Cardiovascular prevention: sometimes dreams can come true.

Cardiovascular disease (CVD) is a chronic condition driven by the complex interaction of different risk factors including genetics, lifestyle, environment, etc. which, differently from other pathologies, can be prevented. Treatment of CVD has been inconceivably successful but now it seems that it has reached a plateau suggesting that prevention is the way forward. However, the COVID-19 pandemic has spotted all the limits of the actual health system regarding territorial and, particularly, of preventive medicine. To this end, recently, the SCORE2 risk prediction algorithms, a contemporary model to estimate 10 years risk of CVD in Europe and the new guidelines on prevention have been released. The present review article describes a dream: how prevention of CVD should be addressed in the future. New concepts and paradigms like early genetically personalized and imaging driven risk factors, cardiac risk cartography, measurements of the exposome, estimation of costs of a delayed outcome vs. healthy lifespan, are all addressed. We highlight the importance of technologies and the concept of being engaged in a 'healthy' and not just 'sick' system as it is today. The concept of 'clearing house' with a 'care health team' instead of a 'heart team' is described. Finally, we articulate the four points necessary for the dream to come true.

Cardiovascular prevention: sometimes dreams can come true.

Cardiovascular disease (CVD) is a chronic condition driven by the complex interaction of different risk factors including genetics, lifestyle, environment, etc. which, differently from other pathologies, can be prevented. Treatment of CVD has been inconceivably successful but now it seems that it has reached a plateau suggesting that prevention is the way forward. However, the COVID-19 pandemic has spotted all the limits of the actual health system regarding territorial and, particularly, of preventive medicine. To this end, recently, the SCORE2 risk prediction algorithms, a contemporary model to estimate 10-years risk of CVD in Europe and the new guidelines on prevention have been released. The present review article describes a dream: how prevention of CVD should be addressed in the future. New concepts and paradigms like early genetically personalized and imaging driven risk factors, cardiac risk cartography, measurements of the exposome, estimation of costs of a delayed outcome vs. healthy lifespan, are all addressed. We highlight the importance of technologies and the concept of being engaged in a 'healthy' and not just 'sick' system as it is today. The concept of 'clearing house' with a 'healthcare team' instead of a 'heart team' is described. Finally, we articulate the four points necessary for the dream to come true.

Phenotypic heterogeneity of COVID-19 pneumonia: clinical and pathophysiological relevance of the vascular phenotype.

Recent data support the existence of a distinctive 'vascular' phenotype with the involvement of both pulmonary parenchyma and its circulation in COVID-19 pneumonia. Its prompt identification is important for the accurate management of COVID-19 patients. The aim is to analyse the pro and contra of the different modalities to identify the 'vascular' phenotype. Chest computed tomography scan and angiogram may quantify both parenchyma and vascular damage, but the presence of thrombosis of pulmonary microcirculation may be missed. Increased d-dimer concentration confirms a thrombotic state, but it cannot localize the thrombus. An elevation of troponin concentration non-specifically reflects cardiac injury. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the 'vascular' phenotype, which does not necessarily represent the result of thrombo-embolic venous complications, but more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action. CONDENSED ABSTRACT: Despite diagnosis of the 'vascular' phenotype of COVID-19 pneumonia may be subtle, the evidence indicates a reasonable possibility of identifying it already in the initial stage of the infection. Chest computed tomography scan and angiogram, increased d-dimer concentration, and elevation of troponin concentration may be not sufficient to identify 'vascular' phenotype. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the 'vascular' phenotype, which does not necessarily represent the result of thrombo-embolic venous complications, but more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action.

Phenotypic heterogeneity of COVID-19 pneumonia: clinical and phatophysiologic relevance of the vascular phenotype

Recent data support the existence of a distinctive ‘vascular’ phenotype with the involvement of both pulmonary parenchyma and its circulation in COVID-19 pneumonia. Its prompt identification is important for the accurate management of COVID-19 patients. The aim is to analyse the pro and contra of the different modalities to identify the ‘vascular’ phenotype. Chest computed tomography scan and angiogram may quantify both parenchyma and vascular damage, but the presence of thrombosis of pulmonary micro-circulation may be missed. Increased d-dimer concentration confirms a thrombotic state, but it cannot localize the thrombus. An elevation of troponin concentration nonspecifically reflects cardiac injury. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the ‘vascular’ phenotype which does not necessarily represent the result of thromboembolic venous complications but, more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action.

Dual-readout calorimetry: Present status and perspective

Dual-readout calorimetry is now a mature and well-known technology which guarantees excellent electromagnetic and hadronic resolution in the same detector. It has recently being proposed in the framework of IDEA (Innovative Detector for Electron–Positron Accelerators) for both Future Circular Collider (FCC-ee) and Circular Electron–Positron Collider (CEPC).After being extensively tested on prototypes, the dual-readout calorimetry is now moving toward a technology design study in order to be realistically available for an experiment. In this context, a full simulation of the calorimeter has been developed and used to estimate the expected performance of the detector. At the same time, the development of a novel technique for mass production of the detector modules, at an effective cost, is ongoing. As a first step, an electromagnetic-size prototype is under construction for a testbeam data taking originally foreseen in November 2020 and now moved to spring 2021, due to the Covid-19 pandemic spread.

Well-Known and Novel Players in Endothelial Dysfunction: Updates on a Notch(ed) Landscape.

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for the progression of vascular disorders, which responds to drug intervention and lifestyle changes. Virtually all of the drugs used to prevent cardiovascular disorders, such as long-used and new antilipidemic agents and inhibitors of angiotensin enzyme (ACEi), exert an important effect on the endothelium. Endothelial dysfunction is a central feature of coronavirus disease -19 (COVID-19), and it is now clear that life-risk complications of the disease are prompted by alterations of the endothelium induced by viral infection. As a consequence, the progression of COVID-19 is worse in the subjects in whom endothelial dysfunction is already present, such as elderly, diabetic, obese, and hypertensive patients. Importantly, circulating biomarkers of endothelial activation and injury predict the severity and mortality of the disease and can be used to evaluate the efficacy of treatments. The purpose of this review is to provide updates on endothelial function by discussing its clinical relevance in the cardiovascular continuum, the latest insights from molecular and cellular biology, and their implications for clinical practice, with a focus on new actors, such as the Notch signaling and emerging therapies for cardiovascular disease.

The Combination of Chest Computed Tomography and Standard Electrocardiogram Provides Prognostic Information and Pathophysiological Insights in COVID-19 Pneumonia.

AIMS: Several studies have unveiled the great heterogeneity of COVID-19 pneumonia. Identification of the "vascular phenotype" (involving both pulmonary parenchyma and its circulation) has prognostic significance. Our aim was to explore the combined role of chest computed tomography (CT) scan and electrocardiogram (ECG) at hospital admission in predicting short-term prognosis and to draw pathophysiological insights. METHODS AND RESULTS: We analyzed the chest CT scan and ECG performed at admission in 151 consecutive COVID-19 patients admitted between 20 March and 4 April 2020. All-cause mortality within 30 days was the primary endpoint. Median age was 71 years (IQR: 62-76). Severe pneumonia was present in 25 (17%) patients, and 121 (80%) had abnormal ECG. During a median follow-up of 7 days (IQR: 4-13), 54 (36%) patients died. Deceased patients had more severe pneumonia than survivors did (80% vs. 64%, p = 0.044). ECG in deceased patients showed more frequently atrial fibrillation/flutter (17% vs. 6%, p = 0.039) and acute right ventricular (RV) strain (35% vs. 10%, p < 0.001), suggesting the "vascular phenotype". ECG signs of acute RV strain (HR 2.46, 95% CIs 1.36-4.45, p = 0.0028) were independently associated with all-cause mortality in multivariable analysis, and in the likelihood ratio test, showed incremental prognostic value over chest CT scan, age, and C-reactive protein. CONCLUSIONS: Combining chest CT scan and ECG data improves risk stratification in COVID-19 pneumonia by identifying a distinctive phenotype with both parenchymal and vascular damage of the lung. Patients with severe pneumonia at chest CT scan plus ECG signs of acute RV strain have an extremely poor short-term prognosis.

Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.

BACKGROUND AND AIMS: The potential impact of coronary atherosclerosis, as detected by coronary artery calcium, on clinical outcomes in COVID-19 patients remains unsettled. We aimed to evaluate the prognostic impact of clinical and subclinical coronary artery disease (CAD), as assessed by coronary artery calcium score (CAC), in a large, unselected population of hospitalized COVID-19 patients undergoing non-gated chest computed tomography (CT) for clinical practice. METHODS: SARS-CoV 2 positive patients from the multicenter (16 Italian hospitals), retrospective observational SCORE COVID-19 (calcium score for COVID-19 Risk Evaluation) registry were stratified in three groups: (a) "clinical CAD" (prior revascularization history), (b) "subclinical CAD" (CAC >0), (c) "No CAD" (CAC = 0). Primary endpoint was in-hospital mortality and the secondary endpoint was a composite of myocardial infarction and cerebrovascular accident (MI/CVA). RESULTS: Amongst 1625 patients (male 67.2%, median age 69 [interquartile range 58-77] years), 31%, 57.8% and 11.1% had no, subclinical and clinical CAD, respectively. Increasing rates of in-hospital mortality (11.3% vs. 27.3% vs. 39.8%, p < 0.001) and MI/CVA events (2.3% vs. 3.8% vs. 11.9%, p < 0.001) were observed for patients with no CAD vs. subclinical CAD vs clinical CAD, respectively. The association with in-hospital mortality was independent of in-study outcome predictors (age, peripheral artery disease, active cancer, hemoglobin, C-reactive protein, LDH, aerated lung volume): subclinical CAD vs. No CAD: adjusted hazard ratio (adj-HR) 2.86 (95% confidence interval [CI] 1.14-7.17, p=0.025); clinical CAD vs. No CAD: adj-HR 3.74 (95% CI 1.21-11.60, p=0.022). Among patients with subclinical CAD, increasing CAC burden was associated with higher rates of in-hospital mortality (20.5% vs. 27.9% vs. 38.7% for patients with CAC score thresholds≤100, 101-400 and > 400, respectively, p < 0.001). The adj-HR per 50 points increase in CAC score 1.007 (95%CI 1.001-1.013, p=0.016). Cardiovascular risk factors were not independent predictors of in-hospital mortality when CAD presence and extent were taken into account. CONCLUSIONS: The presence and extent of CAD are associated with in-hospital mortality and MI/CVA among hospitalized patients with COVID-19 disease and they appear to be a better prognostic gauge as compared to a clinical cardiovascular risk assessment.

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients.

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement.

AIMS: Our aim was to describe the electrocardiographic features of critical COVID-19 patients. METHODS AND RESULTS: We carried out a multicentric, cross-sectional, retrospective analysis of 431 consecutive COVID-19 patients hospitalized between 10 March and 14 April 2020 who died or were treated with invasive mechanical ventilation. This project is registered on ClinicalTrials.gov (identifier: NCT04367129). Standard ECG was recorded at hospital admission. ECG was abnormal in 93% of the patients. Atrial fibrillation/flutter was detected in 22% of the patients. ECG signs suggesting acute right ventricular pressure overload (RVPO) were detected in 30% of the patients. In particular, 43 (10%) patients had the S1Q3T3 pattern, 38 (9%) had incomplete right bundle branch block (RBBB), and 49 (11%) had complete RBBB. ECG signs of acute RVPO were not statistically different between patients with (n = 104) or without (n=327) invasive mechanical ventilation during ECG recording (36% vs. 28%, P = 0.10). Non-specific repolarization abnormalities and low QRS voltage in peripheral leads were present in 176 (41%) and 23 (5%), respectively. In four patients showing ST-segment elevation, acute myocardial infarction was confirmed with coronary angiography. No ST-T abnormalities suggestive of acute myocarditis were detected. In the subgroup of 110 patients where high-sensitivity troponin I was available, ECG features were not statistically different when stratified for above or below the 5 times upper reference limit value. CONCLUSIONS: The ECG is abnormal in almost all critically ill COVID-19 patients and shows a large spectrum of abnormalities, with signs of acute RVPO in 30% of the patients. Rapid and simple identification of these cases with ECG at hospital admission can facilitate classification of the patients and provide pathophysiological insights.

Myocarditis in COVID-19 patients: current problems.

Myocarditis has been reported as a possible clinical presentation or complication in patients with coronavirus disease (COVID)-19 due to SARS-CoV-2. Despite the alarm that this possibility generated among physicians, there is paucity of information about mechanisms, prevalence, prognosis, diagnosis and therapy of myocarditis in the context of COVID-19. This brief review has the goal to revise and summarize current knowledge on myocarditis in COVID-19 patients and underline problems especially related to diagnosis and treatment.

Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.