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).

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.

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.

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.

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.

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.

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.

Biomarkers of the extracellular matrix and of collagen fragments.

A great body of evidence has shown that extracellular matrix (ECM) alterations are present in the major types of cardiac diseases: ischemic heart disease, heart disease associated with pressure overload, heart disease associated with volume overload, and intrinsic myocardial disease or cardiomyopathy. Collagen, type I and III, is the principal structural protein found in the myocardium and its pro- or telopeptides are released into the circulation during the course of cardiovascular diseases. Therefore, these peptides may reflect collagen synthesis and break-down and also represent a much more useful tool to address ECM changes from a distance. Clinical trials have been performed during recent years to examine the usage of these peptides as diagnostic or prognostic biomarkers in heart failure (HF) patients. This review aims to summarize published data concerning cardiac ECM and its circulating biomarkers. Studies that focused on collagen metabolism related biomarkers in patients with HF are analyzed. Finally, limitations associated with the clinical use of the aforementioned biomarkers are also discussed.

Organization, structure and data of the Hellenic Heart Registry on Percutaneous Coronary Interventions: a step forward towards outcomes research.

INTRODUCTION: The Hellenic Heart Registry on Percutaneous Coronary Interventions (HHR-PCI) was a prospective, observational registry of patients with stable angina or acute coronary syndromes who underwent percutaneous coronary intervention (PCI) between January 2008 and October 2010. METHODS: HHR-PCI was a database that used a secure web-based interface for data entry by individual users. All PCI centers and operators were invited to participate. The participating PCI centers were geographically divided into three main regions: Athens Metro Area, Thessaloniki Metro Area, and Rest of Greece. Indications, demographics, procedural characteristics, and in-hospital outcomes (death, myocardial infarction, cerebrovascular accidents) were recorded. RESULTS: Eighteen (18) centers participated in the registry (2008-2010) in a systematic fashion, entering complete data for 3441 patients (males 83.1%, mean age 64.1 years, 5521 lesions). PCI was elective in 47.1% of patients and was used to treat an acute coronary syndrome in 52.5%. There were 742 (21.6%) patients treated for ST-segment elevation myocardial infarction, with 225 (30.3%) receiving primary PCI (mean door-to-balloon time 140 minutes). The mean numbers of stents per lesion and per patient were 1.14 and 1.74, respectively, with drug eluting stents being used in 74.2% of coronary lesions. Periprocedural complications were observed in 105 patients (3.1%), while the incidence of in-hospital death, myocardial infarction, and cerebrovascular event were 0.5%, 1%, and 0.6%, respectively. CONCLUSIONS: HHR-PCI was the first web-based national PCI registry in Greece and has provided useful insights regarding the practice of interventional cardiology in this country. Efforts should be made to maintain and extend this type of PCI registry, with a view to improving quality and outcomes research in the field of interventional cardiology.

Chest pain in patients with arterial hypertension, angiographically normal coronary arteries and stiff aorta: the aortic pain syndrome.

INTRODUCTION: Arterial hypertension is often associated with a stiff aorta as a result of collagen accumulation in the aortic wall and may produce chest pain. In the present study, possible interrelationships between aortic function, collagen turnover and exercise-induced chest pain in patients with arterial hypertension and angiographically normal coronary arteries were investigated. METHODS: Ninety-seven patients with arterial hypertension, angiographically normal coronary arteries and no evidence of myocardial ischemia on nuclear cardiac imaging during exercise test were studied. Of these, 43 developed chest pain during exercise (chest pain group) while 54 did not (no chest pain group). Carotid femoral pulse-wave velocity (PWVc-f) was used to assess the elastic properties of the aorta. Amino-terminal pro-peptides of pro-collagen type I, (PINP, reflecting collagen synthesis), serum telopeptides of collagen type I (CITP, reflecting collagen degradation), pro-metalloproteinase 1 (ProMMP-1), and tissue inhibitor of metalloproteinase 1 (TIMP-1, related to collagen turnover) were measured in plasma by immunoassay. RESULTS: The chest pain group had higher PWVc-f, higher and /CITP ratio, and lower proMMP-1/ TIMP-1 ratio compared to the no chest pain group. PWVc-f (t=2.53, p=0.02) and PINP (t=2.42, p=0.02) were independently associated with the presence of chest pain in multiple regression analysis. CONCLUSIONS: Patients with arterial hypertension, exercise-induced chest pain and angiographically normal coronary arteries, without evidence of exercise-induced myocardial ischemia, had a stiffer aorta compared to those without chest pain. Alterations in collagen type I turnover that favor collagen accumulation in the aortic wall may contribute to aortic stiffening and chest pain in these patients.

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.

Mechanisms of platelet activation in acute coronary syndromes.

Platelets are known to play a fundamental role in acute coronary syndromes. After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. Today there are promising results from recently developed antiplatelet agents. However, morbidity and mortality from acute coronary syndromes remain significant despite the administration of combination therapies (aspirin, thienopyridines). Sharing similar mechanisms, platelets may also form a thin monolayer in areas of damaged endothelium contributing to primary hemostasis. For this reason, administration of antiplatelet drugs is often associated with increased bleeding risk. As a result, currently available antiplatelet therapy cannot be characterized as optimal. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. The study of basic mechanisms of platelet adhesion, activation and aggregation after atherosclerotic plaque rupture may help to define new targets for their inhibition. In the future, newer antiplatelet agents may offer more comprehensive platelet inhibition without interfering with primary hemostasis, thus offering greater protection with lower hemorrhagic risk.