Publications by authors named "George Giannakoulas"

124 Publications

Haemodynamic effects of PAH-targeted therapies in pulmonary hypertension due to lung disease: A systematic review and meta-analysis.

Pulm Pharmacol Ther 2021 May 9:102036. Epub 2021 May 9.

Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece. Electronic address:

Background: Pulmonary hypertension (PH) is a negative predictor in patients with lung disease and/or hypoxia (group 3 PH). Current guidelines do not endorse the use of targeted therapies for pulmonary arterial hypertension (PAH) in patients with group 3 PH, due to lack of strong evidence. However, a variety of studies have examined the effect of PAH-targeted therapies in group 3 PH with mixed methods and conflicting results.

Objective: To evaluate the effect of PAH-targeted therapies on haemodynamic parameters as assessed by right heart catheterization in patients with group 3 PH.

Methods: Search strategy included PubMed and CENTRAL databases for randomized controlled trials from inception until 30 Jan 2020. We hand searched review articles, clinical trial registries and reference lists of retrieved articles. The primary outcome was the effect of PAH-targeted therapies on haemodynamic parameters [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and right atrial pressure (RAP)] in patients with group 3 PH, while secondary outcomes were 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) and quality of life (QoL).

Results: Five studies with a total of 140 patients were included. PAH-targeted therapies improved significantly mPAP [mean difference (MD) -4.02 mmHg, 95% CI -7.95;-0.09], and PVR [standardized mean difference (SMD) -0.29, 95% CI -0.50;-0.07], but not CI (SMD 0.23, 95% CI -0.23;0.70) or RAP (MD 0.26 mmHg, 95% CI -18.75;19.27). PAH-targeted therapies significantly increased the 6MWD by 38.5 metres (95% CI 17.6;59.4), while they did not manage to improve QoL (SMD -3.42, 95% CI -14.74;7.91) or BNP values. There was no effect of oxygenation by the PAH-targeted therapies compared to placebo.

Conclusion: PAH-targeted therapies slightly improved mPAP and PVR in group 3 PH, without affecting CI. Larger RCTs targeted in specific subpopulations are needed to extract more robust conclusions.

Protocol Registration: Open Science Framework doi 10.17605/OSF.IO/56FDW.
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http://dx.doi.org/10.1016/j.pupt.2021.102036DOI Listing
May 2021

Nailfold videocapillaroscopic changes in patients with pulmonary arterial hypertension associated with connective tissue diseases.

Rheumatol Int 2021 May 12. Epub 2021 May 12.

Fourth Department of Internal Medicine, Hippokration University Hospital, Medical School, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece.

Pulmonary arterial hypertension (PAH) represents one of the most devastating complications in connective tissue diseases (CTDs). The aim of this study was to investigate the presence of peripheral microangiopathy in patients with PAH associated with CTDs (CTD-PAH) by exploring nailfold videocapillaroscopic (NVC) changes and identify possible associations of NVC characteristics with markers of disease severity. Α cross-sectional study was performed in 18 CTD-PAH patients [13 PAH due to systemic sclerosis (SSc-PAH) and 5 with other types of CTD-PAH], 14 patients with SSc without PAH (SSc-non-PAH) and 20 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability, capillaroscopic images were reviewed by two independent investigators. When compared to healthy controls, patients with CTD-PAH (77.8% women, mean age 65.9 years) presented reduced capillary density (6.5 ± 1.6 loops/mm vs. 9.7 ± 0.7 loops/mm, p < 0.001) and increased capillary loop width (23.3 ± 10.1 μm vs. 11.2 ± 2.5 μm, p < 0.001). SSc-PAH patients presented lower capillary density in comparison with other CTD-PAH patients and SSc-non-PAH subjects and abnormal and disorganized capillaries compared to controls. Patients with other CTD-PAH had also reduced capillary density and increased loop diameter compared to controls. A significant linear correlation was identified between capillary density and estimated glomerular filtration rate in the total CTD-PAH population (r = 0.63, p = 0.007). In SSc-PAH group, capillary loop diameter was positively correlated to cardiac index (r = 0.61, p = 0.02). Significant NVC microvascular changes were detected in patients with various types of CTD-PAH, suggesting an impaired peripheral microcirculation parallel to pulmonary vasculopathy.
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http://dx.doi.org/10.1007/s00296-021-04839-xDOI Listing
May 2021

Micro-CT-Based Quantification of Extracted Thrombus Burden Characteristics and Association With Angiographic Outcomes in Patients With ST-Elevation Myocardial Infarction: The QUEST-STEMI Study.

Front Cardiovasc Med 2021 21;8:646064. Epub 2021 Apr 21.

First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Angiographic detection of thrombus in STEMI is associated with adverse outcomes. However, routine thrombus aspiration failed to demonstrate the anticipated benefit. Hence, management of high coronary thrombus burden remains challenging. We sought to assess for the first time extracted thrombotic material characteristics utilizing micro-computed tomography (micro-CT). One hundred thirteen STEMI patients undergoing thrombus aspiration were enrolled. Micro-CT was undertaken to quantify retrieved thrombus volume, surface, and density. Correlation of these indices with angiographic and electrocardiographic outcomes was performed. Mean aspirated thrombus volume, surface, and density (±standard deviation) were 15.71 ± 20.10 mm, 302.89 ± 692.54 mm, and 3139.04 ± 901.88 Hounsfield units, respectively. Aspirated volume and surface were significantly higher ( < 0.001) in patients with higher angiographic thrombus burden. After multivariable analysis, independent predictors for thrombus volume were reference vessel diameter (RVD) ( = 0.011), right coronary artery (RCA) ( = 0.039), and smoking ( = 0.027), whereas RVD ( = 0.018) and RCA ( = 0.019) were predictive for thrombus surface. Thrombus volume and surface were independently associated with distal embolization ( = 0.007 and = 0.028, respectively), no-reflow phenomenon ( = 0.002 and = 0.006, respectively), and angiographically evident residual thrombus ( = 0.007 and = 0.002, respectively). Higher thrombus density was correlated with worse pre-procedural TIMI flow ( < 0.001). Patients with higher aspirated volume and surface developed less ST resolution ( = 0.042 and = 0.023, respectively). Angiographic outcomes linked with worse prognosis were more frequent among patients with larger extracted thrombus. Despite retrieving larger thrombus load in these patients, current thrombectomy devices fail to deal with thrombotic material adequately. Further studies of novel thrombus aspiration technologies are warranted to improve patient outcomes. QUEST-STEMI trial ClinicalTrials.gov number: NCT03429608 Date of registration: February 12, 2018. The study was prospectively registered.
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http://dx.doi.org/10.3389/fcvm.2021.646064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096895PMC
April 2021

Effects of Major Antihypertensive Drug Classes on Erectile Function: a Network Meta-analysis.

Cardiovasc Drugs Ther 2021 May 4. Epub 2021 May 4.

Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Purpose: To determine the effect of major antihypertensive classes on erectile function (EF) in patients with or at high risk of cardiovascular disease.

Methods: We performed a systematic review and frequentist network meta-analysis of randomized controlled trials assessing the effect of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and thiazide diuretics on EF compared to each other and to placebo (PROSPERO: CRD42020189529). Similarly, we performed a network meta-analysis to explore the effect of different β-blockers on erectile function (nebivolol, other vasodilating and non-vasodilating β-blockers, placebo). Records were identified through search of PubMed, Cochrane Library, and Scopus databases and sources of grey literature until September 2020.

Results: We included 25 studies (7784 patients) in the qualitative and 16 studies in the quantitative synthesis. The risk of bias was concerning or high in the majority of studies, and inconsistency was also high. No significant differences in EF were demonstrated in the pairwise comparisons between major antihypertensive classes. Similarly, when placebo was set as the reference treatment group, no treatment strategy yielded significant effects on EF. In the β-blockers analysis, nebivolol contributed a beneficial effect on EF only when compared to non-vasodilatory β-blockers (OR 2.92, 95%CI 1.3-6.5) and not when compared to placebo (OR 2.87, 95%CI 0.75-11.04) or to other vasodilatory β-blockers (OR 2.15, 95%CI 0.6-7.77).

Conclusion: All antihypertensive medication classes seem to exert neutral or insignificant effects on EF. Further high-quality studies are needed to better explore the effects of antihypertensive medication on EF.
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http://dx.doi.org/10.1007/s10557-021-07197-9DOI Listing
May 2021

Angiotensin receptor-neprilysin inhibition in patients with acute decompensated heart failure: an expert consensus position paper.

Heart Fail Rev 2021 May 1. Epub 2021 May 1.

Department of Clinical Therapeutics, Catheterization Laboratory, University of Athens, Athens, Greece.

The short-term mortality and rehospitalization rates after admission for acute heart failure (AHF) remain high, despite the high level of adherence to contemporary practice guidelines. Observational data from non-randomized studies in AHF strongly support the in-hospital administration of oral evidence-based modifying chronic heart failure (HF) medications (i.e., b-blockers, ACE inhibitors, mineralocorticoid receptor antagonists) to reduce morbidity and mortality. Interestingly, a well-designed prospective randomized multicenter study (PIONEER-HF) showed an improved clinical outcome and stress/injury biomarker profile after in-hospital administration of sacubitril/valsartan (sac/val) as compared to enalapril, in hemodynamically stable patients with AHF. However, sac/val implementation during hospitalization remains suboptimal due to the lack of an integrated individualized plan or well-defined appropriateness criteria for transition to oral therapies, an absence of specific guidelines regarding dose selection and the up-titration process, and uncertainty regarding patient eligibility.In the present expert consensus position paper, clinical practical recommendations are proposed, together with an action plan algorithm, to encourage and facilitate sac/val administration during hospitalization after an AHF episode with the aim of improving efficiencies of care and resource utilization.
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http://dx.doi.org/10.1007/s10741-021-10115-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087533PMC
May 2021

Chronic hypertension in pregnancy: synthesis of influential guidelines.

J Perinat Med 2021 Apr 19. Epub 2021 Apr 19.

Third Department of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Chronic hypertension in pregnancy accounts for a substantial proportion of maternal morbidity and mortality and is associated with adverse perinatal outcomes, most of which can be mitigated by appropriate surveillance and management protocols. The aim of this study was to review and compare recommendations of published guidelines on this condition. Thus, a descriptive review of influential guidelines from the National Institute for Health and Care Excellence, the Society of Obstetric Medicine of Australia and New Zealand, the International Society of Hypertension, the International Society for the Study of Hypertension in Pregnancy, the European Society of Cardiology, the International Federation of Gynecology and Obstetrics, the Society of Obstetricians and Gynaecologists of Canada and the American College of Obstetricians and Gynecologists on chronic hypertension in pregnancy was conducted. All guidelines agree on the definition and medical management, the need for more frequent antenatal care and fetal surveillance and the re-evaluation at 6-8 weeks postpartum. There is also a consensus that the administration of low-dose aspirin is required to prevent preeclampsia, although the optimal dosage remains controversial. No universal agreement has been spotted regarding optimal treatment blood pressure (BP) targets, need for treating mild-to-moderate hypertension and postnatal BP measurements. Additionally, while the necessity of antenatal corticosteroids and magnesium sulfate for preterm delivery is universally recommended, the appropriate timing of delivery is not clearly outlined. Hence, there is a need to adopt consistent practice protocols to optimally manage these pregnancies; i.e. timely detect and treat any potential complications and subsequently reduce the associated morbidity and mortality.
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http://dx.doi.org/10.1515/jpm-2021-0015DOI Listing
April 2021

Repeat Coronary Artery Bypass Grafting: A Meta-Analysis of Off-Pump versus On-Pump Techniques in a Large Cohort of Patients.

Heart Lung Circ 2021 Mar 30. Epub 2021 Mar 30.

Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York Presbyterian, New York, NY, USA.

Background: Redo coronary artery bypass grafting (CABG) can be performed with either the off-pump (OPCAB) or the on-pump (ONCAB) technique.

Method: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this meta-analysis compared the safety and efficacy of OPCAB versus ONCAB redo CABG.

Results: Twenty-three (23) eligible studies were included (OPCAB, n=2,085; ONCAB, n=3,245). Off-pump CABG significantly reduced the risk of perioperative death (defined as in-hospital or 30-day death rate), myocardial infarction, atrial fibrillation, and acute kidney injury. The two treatment approaches were comparable regarding 30-day stroke and late all-cause mortality.

Conclusions: Off-pump redo CABG resulted in lower perioperative death and periprocedural complication rates. No difference was observed in perioperative stroke rates and long-term survival between the two techniques.
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http://dx.doi.org/10.1016/j.hlc.2021.02.015DOI Listing
March 2021

COVID-19 in Adults With Congenital Heart Disease.

J Am Coll Cardiol 2021 04;77(13):1644-1655

Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA.

Background: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications.

Objectives: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes.

Methods: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined.

Results: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not.

Conclusions: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.
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http://dx.doi.org/10.1016/j.jacc.2021.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006800PMC
April 2021

Reinforcing adherence to lipid-lowering therapy after an acute coronary syndrome: A pragmatic randomized controlled trial.

Atherosclerosis 2021 Apr 17;323:37-43. Epub 2021 Mar 17.

1st Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address:

Background And Aims: Achieving the low-density lipoprotein cholesterol (LDL-C) goal following an acute coronary syndrome (ACS) is a milestone often missed due to suboptimal adherence to secondary prevention treatments. Whether improved adherence could result in reduced LDL-C levels is unclear. We aimed to evaluate whether an educational-motivational intervention increases long-term lipid-lowering therapy (LLT) adherence and LDL-C goal attainment rate among post-ACS patients.

Methods: IDEAL-LDL was a parallel, two-arm, single-center, pragmatic, investigator-initiated randomized controlled trial. Hospitalized patients for ACS were randomized to a physician-led integrated intervention consisting of an educational session at baseline, followed by regular motivational interviewing phone sessions or usual care. Co-primary outcomes were the LLT adherence (measured by Proportion of Days Covered (PDC); good adherence defined as PDC>80%), and LDL-C goal (<70 mg/dl or 50% reduction from baseline) achievement rate at one year.

Results: In total, 360 patients (mean age 62 years, 81% male) were randomized. Overall, good adherence was positively associated with LDL-C goal achievement rate at one year. Median PDC was higher in the intervention group than the control group [0.92 (IQR, 0.82-1.00) vs. 0.86 (0.62-0.98); p = 0.03] while the intervention group had increased odds of good adherence (odds ratio: 1.76 (95% confidence interval 1.02 to 2.62; p = 0.04). However, neither the LDL-C goal achievement rate (49.6% in the intervention vs. 44.9% in the control group; p = 0.49) nor clinical outcomes differed significantly between the two groups.

Conclusions: Α multifaceted intervention improved LLT adherence in post-ACS patients without a significant difference in LDL-C goal attainment.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.013DOI Listing
April 2021

Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: A Milestone Achieved.

Hypertension 2021 May 29;77(5):1442-1455. Epub 2021 Mar 29.

Second Propaedeutic Department of Internal Medicine (M.D.), Aristotle University of Thessaloniki, Greece.

Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17005DOI Listing
May 2021

Peripheral microangiopathy in Eisenmenger syndrome: A nailfold video capillaroscopy study.

Int J Cardiol 2021 Mar 16. Epub 2021 Mar 16.

Fourth Department of Internal Medicine, Hippokration University Hospital, Medical School, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 54642 Thessaloniki, Greece.

Background: Eisenmenger syndrome (ES) comprises a severe phenotype of pulmonary arterial hypertension characterized by angiopathy of the lung circulation. The aim of the present study was to demonstrate the presence of systemic microvascular abnormalities in patients with ES using nailfold video-capillaroscopy (NVC) and to identify potential correlations of nailfold capillaroscopic characteristics with non-invasive markers of systemic organ function.

Methods: Α cross-sectional NVC study was performed in 17 consecutive patients with ES and 17 healthy controls matched for age and sex. NVC quantitative (capillary density, capillary dimensions, haemorrhages, thrombi, shape abnormalities) and qualitative (normal, non-specific or scleroderma pattern) parameters were evaluated.

Results: Patients with ES [median age 40 (18-65) years, 11 women] presented reduced capillary density [8.8 (7.2-10.2) loops/mm vs. 9.9 (8.3-10.9) loops/mm, p = .004] and increased loop width [15.9 (10.3-21.7) μm vs. 12.3 (7.6-15.2) μm, p < .001], while they had significantly more abnormal capillaries than healthy controls [2.5 (0.9-5.4) abnormal loops/mm vs. 1.0 (0.0-1.7) abnormal loops/mm, p < .001]. NVC shape abnormalities in ES were positively correlated with NT-proBNP (r = 0.52, p = .03) and were negatively associated with estimated glomerular filtration rate (r = -0.60, p = .02). Additionally, capillary loop diameter was positively correlated with increased haemoglobin levels (r = 0.55, p = .03) and negatively correlated with reduced peripheral oxygen saturation (r = - 0.56, p = .02).

Conclusions: This study supports the hypothesis of peripheral microvascular involvement in ES parallel to pulmonary microangiopathy detected by NVC. Further longitudinal studies are needed to confirm our preliminary results.
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http://dx.doi.org/10.1016/j.ijcard.2021.03.033DOI Listing
March 2021

Long-Term Effect of an Exercise Training Program on Physical Functioning and Quality of Life in Pulmonary Hypertension: A Randomized Controlled Trial.

Biomed Res Int 2021 26;2021:8870615. Epub 2021 Feb 26.

Laboratory of Sports Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

The aim of this study was to evaluate the effects of a 6-month combined aerobic and strength exercise training program on functional and psychological aspects and health-related quality of life in patients with PH and to evaluate its longer-term impact. In total, 22 stable patients (mean age 53.9 ± 13.8, 13 female) with pulmonary hypertension of World Health Organization (WHO) class I-III participated in a nine-month study. They were randomly assigned into two groups: Group A participated in a 6-month combined aerobic and strength exercise training program, whereas Group B remained untrained. All patients underwent physical and psychological assessment at baseline and at month 6 (after completing the exercise program) and physical assessment after 9 months (3 months posttraining). After the 6-month exercise training program, patients of Group A significantly improved their physical (6MWD, STS 10 rep, STS 20 rep, TUG, lower limb strength, cardiopulmonary exercise time, METs, peak VO, VCO, and VE/VCO slope) and psychological aspects (SF-36, STAI, and BDI). Between the two groups, differences were observed at the 6MWD (95% CI: 36.2-64.6, = 0.72), STS 10 rep (95% CI: 6.6-2.2, = 0.4), STS 20 rep (95% CI: 10.8-2.4, = 0.34), lower limb strength (95% CI: 7.2-3.6, = 0.38), cardiopulmonary exercise time (95% CI: 0.1-3.3, = 0.2), and VCO (95% CI: 0.1-0.5, = 0.2). Additionally, psychological changes were noted at SF-36, PCS (95% CI: 3.6-14.8, = 0.35), MCS (95% CI: 1.3-16.1, = 0.22), TCS (95% CI: 1.3-16.1, = 0.22), and STAI (95% CI: 1.8-28.2, = 0.18). The favorable results of exercise were maintained at the 3-month posttraining follow-up assessment. No exercise-induced complications were observed throughout the study. In conclusion, a long-term exercise training program is a safe and effective intervention to improve functional status, psychological aspects, and health-related quality of life in patients with PH.
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http://dx.doi.org/10.1155/2021/8870615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936903PMC
February 2021

5-Fluorouracil, capecitabine and vasospasm: a scoping review of pathogenesis, management options and future research considerations.

Acta Cardiol 2021 Mar 8:1-13. Epub 2021 Mar 8.

Third Department of Cardiology, Ιppokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: 5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that can cause cardiotoxicity manifesting, among others, as chest pain. Capecitabine is an oral prodrug of 5-FU, with reported preferential activation in malignant cells that may also cause cardiotoxic reactions. Standard treatment of 5-FU and capecitabine induced chest pain with vasodilators is mostly effective, but there are several cases of patients unresponsive to these agents.

Methods: We performed a PubMed search on 31st May 2020. We used a three keyword search strategy using Boolean search operators. More specifically, we included fluorouracil or 5-FU or capecitabine and chest pain or angina and mechanism or treatment or management. We included primary reports of clinical and non-clinical data, as well as systematic reviews. Narrative reviews, expert opinions, letters to the editor and other forms of non-primary literature were excluded.

Results: Our search yielded a total of 1595 reports. Of these, 1460 were narrative reviews or irrelevant to the topic and were excluded. A total of 135 reports were used for our review. We used 81 reports for data extraction, which included 13 clinical trials, 4 retrospective reports, 61 case reports, and 3 systematic reviews.

Conclusion: We report the incidence and predisposing factors, the value of available diagnostic procedures, and standard medical and invasive treatments. We also speculate on the potential benefit of arginine as a promising option both in prevention as well as treatment of 5-FU-induced chest pain. Finally, gaps of evidence are identified and proposals are made in terms of future research.
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http://dx.doi.org/10.1080/00015385.2021.1873548DOI Listing
March 2021

Sarcopenia in heart failure: 'waste' the appropriate time and resources, not the muscles.

Eur J Prev Cardiol 2020 Dec 22. Epub 2020 Dec 22.

Division of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

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http://dx.doi.org/10.1093/eurjpc/zwaa139DOI Listing
December 2020

Prognostic significance of diabetes mellitus in patients with atrial fibrillation.

Cardiovasc Diabetol 2021 Feb 11;20(1):40. Epub 2021 Feb 11.

First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece.

Background: There are limited data on the association of diabetes mellitus (DM) and levels of glycated hemoglobin (HbA1c) with outcomes in patients with atrial fibrillation (AF).

Methods: This retrospective cohort study included patients who were recently hospitalized with a primary or secondary diagnosis of AF from December 2015 through June 2018. Kaplan-Meier curves and Cox-regression adjusted hazard ratios (aHR) were calculated for the primary outcome of all-cause mortality and for the secondary outcomes of cardiovascular (CV) mortality and the composite outcome of CV death or hospitalization. Competing-risk regression analyses were performed to calculate the cumulative risk of stroke, major bleeding, AF- or HF-hospitalizations adjusted for the competing risk of all-cause death. Spline curve models were fitted to investigate associations of HbA1c values and mortality among patients with AF and DM.

Results: In total 1109 AF patients were included, of whom 373 (33.6%) had DM. During a median follow-up of 2.6 years, 414 (37.3%) patients died. The presence of DM was associated with a higher risk of all-cause mortality (aHR = 1.40 95% confidence intervals [CI] 1.11-1.75), CV mortality (aHR = 1.39, 95% CI 1.07-1.81), sudden cardiac death (aHR = 1.73, 95% CI 1.19-2.52), stroke (aHR = 1.87, 95% CI 1.01-3.45) and the composite outcome of hospitalization or CV death (aHR = 1.27, 95% CI 1.06-1.53). In AF patients with comorbid DM, the spline curves showed a positive linear association between HbA1c levels and outcomes, with values 7.6-8.2% being independent predictors of increased all-cause mortality, and values < 6.2% predicting significantly decreased all-cause and CV mortality.

Conclusions: The presence of DM on top of AF was associated with substantially increased risk for all-cause or CV mortality, sudden cardiac death and excess morbidity. HbA1c levels lower than 6.2% were independently related to better survival rates suggesting that optimal DM control could be associated with better clinical outcomes in AF patients with DM.
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http://dx.doi.org/10.1186/s12933-021-01232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879654PMC
February 2021

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

Respir Med 2021 03 12;178:106220. Epub 2020 Nov 12.

Bayer AG, Global Development, Global Medical Affairs, Berlin, Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.

Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]).

Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.
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http://dx.doi.org/10.1016/j.rmed.2020.106220DOI Listing
March 2021

Prediction of long-term survival in patients with transfusion-dependent hemoglobinopathies: Insights from cardiac imaging and ferritin.

Hellenic J Cardiol 2021 Jan 29. Epub 2021 Jan 29.

1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

Aims: The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients.

Methods: Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected.

Results: In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively).

Conclusions: In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.
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http://dx.doi.org/10.1016/j.hjc.2021.01.010DOI Listing
January 2021

A novel prognostic tool to predict mortality in patients with atrial fibrillation: The BASIC-AF risk score.

Hellenic J Cardiol 2021 Jan 29. Epub 2021 Jan 29.

1st Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; Interbalkan European Medical Center, Asklipiou 10, Pylaia, Thessaloniki, Greece. Electronic address:

Background: This study sought to develop and validate a risk score to predict mortality in patients with atrial fibrillation (AF) after a hospitalization for cardiac reasons.

Methods: The new risk score was derived from a prospective cohort of hospitalized patients with concurrent AF. The outcome measures were all-cause and cardiovascular mortality. Random forest was used for variable selection. A risk points model with predictor variables was developed by weighted Cox regression coefficients and was internally validated by bootstrapping.

Results: In total, 1130 patients with AF were included. During a median follow-up of 2 years, 346 (30.6%) patients died and 250 patients had a cardiovascular cause of death. N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin-T were the most important predictors of mortality, followed by indexed left atrial volume, history and type of heart failure, age, history of diabetes mellitus, and intraventricular conduction delay, all forming the BASIC-AF risk score (Biomarkers, Age, ultraSound, Intraventricular conduction delay, and Clinical history). The score had good discrimination for all-cause (c-index = 0.85 and 95% CI 0.82-0.88) and cardiovascular death (c-index = 0.84 and 95% CI 0.81-0.87). The predicted probability of mortality varied more than 50-fold across deciles and adjusted well to observed mortality rates. A decision curve analysis revealed a significant net benefit of using the BASIC-AF risk score to predict the risk of death, when compared with other existing risk schemes.

Conclusions: We developed and internally validated a well-performing novel risk score for predicting death in patients with AF. The BASIC-AF risk score included routinely assessed parameters, selected through machine-learning algorithms, and may assist in tailored risk stratification and management of these patients.
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http://dx.doi.org/10.1016/j.hjc.2021.01.007DOI Listing
January 2021

Peripheral microangiopathy in precapillary pulmonary hypertension: a nailfold video capillaroscopy prospective study.

Respir Res 2021 Jan 21;22(1):27. Epub 2021 Jan 21.

Fourth Department of Internal Medicine, Hippokration University Hospital, Medical School, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 54642, Thessaloniki, Greece.

Background: Although pulmonary vascular bed has been the main subject of research for many years in pulmonary hypertension (PH), interest has recently started to divert towards the possibility of a co-existing peripheral microangiopathy. The aim of the current study was to investigate the presence of nailfold video-capillaroscopic (NVC) structural changes in patients with precapillary PH and to identify possible associations of NVC measurements with markers of disease severity.

Methods: Α prospective case-control study was performed in 28 consecutive patients with precapillary PH [14 with idiopathic pulmonary arterial hypertension (IPAH) and 14 with chronic thromboembolic pulmonary hypertension (CTEPH)] and 30 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability capillaroscopic images were reviewed by two independent investigators. For multiple comparisons among continuous variables, one-way ANOVA or the Kruskal-Wallis test were used. Differences between the groups were tested with post-hoc analysis with adjustment for multiple comparisons (Bonferroni test).

Results: Both IPAH (71.4% were women, mean age 53.1 ± 13.4 years) and CTEPH (64.3% women, mean age 60.9 ± 14.4 years) groups presented reduced capillary density compared to healthy controls (8.4 ± 1.2 loops/mm and 8.0 ± 1.2 loops/mm vs. 9.7 ± 0.81 loops/mm, p < 0.001) and increased loop width (15.7 ± 3.9 μm and 15.8 ± 1.9 μm vs. 11.5 ± 2.3 μm, p < 0.001). More than half of patients with IPAH presented microhaemorrhages on capillary nailfold, while increased shape abnormalities in capillary morphology and more capillary thrombi per linear mm were detected in patients with CTEPH compared to patients with IPAH and healthy controls. All PH patients presented a non-specific NVC pattern compared to controls (p < 0.001).

Conclusion: The findings of the study reveal a degree of significant peripheral microvascular alterations in patients with IPAH and CTEPH, suggesting a generalized impairment of peripheral microvasculature in pulmonary vascular disease.
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http://dx.doi.org/10.1186/s12931-021-01622-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819216PMC
January 2021

Cardio-protective Effects of Glucagon-like Peptide-1 Receptor Agonists: An Overview of Systematic Reviews and Publication Overlap.

Curr Pharm Des 2021 ;27(8):1068-1079

1st Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a new antihyperglycemic class with the demonstrated advantage of reducing major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM), atherosclerotic cardiovascular disease, or high cardiovascular risk.

Objective: Τo summarize the evidence of systematic reviews (SRs) that assess MACE (cardiovascular mortality, nonfatal myocardial infarction, and stroke) and hospitalizations for heart failure in GLP-1RAs-treated patients and to evaluate possible overlap in pertinent SRs.

Methods: We performed a comprehensive search via MEDLINE, Cochrane Library, and PROSPERO databases up to February 23, 2020, for SRs examining cardiovascular outcomes of GLP-1RAs in T2DM patients. Three independent authors extracted data and assessed the methodological quality of the included SRs using the ROBIS tool.

Results: We found 37 SRs - published between 2009 and 2020 in English - of which 35 collected data only from randomized clinical trials while two from observational studies as well. The methodological quality of the 37 SRs ranged from low to high, while only 3 have evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach. All the included SRs showed cardiovascular safety of GLP-1RAs while the latest ones demonstrated a reduction in composite MACE endpoint as well as its every individual component and heart failure hospitalizations.

Conclusion: In the first overview of SRs about cardiovascular outcomes of GLP-1RAs, they proved favorable effects on reducing cardiovascular events in T2DM patients. There are, however, many overlapping reviews based on relatively few cardiovascular outcomes trials.
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http://dx.doi.org/10.2174/1381612827666210119103153DOI Listing
January 2021

Prediction Models and Scores in Adult Congenital Heart Disease.

Curr Pharm Des 2021 Jan 11. Epub 2021 Jan 11.

National Heart and Lung Institute, Imperial College London,. United Kingdom.

Nowadays, most patients with congenital heart disease survive to adulthood, thanks to advances in pediatric cardiac surgery, but often present with various comorbidities and long-term complications, posing challenges in their management. The development and clinical use of risk scores for the prediction of morbidity and/or mortality in adults with congenital heart disease (ACHD) is fundamental in achieving optimal management for these patients, including appropriate follow-up frequency, treatment escalation and timely referral for invasive procedures or heart transplantation. In comparison with other fields of cardiovascular medicine, there are relatively few studies that report prediction models developed in the ACHD population, given the small sample size, heterogeneity of the population and relatively low event rate. Some studies report risk scores originally developed in pediatric congenital or non-congenital population, externally validated in ACHD with variable success. Available risk scores are designed to predict heart failure or arrhythmic events, all-cause mortality, post-intervention outcomes, infective endocarditis or atherosclerosis-related cardiovascular disease in ACHD. A substantial number of these scores are derived from retrospective studies and are not internally or externally validated. Adequately validated risk scores can be invaluable in clinical practice and an important step towards personalized medicine. Multicenter collaboration, adequate study design and the potential use of artificial intelligence are important elements in the effort to develop reliable risk scores for the ACHD population.
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http://dx.doi.org/10.2174/1381612827999210111181554DOI Listing
January 2021

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

Respir Med 2020 Dec 3;177:106241. Epub 2020 Dec 3.

Bayer AG, Global Development, Global Medical Affairs, Berlin, Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms.

Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years.

Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.
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http://dx.doi.org/10.1016/j.rmed.2020.106241DOI Listing
December 2020

Atrial conduction time associated predictors of recurrent atrial fibrillation.

Int J Cardiovasc Imaging 2021 Apr 3;37(4):1267-1277. Epub 2021 Jan 3.

First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi str 1, 54636, Thessaloniki, Greece.

Identifying patients at high risk of atrial fibrillation (AF) recurrence remains challenging. This study aimed to evaluate total atrial conduction time (TACT) and left atrial (LA) asynchrony as predictors of AF recurrence. Consecutive patients after the first AF episode, terminated either spontaneously or with cardioversion, underwent transthoracic echocardiography. TACT, estimated by the time delay between the onset of P-wave and the peak A'-wave on the Tissue Doppler Imaging (PA-TDI duration), atrial volumetric and functional parameters, and biatrial strain were assessed. We calculated mean PA-TDI-the average of PA-TDI measurements in all left atrial (LA) walls-and the difference between the longest and the shortest PA interval (DLS) and the standard deviation of 4 PA intervals (SD4) to assess the LA global remodeling and asynchrony, respectively. The primary endpoint was AF recurrence. Patients with recurrent AF had significantly prolonged PA-TDI intervals in each LA wall-and thus mean PA-TDI-than those without recurrence (mean PA-TDI: 157.4 ± 17.9 vs. 110.2 ± 7.7 ms, p < 0.001). At univariate analysis, LA maximum volume index, total LA emptying fraction, right atrial maximum volume index, PA-TDI, DLS, and SD4 were predictors of AF recurrence. At multivariable analysis, PA-TDI intervals in all LA walls remained strong predictors with mean PA-TDI (odds ratio 1.04; 95% confidence interval 1.03-1.06) having an optimal cutoff of 125.8 ms in receiver operator characteristics curve analysis providing 98% sensitivity and 100% specificity for AF recurrence (area under the curve = 0.989). PA-TDI was an independent predictor of AF recurrence and outperformed established echocardiographic parameters.
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http://dx.doi.org/10.1007/s10554-020-02113-yDOI Listing
April 2021

Left Atrial Strain Identifies Increased Atrial Ectopy in Patients with Beta-Thalassemia Major.

Diagnostics (Basel) 2020 Dec 22;11(1). Epub 2020 Dec 22.

1st Cardiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, Stilponos Kyriakidi 1, 54621 Thessaloniki, Greece.

Patients with beta-thalassemia major (β-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in β-ΤΜ patients. This prospective study included consecutive β-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 β-TM patients (37.6 ± 9.1 years old, 50% male) were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years, < 0.007), compared to their counterparts. Older age (OR: 1.121, 95% CI: 1.032-1.217, = 0.007), longer duration of blood transfusion (OR:1.101, 95% CI:1.019-1.188, = 0.014), larger LV end-diastolic diameter (OR: 4.522, 95% CI:1.009-20.280, = 0.049), higher values of LA peak systolic strain (OR: 0.869, 95% CI: 0.783-0.964, = 0.008), higher MV E/E' average (OR: 1.407, 95% CI: 1.028-1.926, = 0.033) and higher right ventricular systolic pressure (OR: 1.147, 95% CI: 1.039-1.266, = 0.006) were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value (83% sensitivity, 68% specificity) for prediction of PACs > 24/day. In β-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.
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http://dx.doi.org/10.3390/diagnostics11010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822012PMC
December 2020

Lipoprotein(a) Reduction With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic Review and Meta-analysis.

J Cardiovasc Pharmacol 2021 Mar;77(3):397-407

Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Abstract: Lipoprotein(a) [Lp(a)] is a cardiovascular factor, for which there is no approved specific lowering treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to have lowering effects on Lp(a). Aim of this systematic review is to synthesize the current literature and quantify the effects of PCSK9 inhibitors on the serum Lp(a) levels in human subjects. Double-blind, phase 2 or 3, randomized-controlled trials comparing PCSK9 inhibitors (alirocumab or evolocumab) to placebo and/or ezetimibe and/or other lipid-lowering therapy were deemed eligible for inclusion. We searched MEDLINE (via PubMed), CENTRAL, Scopus, and Web of Science as of 17 June 2020. Quality assessment was performed using the Revised Cochrane risk-of-bias tool for randomized trials. Forty-three studies were identified (64,107 patients randomized) and 41 studies were included in the quantitative analysis. PCSK9 inhibitors reduced Lp(a) levels by -26.7% (95% CI, -29.5% to -23.9%) with a significant heterogeneity within studies. There was significant difference in Lp(a) change from baseline according to comparator (placebo: mean -27.9%; 95% CI, -31.1% to -24.6% vs. ezetimibe: mean, -22.2%; 95% CI, -27.2% to -17.2%; P = 0.04) and duration of treatment (≤12 weeks: mean, -30.9%; 95% CI, -34.7% to -27.1% vs. >12 weeks: mean, -21.9%; 95% CI, -25.2% to -18.6%; P < 0.01). Meta-regression analysis showed that only the mean percentage change from baseline low-density lipoprotein cholesterol due to the intervention is significantly associated with the effect size difference (P < 0.0001). PCSK9 inhibitors reduced low-density lipoprotein cholesterol by -54% (95% CI -57.6% to -50.6%). There is substantial efficacy of the currently approved PCSK9 inhibitors in the lowering of Lp(a) levels. Dedicated randomized controlled trials are needed to establish the benefit of this intervention.
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http://dx.doi.org/10.1097/FJC.0000000000000963DOI Listing
March 2021

Venous thromboembolism in the era of COVID-19.

Phlebology 2021 Mar 10;36(2):91-99. Epub 2020 Sep 10.

Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, USA.

Coronavirus disease 2019 (COVID-19) does not only affect the respiratory system but appears to be a systemic disease. Venous thromboembolism is a common manifestation in hospitalized patients with COVID-19 with a reported incidence that is significantly higher compared to other acute viral infections. The pathophysiology mechanisms have not been fully explored and autopsy studies might enhance our understanding on this topic. Microthrombi formation occurs mainly in the pulmonary vasculature but can also occur in other organs. The high inflammatory burden related to COVID-19 seems to be associated with the coexisting coagulopathy. Concomitant manifestations of COVID-19, such as severe pneumonia, which has similar clinical presentation with pulmonary embolism (PE), and barriers related to strict isolation protocols are the two main reasons why PE diagnosis might be more challenging in patients with COVID-19. Medical societies have published guidance reports suggesting the administration of prophylactic anticoagulant therapy in hospitalized patients with COVID-19, but several questions regarding the optimal acute and long-term treatment of these patients remain unanswered.
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http://dx.doi.org/10.1177/0268355520955083DOI Listing
March 2021

Association of anticoagulant-related bleeding events with cancer detection in atrial fibrillation: A systematic review and meta-analysis.

Hellenic J Cardiol 2020 Nov 24. Epub 2020 Nov 24.

First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece. Electronic address:

Background: A bleeding episode may herald cancer in the general population. Oral anticoagulants (OACs), the mainstay treatment for atrial fibrillation (AF), are known to increase the risk of bleeding, and may thus promote an earlier diagnosis of cancer. Data regarding the association of bleeding episodes with cancer in patients with AF on OACs are scarce.

Methods: In this systematic review and meta-analysis, we searched electronic databases (Medline, Scopus, and Central) and gray literature sources for studies of patients with nonvalvular AF under any OAC, from inception until 14 October 2020. The primary outcome was the association of bleeding occurrences with the detection of cancer. A subgroup analysis was performed according to OAC type [NOAC (non-vitamin K oral anticoagulant) versus VKA (vitamin K antagonist)].

Results: Overall, 4 studies were included, accounting for a total of 144,362 patients with AF receiving OAC. During follow-up, 816 (0.57%) cases of cancer were confirmed. The presence of a bleeding event, either major or minor, was associated with a higher risk for cancer detection (odds ratio [OR] 8.79, 95% confidence interval [CI] 4.98-15.51, and I 85%). Heterogeneity was explained after studies were stratified by the type of OAC (NOACs: OR 6.12, 95% CI 4.47-8.37, I 0%, VKAs: OR 15.16, 95% CI 12.61-18.23, and I 0%).

Conclusion: The detection of a bleeding event could be an alerting sign of cancer in patients with AF on OACs, particularly in patients receiving VKAs. REGISTRATION NUMBER (DOI): available in https://doi.org/10.17605/OSF.IO/3948R, DOI: 10.17605/OSF.IO/3948R.
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http://dx.doi.org/10.1016/j.hjc.2020.11.007DOI Listing
November 2020

Peripheral Microangiopathy in Patients with Precapillary Pulmonary Hypertension: Correlation with Cardiac Function and Patients' Functional Capacity. Study Design and Rationale.

Mediterr J Rheumatol 2020 Sep 10;31(3):369-373. Epub 2020 Jun 10.

Fourth Department of Internal Medicine, Hippokration University Hospital, Medical School, Aristotle University of Thessaloniki, Greece.

Pulmonary hypertension (PH) is a rare, heterogenous clinical entity characterised by a progressive remodelling of pulmonary arterioles, which leads to obstructive pulmonary arteriopathy, increased pulmonary vascular resistance, and eventually, right heart failure. Inflammation, endothelial dysfunction, and microvascular changes of the pulmonary vasculature constitute the hallmarks of pulmonary arterial hypertension (PAH), explaining much of the pathophysiology and clinical manifestations of the disease. Besides pulmonary vasculature, a systemic component of endothelial dysfunction and microcirculation may be involved in PAH, affecting different vascular beds. Nailfold videocapillaroscopy (NVC) is an established method for the assessment of the microvasculature with clinical implications in the diagnostic assessment of individuals with Raynaud syndrome and systemic sclerosis (SSc). Nowadays, growing amounts of evidence suggest that NVC changes in SSc are correlated with other vascular complications such as PAH, supporting a potential link between peripheral and internal organ vasculopathy. The purpose of the current prospective observational study is to explore: 1. the presence of peripheral microangiopathy in precapillary PH using NVC, 2. possible NVC differences among PH subgroups, 3. a potential relationship between NVC morphological abnormalities and clinical, functional, biochemical, echocardiographic and hemodynamic markers of cardiac dysfunction in precapillary PH.
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http://dx.doi.org/10.31138/mjr.31.3.369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641020PMC
September 2020

Rationale and design of a prospective, observational, multicentre study on the safety and efficacy of apixaban for the prevention of thromboembolism in adults with congenital heart disease and atrial arrhythmias: the PROTECT-AR study.

BMJ Open 2020 09 22;10(9):e038012. Epub 2020 Sep 22.

Cardiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece

Introduction: The risk for stroke in adults with congenital heart disease (ACHD) is increased, especially in the setting of commonly ensuing atrial arrhythmias (AA), namely atrial fibrillation, atrial flutter or intra-atrial re-entrant tachycardia. Data are limited regarding treatment with non-vitamin K oral anticoagulants in long-term studies involving patients with ACHD and AA.

Methods And Analysis: PReventiOn of ThromboEmbolism in Adults with Congenital HearΤ disease and Atrial aRrhythmias is a prospective, multicenter, single-arm, non-interventional cohort study designed to investigate the safety and efficacy of apixaban for the prevention of thromboembolism in ACHD with AA in a 'real-world' setting. Eligible patients will be evaluated by the means of available registries and clinical counter. The study aims to accumulate approximately 500 patient-years of exposure to apixaban as part of routine care. Enrolment will take place at four ACHD centres in Greece. The first patient was enrolled in July 2019. The primary efficacy endpoint is a composite of stroke, systemic or pulmonary embolism and intracardiac thrombosis. The primary safety endpoint is major bleeding, according to the International Society on Thrombosis and Haemostasis bleeding criteria.

Ethics And Dissemination: The study protocol has been approved by the institutional review board/independent ethics committee at each site prior to study commencement. All patients will provide written informed consent. Results will be disseminated at scientific meetings and published in peer-reviewed journals.

Trial Registration Number: NCT03854149; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-038012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509965PMC
September 2020

Hospitalizations in adult patients with congenital heart disease: an emerging challenge.

Heart Fail Rev 2021 Mar 10;26(2):347-353. Epub 2020 Sep 10.

Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kyriakidi str 1, 546 36, Thessaloniki, Greece.

The vast majority of patients with congenital heart disease (CHD) survive into adulthood, but many face lifelong complications, which often result in a hospital admission. The increasing number of hospitalizations in adults with CHD (ACHD) poses a significant challenge for healthcare systems globally, especially as heart failure (HF) is becoming increasingly common in this population and is the leading cause of morbidity and mortality. Besides HF, other major contributors to this increase in admission volume are hospitalizations related to mild lesions, comorbidities and pregnancies. Ιn-hospital mortality ranges between 0.8 and 6.1%, while hospitalizations related to HF predict medium-term mortality in ACHD population. Understanding the predictors of hospitalization and in-hospital mortality is, therefore, important for ACHD healthcare providers, who should identify patients at risk that require escalation of treatment and/or close monitoring. This article reviews the available literature on hospitalization patterns in ACHD patients, with a focus on HF-related hospital admissions and specific diagnostic subgroups.
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http://dx.doi.org/10.1007/s10741-020-10026-0DOI Listing
March 2021