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Wolfgang Hohenforst-Schmidt,1 Paul Zarogoulidis,2 Michael Steinheimer,1 Naim Benhassen,3 Chrysanthi Sardeli,4 Nikos Stalikas,2 Melpomeni Toitou,2 Haidong Huang5 1Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, “Hof” Clinics, University of Erlangen, Hof, Germany; 2Pulmonary Department – Oncology Unit, “G Papanikolaou” General Hospital, Thessaloniki, Greece; 3Medical Clinic I, “Fuerth” Hospital, University of Erlangen, Fuerth, Germany; 4Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Department of Respiratory and Critical Care Medicine, Changhai Hospital/First Affiliated Hospital of the Secondary Military Medical University, Shanghai, China Introduction: The majority of cases of lung cancer are still diagnosed at a late stage. At this stage, palliative therapeutic options including nonspecific cytotoxic drugs, targeted therapy, or immunotherapy can be utilized. In 2016, immunotherapy was approved in Europe for squamous cell carcinoma and adenocarcinoma. Moreover, afatinib was also approved as second-line therapy for squamous cell carcinoma. Case report: This article presents a case of a 76-year-old male with squamous cell carcinoma who received nab-paclitaxel as first-line therapy, and his treatment was switched to the tyrosine kinase inhibitor afatinib (40 mg) after disease progression with left lung atelectasis. After receiving afatinib for only 28 days, the atelectasis resolved. No adverse effects were observed from the afatinib therapy. Discussion: In this case, afatinib 40 mg proved to be an effective alternative treatment for an elderly patient. Treatment choice should be based on the performance status of the patient, cost-effectiveness, and drug treatment guidelines. Keywords: lung cancer, EGFR, afatinib

Background: Diastolic dysfunction (DD) is a long-established marker of disease progression in patients with aortic valve stenosis (AS), indicating valvular myocardial damage. Recently, substantial observational data have emerged demonstrating that worse pre-operative DD assessed using echocardiography is associated with adverse long-term clinical outcomes after transcatheter aortic valve replacement (TAVR)., Aim: To systematically appraise and quantitatively synthesize current evidence on the prognostic impact of echocardiographic severe DD derived by echocardiography before TAVR., Methods: A systemic literature review was undertaken in electronic databases to identify studies reporting the predictive value of severe DD in AS subjects undergoing TAVR. A random-effects meta-analysis was conducted to quantify the adjusted and unadjusted hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACEs) for the presence of severe DD., Results: Ten studies were deemed eligible for inclusion. Of those, 9 provided appropriate quantitative data for the meta-analysis, encompassing a total of 4,619 patients. The presence of severe DD was associated with increased risk for all-cause mortality (pooled unadjusted HR=2.56 [1.46-4.48]; p<0.01; I 2 =76 %) and MACEs (pooled unadjusted HR=1.82 [1.29-2.58]; p<0.01; I 2 =86 %). When adjusted for clinically-relevant parameters, the presence of severe DD retained independent association with all-cause mortality (pooled adjusted HR=2.35 [1.26-4.37]; p<0.01; I 2 =79 %) and MACEs (pooled adjusted HR= 2.52 [1.72-3.65]; p<0.01; I 2 =0 %). In subgroup analysis there was no difference on post-TAVR risk between the use of different diastolic function grading scores., Conclusion: Presence of severe DD assessed by echocardiography pre-TAVR is a major determinant of long-term adverse outcomes after the procedure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The present systematic review and meta-analysis aimed to investigate the prognostic value of stress hyperglycemia ratio (SHR) in patients with acute myocardial infarction (AMI). A total of 26 cohort studies, involving 87,974 patients, were analyzed. The frequentist meta-analysis showed that AMI patients with SHR in the upper quantile had a significantly higher hazard of major adverse cardiovascular and cerebrovascular events (MACCE, HR = 1.7; 95 % CI= [1.42, 2.03]; P < 0.001; I 2  = 71 %; P <0.01), long-term (HR = 1.64; 95 % CI= [1.49, 1.8]; P < 0.001; I 2  = 16 %; P = 0.29) and in-hospital all-cause mortality (OR = 3.87; 95 % CI= [2.98, 5.03]; P < 0.001; I 2  = 54 %; P = 0.03) compared to those with lower SHR. Prespecified subgroup analyses revealed that these results were consistent irrespective of diabetes status (P = 0.32 and 0.73 for subgroup differences) and that SHR was a significant predictor of MACCE both in AMI with obstructive coronary arteries (HR = 1.57; 95 % CI= [1.34, 1.83]; P < 0.001; I 2  = 66 %; P < 0.01) and MINOCA (HR = 2.57; 95 % CI= [1.86, 3.56]; P < 0.001; I 2  = 0 %; P = 0.84). The Bayesian analyses with weakly prior assumptions yielded comparable results with the frequentist approach and provided strong evidence that higher SHR values were associated with significantly greater hazard of MACCE, short-term and long-term mortality. Further, prospective research is warranted to provide deeper insights into this newer index of stress hyperglycemia before its potential incorporation in clinical prediction scores., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Right ventricular (RV) dysfunction after acute myocardial infarction (AMI) is a recognized predictor of dismal prognosis. However, the most reliable RV index to predict mortality early after revascularization remains undetermined. This study aimed to explore the ability of RV global longitudinal strain (GLS) to predict inhospital mortality in patients with first AMI. All consecutive patients with first AMI were prospectively enrolled from March 2022 until February 2023. An echocardiogram was performed 24 hours after successful revascularization and RV GLS alongside conventional echocardiographic indexes were measured. Inhospital mortality was recorded. A total of 300 patients (age 61.2 ± 11.8 years, 74% male) were included in the study. RV GLS was the only RV performance index that differed significantly between anterior and inferior ST-segment-elevation patients with AMI (14.5 ± 5.2% vs 17.4 ± 5.1% respectively, p <0.001). After revascularization, 23 patients (7.7%) died in hospital. The model of Global Registry of Acute Coronary Event risk score and left ventricular ejection fraction, built for predicting inhospital mortality, significantly improved its prognostic performance only by the addition of RV GLS (chi-square value increase by 7.485, p = 0.006) compared with the other RV function indexes. RV GLS was independently associated with inhospital mortality (odds ratio 0.83, 95% confidence interval 0.71 to 0.97, p = 0.017) after adjustment for Global Registry of Acute Coronary Event risk score and left ventricular ejection fraction. Echocardiographic RV GLS measured 24 hours after revascularization in patients with first AMI outperformed conventional RV function indexes in predicting inhospital mortality., Competing Interests: Declaration of Competing Interest Dr. Delgado received speaker fees from Edwards Lifesciences, Medtronic, Novartis, and Philips and consulting fees from Edwards Lifesciences and Novo Nordisk. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Acute myocardial infarction (AMI) remains a major cause of death worldwide. Survivors of AMI are particularly at high risk for additional cardiovascular events. Consequently, a comprehensive approach to secondary prevention is necessary to mitigate the occurrence of downstream complications. This may be achieved through a multiparametric tailored risk stratification by incorporating clinical, laboratory and echocardiographic parameters., Methods: The ''CLEAR-AMI Study'' (ClinicalTrials.gov Identifier: NCT05791916) is a non-interventional, prospective study including consecutive patients with AMI without a known history of coronary artery disease. All patients satisfying these inclusion criteria are enrolled in the present study. The rationale of this study is to refine risk stratification by using clinical, laboratory and novel echocardiographic biomarkers. All the patients undergo a comprehensive transthoracic echocardiographic assessment, including strain and myocardial work analysis of the left and right heart chambers, within 48 h of admission after coronary angiography. Their laboratory profile focusing on systemic inflammation is captured during the first 24 h upon admission, and their demographic characteristics, past medical history, and therapeutic management are recorded. The angioplasty details are documented, the non-culprit coronary lesions are archived, and the SYNTAX score is employed to evaluate the complexity of coronary artery disease. A 24-month follow-up period will be recorded for all patients recruited., Conclusion: The ''CLEAR-AMI" study is an ongoing prospective registry endeavoring to refine risk assessment in patients with AMI without a known history of coronary artery disease, by incorporating echocardiographic parameters, biochemical indices, and clinical and coronary characteristics in the acute phase of AMI.

Background: Stress induced hyperglycemia (SIH) is common among patients with ST-elevation myocardial infarction (STEMI), even in patients without diabetes mellitus. However, evidence regarding its role on the angiographic outcomes and the prognosis of patients presenting with STEMI is scarce., Methods: This study included 309 consecutively enrolled STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Patients were diagnosed with SIH if blood glucose on admission was > 140 mg/dl. Also, patients had to fast for at least 8 hours before blood sampling. The objective was to assess whether SIH was associated with major adverse cardiovascular and cerebrovascular (MACCE) events and explore its relationship with angiographic predictors of worse prognosis such as poor initial TIMI flow, intracoronary thrombus burden, distal embolization, and presence of residual thrombus after pPCI., Results: SIH in diabetic and non-diabetic patients was associated with a higher incidence of LTB (aOR = 2.171, 95% CI 1.27-3.71), distal embolization (aOR = 2.71, 95% CI 1.51-4.86), and pre-procedural TIMI flow grade = 0 (aOR = 2.69, 95% CI 1.43-5.04) after adjusting for relevant clinical variables. Importantly, during a median follow-up of 1.7 years STEMI patients with SIH with or without diabetes experienced increased occurrence of MACCE both in univariate (HR = 1.92, 95% CI 1.19-3.01) and multivariate analysis (aHR = 1.802, 95% CI 1.01-3.21)., Conclusions: SIH in STEMI patients with or without diabetes was independently associated with increased MACCE. This could be attributed to the fact that SIH was strongly correlated with poor pre-procedural TIMI flow, LTB, and distal embolization. Large clinical trials need to validate SIH as an independent predictor of adverse angiographic and clinical outcomes to provide optimal individualized care for patients with STEMI., (© 2022. The Author(s).)

Background: Routine coronary artery disease (CAD) secondary prevention strategies target standard modifiable cardiovascular risk factors (SMuRFs), which include: diabetes mellitus, dyslipidemia, hypertension, and smoking. However, a significant proportion of patients with acute coronary syndrome (ACS) present without any SMuRFs. The angiographic severity of disease in this population has not yet been investigated., Methods: After propensity score matching of patients without SMuRFs and patients with ≥1 SMuRFs (ratio 1:3), we used zero-inflated negative binomial regression modeling to investigate the relationship of SMuRF-less status with the angiographic severity of CAD, as measured by the SYNTAX score. Survival analysis was performed to investigate differences in all-cause mortality at 30 days and at the end of follow-up period., Results: We analyzed 534 patients presenting with ACS who underwent coronary angiography. Of them, 56 (10.5%) presented without any SMuRF. After propensity score matching, the median SYNTAX score was 13.8 (IQR 0-22.1) in 56 SMuRF-less patients and 14 (IQR 5-25) in 166 patients with ≥1 SMuRFs. SMuRF-less status was associated with increased odds of zero SYNTAX score [zero-part model: odds ratio = 2.11, 95% confidence interval (CI): 1.03-4.33], but not with decreased SYNTAX score among patients with non-zero SYNTAX score (count-part model: incidence rate ratio = 0.99, 95% CI: 0.79-1.24); the overall distribution of the SYNTAX score was similar between the two groups ( p = 0.26). The 30-day risk for all-cause mortality was higher for SMuRF-less patients compared to patients with ≥1 SMuRFs [hazard ratio (HR) = 3.58, 95% CI: 1.30-9.88]; however, the all-cause mortality risk was not different between the two groups over a median 1.7-year follow-up (HR = 1.72, 95% CI: 0.83-3.57)., Conclusion: Among patients with ACS, the absence of SMuRFs is associated with increased odds for non-obstructive CAD and with increased short-term mortality rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Papazoglou, Farmakis, Zafeiropoulos, Moysidis, Karagiannidis, Stalikas, Kartas, Stamos, Sofidis, Doundoulakis, Giannopoulos, Giannakoulas and Sianos.)

Cardiovascular disease (CVD) is the leading cause of death worldwide. Management of cardiovascular risk factors, particularly hypertension and dyslipidemia, has been shown to reduce cardiovascular morbidity and mortality. However, current guidelines recommend adjusting the intensity of blood pressure- and lipid-lowering treatment according to the cardiovascular risk of the patient. Therefore, cardiovascular risk prediction is a sine qua non for optimizing cardiovascular prevention strategies, particularly in patients without established CVD or type 2 diabetes mellitus (T2DM). As a result, several cardiovascular risk prediction equations have been developed. Nevertheless, it is still unclear which is the optimal prediction risk equation. In the present review, we summarize the current knowledge regarding the accuracy of the most widely used cardiovascular risk prediction equations. Notably, most of these risk scores have not been validated in external cohorts or were shown to over- or underestimate risk in populations other than those in which they derive. Accordingly, country-specific risk scores, where available, should be preferred for cardiovascular risk stratification.

Background: Polycystic ovary syndrome (PCOS) is closely related to various adverse cardiovascular manifestations and increased cardiovascular risk. However, atrial fibrillation (AF) development and atrial conduction abnormalities have not been thoroughly studied in patients with PCOS. Methods: This meta-analysis (CRD42021261375) was conducted in accordance with the PRISMA guidelines. Our aim was to investigate associations between PCOS and disorders in atrial conduction parameters linked with an increased risk for AF occurrence. Results: Five cohort studies with aggregate data on 406 adult women (229 with PCOS and 177 age-matched without PCOS) were included in this analysis. Our results showed a significantly increased mean difference in P-wave maximum duration (+7.63 ± 7.07 msec; p < 0.01) and P-wave dispersion (+11.42 ± 5.22 msec; p = 0.03) of patients with PCOS compared to healthy women. The mean difference in P-wave minimum duration (−2.22 ± 2.68 msec; p = 0.11) did not reach the statistical threshold between the compared groups. Echocardiographic measurements of atrial electromechanical delay (AED) also indicated a statistically significant mean difference in favour of the PCOS group in all assessed parameters, except for atrial electromechanical coupling (PA) in the tricuspid annulus. Particularly, PCOS was associated with increased lateral PA, septal PA, inter- and intra-AED durations (mean difference: +17.31 ± 9.02 msec; p < 0.01, +11.63 ± 7.42 msec; p < 0.01, +15.31 ± 9.18 msec; p < 0.01, +9.31 ± 6.85 msec; p < 0.01, respectively). Conclusions: PCOS is strongly associated with alterations in several electrocardiographic and echocardiographic parameters indicating abnormal atrial conduction. Therefore, PCOS could be considered as a causal or triggering factor of AF. Larger studies are needed to confirm these results and investigate direct associations between PCOS and AF.

Background/objectives: Religious fasting (RF) is practiced annually by millions of Christian and Muslim followers worldwide. Scarce data exist on the impact of RF on the metabolic and hematological profile of individuals with or without dyslipidemia., Subjects/methods: The present study included: (i) 60 Greek Orthodox participants, 30 with dyslipidemia and 30 without dyslipidemia, who abstained from meat, fish and dairy products for seven consecutive weeks, and (ii) 15 young, non-dyslipidemic Muslim participants abstaining totally from food and liquid from dawn till sunset during 30 days. Biochemical (iron, ferritin, vitamin B12, calcium, low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglyceride and fasting glucose) and hematological (hemoglobin, hematocrit) serum blood test results of study participants were measured pre- and post- RF (at weeks 0 and 7 for Orthodox participants and at weeks 0 and 4 for Muslim participants)., Results: In dyslipidemic and non-dyslipidemic Orthodox participants, a significant reduction of fasting glucose, HDL, LDL and TC levels was found post-RF. Hemoglobin, hematocrit, iron and ferritin levels were significantly increased, while post-RF vitamin B12 and calcium levels were substantially decreased. Subanalysis between dyslipidemic and non-dyslipidemic Orthodox participants revealed a greater decrease of cholesterol levels in the former. In Muslim participants, triglyceride, LDL and total cholesterol levels were increased post-RF (all p values < 0.05)., Conclusions: Our study adds to the existing literature evidence about the significant impact of RF on metabolic and hematological profiles of Orthodox and Muslim followers. The prevention of calcium and B12 deficiency during Orthodox RF by supplement consumption as well as the protection from dehydration and dysregulation of lipid metabolism during Ramadan RF should concern both clinicians and dietician nutritionists. Nevertheless, studies with larger sample size and/or long-term follow-up are warranted before reaching definite conclusions about the effects of RF on human health., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Blood pressure (BP) phenotypes have a prognostic significance for target organ damage in long-term studies. However, it remains uncertain whether a single baseline phenotype classification is reproducible over time and represents accurately the patients' BP status. The aim of this study was to systematically investigate the reproducibility of masked hypertension and office-based hypertension either with ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM). PubMed, Cochrane Library and Web of Science were searched to identify studies with paired baseline office BP and ABPM or HBPM measurements at two timepoints. The outcome of the analysis was the individual phenotype reproducibility between the baseline and follow-up timepoints. The used effect measure was Cohen's kappa coefficient. We found 15 studies eligible for the meta-analysis enrolling a total of 5729 patients. The reproducibility of masked hypertension was better with ABPM, kappa reliability test: 0.41 [95% confidence interval (CI): 0.32-0.49], than with HBPM, kappa reliability test: 0.26 (95% CI: 0.10-0.40). The reproducibility of office-based hypertension with both methods was low, indicating slight agreement. Kappa reliability test was slightly better with ABPM (κ: 0.27, 95% CI: 0.12-0.41) than with HBPM (κ: 0.18, 95% CI: 0.08-0.27). This systematic review and meta-analysis show a slight to fair reproducibility of masked hypertension and office-based hypertension assessed through ABPM and HBPM. Considering that poor reproducibility may be a result of office BP measurements, an ABPM/HBPM-based strategy should be established for the evaluation and treatment of patients with masked hypertension or office-based hypertension., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Diabetes mellitus (DM) and coronary artery disease (CAD) constitute inter-related clinical entities. Biomarker profiling emerges as a promising tool for the early diagnosis and risk stratification of either DM or CAD. However, studies assessing the predictive capacity of novel metabolomics biomarkers in coexistent CAD and DM are scarce., Methods: This post-hoc analysis of the CorLipid trial (NCT04580173) included 316 patients with CAD and comorbid DM who underwent emergency or elective coronary angiography due to acute or chronic coronary syndrome. Cox regression analyses were performed to identify metabolomic predictors of the primary outcome, which was defined as the composite of major adverse cardiovascular or cerebrovascular events (MACCE: cardiovascular death, myocardial infarction, stroke, major bleeding), repeat unplanned revascularizations and cardiovascular hospitalizations. Linear regression analyses were also performed to detect significant predictors of CAD complexity, as assessed by the SYNTAX score., Results: After a median 2-year follow up period (IQR = 0.7 years), the primary outcome occurred in 69 (21.8%) of patients. Acylcarnitine ratio C4/C18:2, apolipoprotein (apo) B, history of heart failure (HF), age > 65 years and presence of acute coronary syndrome were independent predictors of the primary outcome in diabetic patients with CAD (aHR = 1.89 [1.09, 3.29]; 1.02 [1.01, 1.04]; 1.28 [1.01, 1.41]; 1.04 [1.01, 1.05]; and 1.12 [1.05-1.21], respectively). Higher levels of ceramide ratio C24:1/C24:0, acylcarnitine ratio C4/C18:2, age > 65 and peripheral artery disease were independent predictors of higher CAD complexity (adjusted β = 7.36 [5.74, 20.47]; 3.02 [0.09 to 6.06]; 3.02 [0.09, 6.06], respectively), while higher levels of apoA1 were independent predictors of lower complexity (adjusted β= - 0.65 [- 1.31, - 0.02])., Conclusions: In patients with comorbid DM and CAD, novel metabolomic biomarkers and metabolomics-based prediction models could be recruited to predict clinical outcomes and assess the complexity of CAD, thereby enabling the integration of personalized medicine into routine clinical practice. These associations should be interpreted taking into account the observational nature of this study, and thus, larger trials are needed to confirm its results and validate them in different and larger diabetic populations., (© 2022. The Author(s).)

Background: Emerging evidence suggests the potential role of atrial cardiomyopathy (AC) as a direct thromboembolic determinant in embolic stroke of undetermined source (ESUS)., Objective: We aimed to quantify the prevalence of potential AC markers among ESUS, non-cardioembolic (NCE) and cardioembolic (CE) stroke patients., Methods: PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for publications from inception to October 2021, with duplicate data extraction and risk of bias assessment. The Newcastle-Ottawa assessment scale was used to evaluate study quality., Results: Among 398 screened studies, 11 observational studies with 2009 ESUS patients (mean age 66.5 years) fulfilled the inclusion criteria. Of electrocardiographic markers, increased P-wave terminal force in lead V1 was more prevalent in ESUS vs NCE (OR=2.26, 95%CI: 1.40-3.66). Of imaging markers, left atrial volume index (LAVI) and left atrial diameter (LAd) were higher in ESUS vs NCE (OR=1.04, 95%CI: 1.02-1.06 and OR=3.41, 95%CI: 1.35-8.61 respectively). Non-chicken wing morphology of the left atrial appendage was more frequent in ESUS compared to NCE patients in the majority of studies. Of serum biomarkers, the prevalence of NT-proBNP >250 pg/ml did not differ among ESUS vs NCE (OR=0.73, 95%CI: 0.39 -1.35)., Conclusions: Electrocardiographic, echocardiographic markers and advanced imaging modalities able to assess the morphologic characteristics of left atrial appendage and left atrial function may be important tools to discriminate AC among ESUS vs NCE stroke patients. Prospective studies exploring the association of potential AC markers with ESUS occurrence are warranted to validate their clinical utility., (Copyright © 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Accumulating evidence over the last decade suggests the promising role of ceramides as potential mediators of coronary artery disease (CAD) or prognostic biomarkers of its clinical course. This meta-analysis (CRD42021241058) aimed to assess the prognostic value of a ceramide- and phosphatidylcholine-based risk score, Coronary Event Risk Test 2 (CERT2) score, for the prediction of major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction or stroke) in 26,896 individuals with established CAD. Patients with CERT2=0-3 were used as a reference group. Pooled risk ratio (RR) of MACE among patients with CERT2=4-6 was equal to 1.35 (95% confidence intervals, CI: 1.11-1.64). Patients with CERT2=7-8 had an 81% increased risk of MACE (RR=1.81, CI: 1.40-2.34), while those with CERT2=9-12 had a 165% increased risk of MACE (RR=2.65, CI: 1.85-3.80). Subgroup analysis in patients with chronic coronary syndrome yielded an adjusted hazard ratio for MACE equal to 1.20 (CI: 1.09-1.32) per one standard deviation increase of CERT2 score. A summary c-statistic of the score combined with classical risk assessment model was found equal to 0.68 (95% CI: 0.58 to 0.77; approximate 95% prediction interval 0.38 to 0.88). Therefore, CERT2 score seems to emerge as a robust predictor of MACE. However, additional research is warranted to establish the cost-effectiveness of CERT2 score calculation for the determination of residual risk in patients with CAD., (Copyright © 2022. Published by Elsevier Inc.)

Background: Currently, potent P2Y 12 inhibition with the use of prasugrel or ticagrelor is the mainstay of treatment after an acute coronary syndrome (ACS). The 2020 European Society of Cardiology (ESC) Guidelines recommend the use of prasugrel over ticagrelor in patients with non-ST-elevation ACS (NSTE-ACS) intended to receive invasive management (class IIa recommendation), however there are contradictory views regarding this recommendation., Aim: To compare oral P2Y 12 inhibitors in NSTE-ACS in terms of efficacy and safety with a focus on patients intended to proceed to invasive management., Methods: We systematically searched PubMed, Cochrane Central Register of Controlled Trials and Web of Science to identify studies that compared different oral P2Y 12 inhibitors (clopidogrel, prasugrel and ticagrelor) in patients with NSTE-ACS. Efficacy outcomes included the major adverse cardiovascular events outcome and safety outcomes included minor and major bleedings. We performed a frequentist network meta-analysis., Results: Nine studies (n=35 441 patients) were included in the systematic review. There was no difference between prasugrel and ticagrelor in the composite cardiovascular end point (prasugrel vs ticagrelor HR=0.80, 95% CI=0.61 to 1.06) in all patients with NSTE-ACS. In patients intended to receive invasive management, prasugrel resulted in a reduction of the composite cardiovascular end point both versus clopidogrel (HR=0.76, 95% CI=0.61 to 0.95) and ticagrelor (HR=0.74, 95% CI=0.56 to 0.98). Inconsistency was moderate and non-significant (I 2 =27%, total Q p=0.2). Prasugrel ranked as the most efficient treatment in the composite cardiovascular efficacy outcome, all-cause death, myocardial infarction and definite stent thrombosis, while clopidogrel ranked as safest in the bleeding outcomes., Conclusion: In patients with NSTE-ACS intended to receive invasive management, an antiplatelet strategy based on prasugrel is more efficient than a similar strategy based on ticagrelor on a moderate level of evidence. This analysis supports the current recommendations by the ESC guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Our study aims to develop a data-driven framework utilizing heterogenous electronic medical and clinical records and advanced Machine Learning (ML) approaches for: ( i ) the identification of critical risk factors affecting the complexity of Coronary Artery Disease (CAD), as assessed via the SYNTAX score; and ( ii ) the development of ML prediction models for accurate estimation of the expected SYNTAX score. We propose a two-part modeling technique separating the process into two distinct phases: (a) a binary classification task for predicting, whether a patient is more likely to present with a non-zero SYNTAX score; and (b) a regression task to predict the expected SYNTAX score accountable to individual patients with a non-zero SYNTAX score. The framework is based on data collected from the GESS trial (NCT03150680) comprising electronic medical and clinical records for 303 adult patients with suspected CAD, having undergone invasive coronary angiography in AHEPA University Hospital of Thessaloniki, Greece. The deployment of the proposed approach demonstrated that atherogenic index of plasma levels, diabetes mellitus and hypertension can be considered as important risk factors for discriminating patients into zero- and non-zero SYNTAX score groups, whereas diastolic and systolic arterial blood pressure, peripheral vascular disease and body mass index can be considered as significant risk factors for providing an accurate estimation of the expected SYNTAX score, given that a patient belongs to the non-zero SYNTAX score group. The experimental findings utilizing the identified set of important risk factors indicate a sufficient prediction performance for the Support Vector Machine model (classification task) with an F -measure score of ~0.71 and the Support Vector Regression model (regression task) with a median absolute error value of ~6.5. The proposed data-driven framework described herein present evidence of the prediction capacity and the potential clinical usefulness of the developed risk-stratification models. However, further experimentation in a larger clinical setting is needed to ensure the practical utility of the presented models in a way to contribute to a more personalized management and counseling of CAD patients., Competing Interests: FC is employed by Labnet Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mittas, Chatzopoulou, Kyritsis, Papagiannopoulos, Theodoroula, Papazoglou, Karagiannidis, Sofidis, Moysidis, Stalikas, Papa, Chatzidimitriou, Sianos, Angelis and Vizirianakis.)

Micro-computed tomography (micro-CT) is a promising novel medical imaging modality that allows for non-destructive volumetric imaging of surgical tissue specimens at high spatial resolution. The aim of this study is to provide a comprehensive assessment of the clinical applications of micro-CT for the tissue-based diagnosis of lung diseases. This scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews, aiming to include every clinical study reporting on micro-CT imaging of human lung tissues. A literature search yielded 570 candidate articles, out of which 37 were finally included in the review. Of the selected studies, 9 studies explored via micro-CT imaging the morphology and anatomy of normal human lung tissue; 21 studies investigated microanatomic pulmonary alterations due to obstructive or restrictive lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis; and 7 studies examined the utility of micro-CT imaging in assessing lung cancer lesions ( n = 4) or in transplantation-related pulmonary alterations ( n = 3). The selected studies reported that micro-CT could successfully detect several lung diseases providing three-dimensional images of greater detail and resolution than routine optical slide microscopy, and could additionally provide valuable volumetric insight in both restrictive and obstructive lung diseases. In conclusion, micro-CT-based volumetric measurements and qualitative evaluations of pulmonary tissue structures can be utilized for the clinical management of a variety of lung diseases. With micro-CT devices becoming more accessible, the technology has the potential to establish itself as a core diagnostic imaging modality in pathology and to enable integrated histopathologic and radiologic assessment of lung cancer and other lung diseases.

Micro-computed tomography (micro-CT) constitutes an emerging imaging technique, which can be utilized in cardiovascular medicine to study in-detail the microstructure of heart and vessels. This paper aims to systematically review the clinical utility of micro-CT in cardiovascular imaging and propose future applications of micro-CT imaging in cardiovascular research. A systematic scoping review was conducted by searching for original studies written in English according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Medline, Scopus, ClinicalTrials.gov, and the Cochrane library were systematically searched through December 11, 2020 to identify publications concerning micro-CT applications in cardiovascular imaging. Preclinical-animal studies and case reports were excluded. The Newcastle-Ottawa assessment scale for observational studies was used to evaluate study quality. In total, the search strategy identified 30 studies that report on micro-CT-based cardiovascular imaging and satisfy our eligibility criteria. Across all included studies, the total number of micro-CT scanned specimens was 1,227. Six studies involved postmortem 3D-reconstruction of congenital heart defects, while eleven studies described atherosclerotic vessel (coronary or carotid) characteristics. Thirteen other studies employed micro-CT for the assessment of medical devices (mainly stents or prosthetic valves). In conclusion, micro-CT is a novel imaging modality, effectively adapted for the 3D visualization and analysis of cardiac soft tissues and devices at high spatial resolution. Its increasing use could make significant contributions to our improved understanding of the histopathophysiology of cardiovascular diseases, and, thus, has the potential to optimize interventional procedures and technologies, and ultimately improve patient outcomes., (Copyright © 2021 Hellenic Society of Cardiology. All rights reserved.)

Background: Coronary artery disease (CAD) remains one of the leading causes of mortality worldwide and is associated with multiple inherited and environmental risk factors. This study is designed to identify, design, and develop a panel of genetic markers that combined with clinical and angiographic information, will facilitate the creation of a personalized risk prediction algorithm (GEnetic Syntax Score-GESS). GESS score could be a reliable tool for predicting cardiovascular risk for future adverse events and for guiding therapeutic strategies., Methods: GESS (ClinicalTrials.gov Identifier: NCT03150680) is a prospective, non-interventional clinical study designed to enroll 1080 consecutive patients with no prior history of coronary revascularization procedure, who undergo scheduled or emergency coronary angiography in AHEPA, University General Hospital of Thessaloniki. Next generation sequencing (NGS) technology will be used to genotype specific single-nucleotide polymorphisms (SNPs) across the genome of study participants, which were identified as clinically relevant to CAD after extensive bioinformatic analysis of literature-based SNPs. Enrichment analyses of Gene Ontology-Molecular Function, Reactome Pathways and Disease Ontology terms were also performed to identify the top 15 statistically significant terms and pathways. Furthermore, the SYNTAX score will be calculated for the assessment of CAD severity of all patients based on their angiographic findings. All patients will be followed-up for one-year, in order to record any major adverse cardiovascular events., Discussion: A group of 228 SNPs was identified through bioinformatic and pharmacogenomic analysis to be involved in CAD through a wide range of pathways and was correlated with various laboratory and clinical parameters, along with the patients' response to clopidogrel and statin therapy. The annotation of these SNPs revealed 127 genes being affected by the presence of one or more SNPs. The first patient was enrolled in the study in February 2019 and enrollment is expected to be completed until June 2021. Hence, GESS is the first trial to date aspiring to develop a novel risk prediction algorithm, the GEnetic Syntax Score, able to identify patients at high risk for complex CAD based on their molecular signature profile and ultimately promote pharmacogenomics and precision medicine in routine clinical settings. Trial registration GESS trial registration: ClinicalTrials.gov Number: NCT03150680. Registered 12 May 2017- Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03150680 .

The GRACE score constitutes a useful tool for risk stratification in patients with acute coronary syndrome (ACS), while the SYNTAX score determines the complexity of coronary artery disease (CAD). This study sought to correlate these scores and assess the accuracy of the GRACE score in predicting the extent of CAD. A total of 539 patients with ACS undergoing coronary angiography were included in this analysis. The patients were classified into those with a SYNTAX score < 33 and a SYNTAX score ≥ 33. Spearman's correlation and receiver operator characteristic analysis were conducted to investigate the role of the GRACE score as a predictor of the SYNTAX score. There was a significantly positive correlation between the SYNTAX and the GRACE scores (r = 0.32, p < 0.001). The GRACE score predicted severe CAD (SYNTAX ≥ 33) moderately well (the area under the curve was 0.595 (0.522-0.667)). A GRACE score of 126 was documented as the optimal cut-off for the prediction of a SYNTAX score ≥ 33 (sensitivity = 53.5% and specificity = 66%). Therefore, our study reports a significantly positive correlation between the GRACE and the SYNTAX score in patients with ACS. Notably, NSTEMI patients with a high-risk coronary anatomy have higher calculated GRACE scores. A multidisciplinary approach by a heart team could possibly alter the therapeutic approach and management in patients presenting with ACS and a high calculated GRACE score.

Background: 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). Methods: 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. Results: Mean aspirated thrombus volume, surface, and density (±standard deviation) were 15.71 ± 20.10 mm 3 , 302.89 ± 692.54 mm 2 , and 3139.04 ± 901.88 Hounsfield units, respectively. Aspirated volume and surface were significantly higher ( p < 0.001) in patients with higher angiographic thrombus burden. After multivariable analysis, independent predictors for thrombus volume were reference vessel diameter (RVD) ( p = 0.011), right coronary artery (RCA) ( p = 0.039), and smoking ( p = 0.027), whereas RVD ( p = 0.018) and RCA ( p = 0.019) were predictive for thrombus surface. Thrombus volume and surface were independently associated with distal embolization ( p = 0.007 and p = 0.028, respectively), no-reflow phenomenon ( p = 0.002 and p = 0.006, respectively), and angiographically evident residual thrombus ( p = 0.007 and p = 0.002, respectively). Higher thrombus density was correlated with worse pre-procedural TIMI flow ( p < 0.001). Patients with higher aspirated volume and surface developed less ST resolution ( p = 0.042 and p = 0.023, respectively). Conclusions: 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. Clinical Trial Registration: QUEST-STEMI trial ClinicalTrials.gov number: NCT03429608 Date of registration: February 12, 2018. The study was prospectively registered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Karagiannidis, Papazoglou, Sofidis, Chatzinikolaou, Keklikoglou, Panteris, Kartas, Stalikas, Zegkos, Girtovitis, Moysidis, Stefanopoulos, Koupidis, Hadjimiltiades, Giannakoulas, Arvanitidis, Michaelson, Karvounis and Sianos.)

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.

Background: Coronary artery disease (CAD) remains one of the leading causes of mortality and morbidity worldwide. As oxygen and nutrient supply to the myocardium significantly decrease during ischemic periods, important changes occur regarding myocardial intermediary energy metabolism. Metabolomics is an emerging field in systems biology, which quantifies metabolic changes in response to disease progression. This study aims to evaluate the diagnostic utility of plasma metabolomics-based biomarkers for determining the complexity and severity of CAD, as it is assessed via the SYNTAX score., Methods: Corlipid is a prospective, non-interventional cohort trial empowered to enroll 1065 patients with no previous coronary intervention history, who undergo coronary angiography in University Hospital AHEPA, Thessaloniki. Venous blood samples are collected before coronary angiography. State-of the-art analytical methods are performed to calculate the serum levels of novel biomarkers: ceramides, acyl-carnitines, fatty acids, and proteins such as galectin-3, adiponectin, and the ratio of apolipoprotein B/apolipoprotein A1. Furthermore, all patients will be categorized based on the indication for coronary angiography (acute coronary syndrome, chronic coronary syndrome, preoperative coronary angiography) and on the severity of CAD using the SYNTAX score. Follow-up of 12 months after enrollment will be performed to record the occurrence of major adverse cardiovascular events. A risk prediction algorithm will be developed by combining clinical characteristics with established and novel biomarkers to identify patients at high risk for complex CAD based on their metabolite signatures. The first patient was enrolled in July 2019 and completion of enrollment is expected until May 2021., Discussion: CorLipid is an ongoing trial aiming to investigate the correlation between metabolic profile and complexity of coronary artery disease in a cohort of patients undergoing coronary angiography with the potential to suggest a decision-making tool with high discriminative power for patients with CAD. To our knowledge, Corlipid is the first study aspiring to create an integrative metabolomic biomarkers-based algorithm by combining metabolites from multiple classes, involved in a wide range of pathways with well-established biochemical markers. Trial registration CorLipid trial registration: ClinicalTrials.gov number: NCT04580173. Registered 8 October 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04580173 .

ST-elevation myocardial infarction (STEMI) remains one of the leading causes of mortality worldwide. The identification of novel metabolic and imaging biomarkers could unveil key pathophysiological mechanisms at the molecular level and promote personalized care in patients with acute coronary syndromes. We studied 38 patients with STEMI who underwent primary percutaneous coronary intervention and thrombus aspiration. We sought to correlate serum ceramide levels with micro-CT quantified aspirated thrombus volume and relevant angiographic outcomes, including modified TIMI thrombus grade and pre- or post-procedural TIMI flow. Higher ceramide C16:0 levels were significantly but weakly correlated with larger aspirated thrombus volume (Spearman r = 0.326, p = 0.046), larger intracoronary thrombus burden (TB; p = 0.030) and worse pre- and post-procedural TIMI flow ( p = 0.049 and p = 0.039, respectively). Ceramides C24:0 and C24:1 were also significantly associated with larger intracoronary TB ( p = 0.008 and p = 0.001, respectively). Receiver operating characteristic analysis demonstrated that ceramides C24:0 and C24:1 could significantly predict higher intracoronary TB (area under the curve: 0.788, 95% CI: 0.629-0.946 and 0.846, 95% CI: 0.706-0.985, respectively). In conclusion, serum ceramide levels were higher among patients with larger intracoronary and aspirated TB. This suggests that quantification of serum ceramides might improve risk-stratification of patients with STEMI and facilitate an individualized approach in clinical practice.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Adults with congenital heart disease (ACHD) experience more thromboembolic complications than the general population. We systematically searched and critically appraised all studies on the safety and efficacy of non-vitamin-K oral anticoagulants (NOACs) in adult patients with various forms of congenital heart disease. PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were used, with duplicate extraction of data and risk of bias assessment. The Newcastle-Ottawa quality assessment scale was used to assess study quality. Three studies fulfilled the inclusion criteria and were analyzed. The total number of participants was 766, with a total follow-up of 923 patient-years. The majority of patients (77%) received a NOAC for atrial arrhythmias, while the remainder were prescribed NOACs for secondary (19%) or primary (4%) thromboprophylaxis. The annual rate of thromboembolic and major bleeding events was low: 0.98% (95% CI: 0.51-1.86) and 1.74% (95% CI: 0.86-3.49) respectively. In Fontan patients, the annual rate of thromboembolic and major bleeding events was 3.13% (95% CI: 1.18-8.03) and 3.17% (95% CI: 0.15-41.39) respectively. NOACs appear safe and effective in ACHD without mechanical prostheses. Additional studies are, however, needed to confirm their efficacy in complex ACHD, especially those with a Fontan-type circulation.