Sex-specific Prediction of Cardiogenic Shock After Acute Coronary Syndromes: The SEX-SHOCK Score.

BACKGROUND: and aims: Cardiogenic shock (CS) remains the primary cause of in-hospital death after acute coronary syndromes (ACS), with its plateauing mortality rates approaching 50%. To test novel interventions, personalized risk prediction is essential. The ORBI (Observatoire Régional Breton sur l'Infarctus) score represents the first-of-its-kind risk score to predict in-hospital CS in ACS patients undergoing percutaneous coronary intervention (PCI). However, its sex-specific performance remains unknown, and refined risk prediction strategies are warranted. METHODS: This multinational study included a total of 53 537 ACS patients without CS on admission undergoing PCI. Following sex-specific evaluation of ORBI, regression and machine-learning models were used for variable selection and risk prediction. By combining best-performing models with highest-ranked predictors, SEX-SHOCK was developed, and internally and externally validated. RESULTS: The ORBI score showed lower discriminative performance for the prediction of CS in females than males in Swiss (AUC [95% CI]: 0.78 [0.76-0.81] vs. 0.81 [0.79-0.83]; p=0.048) and French ACS patients (0.77 [0.74-0.81] vs. 0.84 [0.81-0.86]; p=0.002). The newly developed SEX-SHOCK score, now incorporating ST-segment elevation, creatinine, C-reactive protein, and left ventricular ejection fraction, outperformed ORBI in both sexes (females: 0.81 [0.78-0.83]; males: 0.83 [0.82-0.85]; p<0.001), which prevailed following internal and external validation in RICO (females: 0.82 [0.79-0.85]; males: 0.88 [0.86-0.89]; p<0.001) and SPUM-ACS (females: 0.83 [0.77-0.90], p=0.004; males: 0.83 [0.80-0.87], p=0.001). CONCLUSIONS: The ORBI score showed modest sex-specific performance. The novel SEX-SHOCK score provides superior performance in females and males across the entire spectrum of ACS, thus providing a basis for future interventional trials and contemporary ACS management.

Proenkephalin Improves Cardio-Renal Risk Prediction in Acute Coronary Syndromes: The KID-ACS Score.

BACKGROUND AND AIMS: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS). METHODS: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. RESULTS: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively. CONCLUSIONS: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

MicroRNA in cardiometabolic health and disease: The perspectives of sex, gender and personalised medicine.

BACKGROUND: Personalized medicine represents a novel and integrative approach that focuses on an individual's genetics and epigenetics, precision medicine, lifestyle and exposures as key players of health status and disease phenotypes. METHODS: In this narrative review, we aim to carefully discuss the current knowledge on gender disparities in cardiometabolic diseases, and we consider the sex- specific expression of miRNAs and their role as promising tool in precision medicine. RESULTS: Personalised medicine overcomes the restricted care of patient based on a binomial sex approach, by enriching itself with a holistic and dynamic gender integration. Recognized as a major worldwide health emergency, cardiometabolic disorders continue to rise, impacting on health systems and requiring more effective and targeted strategies. Several sex and gender drivers might affect the onset and progression of cardiometabolic disorders in males and females at multiple levels. In this respect, distinct contribution of genetic and epigenetic mechanisms, molecular and physiological pathways, sex hormones, visceral fat and subcutaneous fat and lifestyle lead to differences in disease burden and outcomes in males and females. CONCLUSIONS: Sex and gender play a pivotal role in precision medicine because the influence the physiology of each individual and the way they interact with environment from intrauterine life.

JCAD promotes arterial thrombosis through PI3K/Akt modulation: a translational study.

AIMS: Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis. METHODS AND RESULTS: JCAD knockout (Jcad-/-) mice underwent photochemically induced endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with JCAD small interfering RNA (siJCAD), LATS2 small interfering RNA (siLATS2) or control siRNA (siSCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome or ST-elevation myocardial infarction (STEMI). Jcad-/- mice displayed reduced thrombogenicity as reflected by delayed time to carotid occlusion. Mechanisms include reduced activation of the coagulation cascade [reduced tissue factor (TF) expression and activity] and increased fibrinolysis [higher thrombus embolization episodes and D-dimer levels, reduced vascular plasminogen activator inhibitor (PAI)-1 expression]. In vitro, JCAD silencing inhibited TF and PAI-1 expression in HAECs. JCAD-silenced HAECs (siJCAD) displayed increased levels of LATS2 kinase. Yet, double JCAD and LATS2 silencing did not restore the control phenotype. si-JCAD HAECs showed increased levels of phosphoinositide 3-kinases (PI3K)/ proteinkinase B (Akt) activation, known to downregulate procoagulant expression. The PI3K/Akt pathway inhibitor-wortmannin-prevented the effect of JCAD silencing on TF and PAI-1, indicating a causative role. Also, co-immunoprecipitation unveiled a direct interaction between JCAD and Akt. Confirming in vitro findings, PI3K/Akt and P-yes-associated protein levels were higher in Jcad-/- animals. Lastly, as compared with chronic coronary syndrome, STEMI patients showed higher plasma JCAD, which notably correlated positively with both TF and PAI-1 levels. CONCLUSIONS: JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis.

Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes.

BACKGROUND AND AIMS: Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS). METHODS: Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787). RESULTS: Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05-1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28-2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < .001). Results were consistent across various patient subgroups. CONCLUSIONS: This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment.

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC.

BACKGROUND: High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS: Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS: Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS: High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.

Cytokines as therapeutic targets for cardio- and cerebrovascular diseases.

Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice.

Updating concepts on atherosclerotic inflammation: From pathophysiology to treatment.

BACKGROUND: Atherosclerosis is recognized as a systemic low-grade inflammatory disease. Furthermore, the dysregulation of the inflammatory response and its timely resolution is a pivotal process in determining the clinical manifestations of cardiac and cerebral acute ischaemia following atherothrombosis. METHODS: This narrative review is based on the material searched on PubMed up to October 2020. The search terms we used were as follows: "atherosclerosis, inflammation, acute myocardial infarction and ischemic stroke" in combination with "biomarker, inflammatory cells and molecules, treatment." RESULTS: The expected goal of addressing inflammation for the treatment of atherosclerosis and its acute ischaemic complications is reducing mortality and morbidity related to atherosclerotic cardiovascular disease, which are currently the first cause of death and disability worldwide. In this narrative review, we summarize the evidence about the main cellular and molecular mechanisms of inflammation in atherogenesis, atherothrombosis and acute ischaemic complications, with particular focus on the potential molecular targets for novel pharmacological treatments. CONCLUSION: Although a large amount of evidence from animal models of atherothrombotic disease, and promising results of clinical trials, anti-inflammatory treatments against atherosclerosis are not yet recommended. A deepest understanding of pathophysiological mechanisms underlying the mechanisms driving resolution of the acute inflammation will probably allow to identify the optimal molecular target.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

Effects of structured home-based exercise training on circulating endothelial progenitor cells and endothelial function in patients with intermittent claudication.

INTRODUCTION: Exercise training improves walking capacity in patients with intermittent claudication (IC). Endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and endothelial dysfunction could play a role in this process. METHODS: We measured EPCs and EMPs in a group of 60 patients with IC, and in a control group of 20 individuals without IC, before a treadmill test and 2, 24, and 48 hours after the test. Thirty patients with IC were randomly assigned to perform a 12-week home-based exercise training program. The EPC count, flow-mediated dilation (FMD) of the brachial artery, pain-free walking time (PFWT), and maximum walking time (MWT) were measured at the baseline and after the exercise training program. RESULTS: In patients with IC, EMPs significantly increased 2 hours after the treadmill test, whereas EPCs significantly increased after 24 hours. Among the subjects assigned to complete the training program, we observed a significant increase in the number of EPCs after 12 weeks, as well as an improvement in FMD, PFWT, and MWT. A significant correlation between the variation of EPCs, FMD, and MWT was found. The increase of EPCs and FMD were independent determinants of the walking capacity improvement, without significant interaction. CONCLUSION: Our results suggest that EPCs mobilization contributes to the improvement of walking capacity in patients with IC undergoing structured physical training. A number of different, partly independent, mechanisms are involved in this process, and our results highlight the potential role of EMPs release and endothelial function improvement. ClinicalTrials.gov Identifier: NCT04302571.

Macrophages in the pathophysiology of NAFLD: The role of sex differences.

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial pathological condition, which recognizes a certain sexual dimorphism. Experimental and clinical studies provided evidence for a critical role of macrophages in NAFLD development and progression. Especially, liver-resident macrophages (also known as Kupffer cells) are likely the common final pathway of several pro-steatosic signals. A huge amount of danger-associated molecular patterns recognized by Kupffer cells is provided within the liver by lipid and glucose toxicity. Other pro-inflammatory signals come from surrounding tissues into the portal vein, directly to the liver: they come from dysfunctional adipocytes, adipose tissue macrophages and gut dysbiosis. These complex crosstalks are differently represented across sexes, as sexual hormones control many of these processes. Sexual dimorphism then modulates metabolic and inflammatory cascades driving the liver from a simple steatosis to NAFLD and beyond. Here, metabolic and inflammatory mechanisms underlying NALFD pathophysiology will be updated. A special attention will be paid to describe sex-related differences that could provide insights for patient stratification and more tailored therapeutic approaches.

Chemerin predicts carotid intima-media thickening in severe obesity.

BACKGROUND AND AIMS: Chemerin is an adipokine with an emerging role in the crosstalk between adipose tissue and immune system. It is overexpressed in severe obesity, affects adipogenesis and glucose homeostasis and it correlates with early vascular damage. The aim of this study is to investigate the correlation between circulating levels of chemerin and early vascular damage in subjects with severe obesity, before and after laparoscopic sleeve gastrectomy (LSG). METHODS: Fifty-six obese subjects eligible for LSG were enrolled in the study. The following parameters were evaluated: body mass index (BMI), glycemia, insulinemia, glycated haemoglobin, lipid profile, plasma chemerin levels and carotid intima-media thickness (cIMT). Fifty-four subjects were evaluated 1 year after the intervention. RESULTS: Univariate analysis showed a direct and significant correlation between chemerin and waist circumference, insulin resistance, glycated haemoglobin and cIMT. Chemerin was a better predictor of intima-media thickening than waist circumference and glycated haemoglobin at the ROC curve analysis, with a cut-off value for chemerin of 140 ng/mL. The reduction of chemerin is independently associated with the reduction of cIMT and the improvement of insulin sensitivity after LSG. CONCLUSION: Chemerin is involved in the development and progression of early vascular damage and insulin resistance in subjects with severe obesity, and in their healing after bariatric surgery. Chemerin could also have a role in the assessment of cardiovascular risk in subjects with severe obesity.

Trajectories of cardiovascular ageing - from molecular mechanisms to clinical implementation.

Due to its peculiar structure and function, the cardiovascular system is particularly vulnerable to the detrimental effects of ageing. Current knowledge about the molecular mechanisms of ageing revealed the processes actively promoting ageing, e.g. progressive telomeres shortening, and the mechanisms opposing it, e.g. endogenous production of antioxidant substances. This knowledge can be used to measure biological age at a cellular and molecular level and to interfere with it by pharmacological or non-pharmacological interventions. Biological ageing is determined by the simultaneous occurrence of independent hallmarks, which encompass a wide range of biological processes, from genomic changes to systemic inflammation and dysbiosis. This narrative review will summarize the role of ageing hallmarks in the cardiovascular system, how they can be measured and what are the possible interventions to counteract their effects.

Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet reactivity.

INTRODUCTION: Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown. METHODS: Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated. RESULTS: LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals. CONCLUSIONS: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.

Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients.

INTRODUCTION: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. METHODS: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. RESULTS: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. CONCLUSIONS: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.