typical presentation of myocarditis patients in Greece. It is a first step in developing a better prognostic model for the course of the disease, which will be completed after the incorporation of the patients' follow-up data.

Oxidised low-density lipoprotein and arterial function in beta-thalassemia major.

OBJECTIVES: Vascular abnormalities such as endothelial dysfunction and arterial stiffness have been described in patients with beta-thalassemia major (beta-TM). Increased concentrations of oxidised low-density lipoprotein cholesterol (oxLDL) have been observed in those patients, but possible associations between oxLDL and arterial function in beta-TM have not been defined. METHODS: Twenty-six patients (11 males) with beta-TM (age 23 +/- 4 yr) and 30 age and gender-matched healthy subjects were studied. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWVc-f) using applanation tonometry; brachio-radial artery stiffness was assessed by carotid-radial PWV (PWVc-r). Flow-mediated dilatation (FMD) of the brachial artery and oxLDL (ELISA) were also measured. RESULTS: Patients with beta-TM had higher oxLDL levels (68.6 +/- 13.7 mU/mg vs. 50.0 +/- 12.6 mU/mg, P = 0.005), decreased FMD (3.6 +/- 2.5% vs. 7.3 +/- 3.5%, P = 0.001) and higher PWVc-f compared with controls (8.4 +/- 1.7 vs. 7.2 +/- 1.1. P < 0.002). FMD of the brachial artery was negatively associated with OxLDL concentrations in simple linear (r(2) = -0.25, P = 0.001) and multiple linear regression analysis (beta = -0.242, P = 0.03, R(2) = 0.43, P = 0.0002). PWVc-r was positively associated with OxLDL (r(2) = 0.23, P = 0.003) and showed a tendency in multiple regression analysis (beta = 0.18, P = 0.05). PWVc-r and FMD were also significantly correlated (beta = -0.213, P = 0.04) in beta-TM patients. There was no association between oxLDL and PWVc-f. CONCLUSION: An association between oxLDL, arterial elastic properties and endothelial dysfunction of muscular arteries was found. OxLDL may represent a contributing factor for the vascular manifestations described in beta-TM patients.

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.

Interleukin-8 is increased in the membrane of circulating erythrocytes in patients with acute coronary syndrome.

AIMS: Studies have shown that erythrocyte membranes are present within necrotic cores in atherosclerotic plaques, and that circulating erythrocytes in patients with acute coronary syndrome (ACS) have increased total cholesterol content (CEM). Interleukin-8 (IL-8) binds to erythrocytes and during intraplaque haemorrhage it is released into the plaque and thus may contribute to inflammatory cascade and atherosclerotic plaque instability. The present study was undertaken to test the hypothesis that erythrocyte membrane IL-8 is elevated in patients with ACS compared with those with chronic stable angina (CSA). METHODS AND RESULTS: Consecutive patients who presented with CSA (n = 120, 92 men, 62 +/- 9 years), ACS (n = 118, 90 men, 62 +/- 10 years) or with chest pain who had normal coronary arteries (n = 36, 26 men, 60 +/- 7 years), were studied prospectively. IL-8 concentrations in erythrocyte membranes (rIL-8) and in plasma (pIL-8), C-reactive protein (CRP) and CEM were measured. rIL-8 levels [mean +/- 1 SD (standard deviation)] were higher in ACS (102.9 +/- 70.1 pg/mL) compared with CSA (44.7 +/- 22.8 pg/mL) (P < 0.001). No difference in pIL-8 levels between the two coronary artery disease groups was observed (P = 0.280). Serum CRP levels were correlated with rIL-8 levels (r = 0.294, P < 0.001); no association was found between CRP and pIL-8 levels (r = 0.025, P = 0.706). Further, rIL-8 had an independent association with ACS, when CRP and CEM were taken into consideration. CONCLUSION: This study shows for the first time that rIL-8 content was significantly higher in ACS, compared with CSA. These findings endorse results from our previous studies suggesting that erythrocytes may play an important role in the development of unstable atherosclerotic plaque.

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.

Effect of statins on collagen type I degradation in patients with coronary artery disease and atrial fibrillation.

The present study was undertaken to assess the effect of statins on collagen type I degradation and C-reactive protein in patients with coronary artery disease and atrial fibrillation. One hundred six patients with coronary artery disease and atrial fibrillation were studied: 40 (36 men, mean age 72 +/- 8 years) treated with a statin and 66 (48 men, mean age 74 +/- 9 years) not treated with a statin. Serum concentrations of carboxy-terminal telopeptide of collagen type I, an index of collagen type I degradation, and high-sensitivity C-reactive protein were measured in all patients. Carboxy-terminal telopeptide of collagen type I levels were significantly higher (p <0.001) in statin-treated patients (0.64 ng/ml, 95% confidence interval [CI] 0.57 to 0.71) compared with nonstatin-treated patients (0.38 ng/ml, 95% CI 0.31 to 0.44). These changes were independent of cholesterol levels (before or after therapy). Statin-treated patients had significantly lower (p <0.001) C-reactive protein levels (0.25 mg/dl, 95% CI 0.23 to 0.28) compared to statin nonusers (1.1 mg/dl, 95% CI 0.92 to 1.25). In conclusion, this study suggests that therapy with statins in patients with coronary artery disease and atrial fibrillation is associated with an increase in collagen degradation and an attenuation of inflammation, independently of cholesterol lowering.

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.