Artificial intelligence in cardiovascular prevention: new ways will open new doors.

Prevention and effective treatment of cardiovascular disease are progressive issues that grow in tandem with the average age of the world population. Over recent decades, the potential role of artificial intelligence in cardiovascular medicine has been increasingly recognized because of the incredible amount of real-world data (RWD) regarding patient health status and healthcare delivery that can be collated from a variety of sources wherein patient information is routinely collected, including patient registries, clinical case reports, reimbursement claims and billing reports, medical devices, and electronic health records. Like any other (health) data, RWD can be analysed in accordance with high-quality research methods, and its analysis can deliver valuable patient-centric insights complementing the information obtained from conventional clinical trials. Artificial intelligence application on RWD has the potential to detect a patient's health trajectory leading to personalized medicine and tailored treatment. This article reviews the benefits of artificial intelligence in cardiovascular prevention and management, focusing on diagnostic and therapeutic improvements without neglecting the limitations of this new scientific approach.

Cardiovascular implications of miRNAs in COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in COVID-19, and no strategies are available to prevent or specifically address CV events in COVID patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors and new therapeutic targets. The current report will focus on the role of miRNAs in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. Significance Statement It is essential to identify the molecular mediators of COVID-19 cardiovascular (CV) complications. This report focused on the role of miRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.

Acute Coronary Syndrome in Patients with SARS-CoV-2 Infection: Pathophysiology and Translational Perspectives

Acute coronary syndromes (ACS) may complicate the clinical course of patients with Coronavirus Disease 2019 (COVID-19). It is still unclear whether this condition is a direct consequence of the primary disease. However, several mechanisms including direct cellular damage, endothelial dysfunction, in-situ thrombosis, systemic inflammatory response, and oxygen supply-demand imbalance have been described in patients with COVID-19. The onset of a prothrombotic state may also be facilitated by the endothelial dysfunction secondary to the systemic inflammatory response and to the direct viral cell damage. Moreover, dysfunctional endothelial cells may enhance vasospasm and platelet aggregation. The combination of these factors promotes atherosclerotic plaque instability, thrombosis and, consequently, type 1 myocardial infarction. Furthermore, severe hypoxia due to extensive pulmonary involvement, in association with other conditions described in COVID-19 such as sepsis, tachyarrhythmias, anemia, hypotension, and shock, may lead to mismatch between oxygen supply and demand, and cause type 2 myocardial infarction. A deeper understanding of the potential pathophysiological mechanisms underlying ACS in patients with COVID-19 could help the therapeutic management of these very high-risk patients.

Untargeted lipidomics reveals specific lipid profiles in COVID-19 patients with different severity from Campania region (Italy).

COVID-19 infection evokes various systemic alterations that push patients not only towards severe acute respiratory syndrome but causes an important metabolic dysregulation with following multi-organ alteration and potentially poor outcome. To discover novel potential biomarkers able to predict disease's severity and patient's outcome, in this study we applied untargeted lipidomics, by a reversed phase ultra-high performance liquid chromatography-trapped ion mobility mass spectrometry platform (RP-UHPLC-TIMS-MS), on blood samples collected at hospital admission in an Italian cohort of COVID-19 patients (45 mild, 54 severe, 21 controls). In a subset of patients, we also collected a second blood sample in correspondence of clinical phenotype modification (longitudinal population). Plasma lipid profiles revealed several lipids significantly modified in COVID-19 patients with respect to controls and able to discern between mild and severe clinical phenotype. Severe patients were characterized by a progressive decrease in the levels of LPCs, LPC-Os, PC-Os, and, on the contrary, an increase in overall TGs, PEs, and Ceramides. A machine learning model was built by using both the entire dataset and with a restricted lipid panel dataset, delivering comparable results in predicting severity (AUC= 0.777, CI: 0.639-0.904) and outcome (AUC= 0.789, CI: 0.658-0.910). Finally, re-building the model with 25 longitudinal (t1) samples, this resulted in 21 patients correctly classified. In conclusion, this study highlights specific lipid profiles that could be used monitor the possible trajectory of COVID-19 patients at hospital admission, which could be used in targeted approaches.

Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems.

Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.

Clinical conditions and echocariographic parameters associated with mortality in COVID-19

Aims Coronavirus disease 2019 (COVID-19) is a recently recognized viral infective disease which can be complicated by acute respiratory stress syndrome (ARDS) and cardiovascular complications including severe arrhythmias, acute coronary syndromes, myocarditis, and pulmonary embolism. The aim of the present study was to identify the clinical conditions and echocardiographic parameters associated with in-hospital mortality in COVID-19. Methods and results This is a multicentre retrospective observational study including seven Italian centres. Patients hospitalized with COVID-19 from 1 March to 22 April 2020, were included into the study population. The association between baseline variables and the risk of in-hospital mortality was assessed through multivariable logistic regression and competing risk analyses. Out of 1401 patients admitted at the participating centres with confirmed diagnosis of COVID-19, 226 (16.1%) underwent transthoracic echocardiography (TTE) and were included in the present analysis. The mean age was 68.9 ± 13.9 years and male sex was reported in 141 patients (62.4%). Admission in intensive care unit was required for 72 patients (31.9%);in-hospital death occurred in 68 patients (30.1%). At multivariable analysis, left ventricular ejection fraction (LVEF, P < 0.001), tricuspid annular plane systolic excursion (TAPSE, P < 0.001), and ARDS (P < 0.001) were independently associated with in-hospital mortality. At competing risk analysis, we found a significantly higher risk of mortality in patients with ARDS vs. those without ARDS (HR: 7.66;CI: 3.95–14.8), in patients with TAPSE ≤ 17 mm vs. those with TAPSE > 17 mm (HR: 5.08;CI: 3.15–8.19), and in patients with LVEF ≤ 50% vs. those with LVEF > 50% (HR: 4.06;CI: 2.50–6.59) (Figure). Conclusions TTE might be a useful tool in risk stratification of patients with COVID-19. In particular, reduced LVEF as well as reduced TAPSE may help to identify patients at higher risk of death during hospitalization. Our preliminary findings need to be confirmed in larger, prospective studies.618 Figure 1

Prognostic Implications of Right Ventricular Function and Pulmonary Pressures Assessed by Echocardiography in Hospitalized Patients with COVID-19.

AIMS: Pulmonary involvement in Coronavirus disease 2019 (COVID-19) may affect right ventricular (RV) function and pulmonary pressures. The prognostic value of tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (PAPS), and TAPSE/PAPS ratios have been poorly investigated in this clinical setting. METHODS AND RESULTS: This is a multicenter Italian study, including consecutive patients hospitalized for COVID-19. In-hospital mortality and pulmonary embolism (PE) were identified as the primary and secondary outcome measures, respectively. The study included 227 (16.1%) subjects (mean age 68 ± 13 years); intensive care unit (ICU) admission was reported in 32.2%. At competing risk analysis, after stratifying the population into tertiles, according to TAPSE, PAPS, and TAPSE/PAPS ratio values, patients in the lower TAPSE and TAPSE/PAPS tertiles, as well as those in the higher PAPS tertiles, showed a significantly higher incidence of death vs. the probability to be discharged during the hospitalization. At univariable logistic regression analysis, TAPSE, PAPS, and TAPSE/PAPS were significantly associated with a higher risk of death and PE, both in patients who were and were not admitted to ICU. At adjusted multivariable regression analysis, TAPSE, PAPS, and TAPSE/PAPS resulted in independently associated risk of in-hospital death (TAPSE: OR 0.85, CI 0.74-0.97; PAPS: OR 1.08, CI 1.03-1.13; TAPSE/PAPS: OR 0.02, CI 0.02 × 10-1-0.2) and PE (TAPSE: OR 0.7, CI 0.6-0.82; PAPS: OR 1.1, CI 1.05-1.14; TAPSE/PAPS: OR 0.02 × 10-1, CI 0.01 × 10-2-0.04). CONCLUSIONS: Echocardiographic evidence of RV systolic dysfunction, increased PAPS, and poor RV-arterial coupling may help to identify COVID-19 patients at higher risk of mortality and PE during hospitalization.

COVID-19 and Acute Coronary Syndromes: From Pathophysiology to Clinical Perspectives.

Acute coronary syndromes (ACS) are frequently reported in patients with coronavirus disease 2019 (COVID-19) and may impact patient clinical course and mortality. Although the underlying pathogenesis remains unclear, several potential mechanisms have been hypothesized, including oxygen supply/demand imbalance, direct viral cellular damage, systemic inflammatory response with cytokine-mediated injury, microvascular thrombosis, and endothelial dysfunction. The severe hypoxic state, combined with other conditions frequently reported in COVID-19, namely sepsis, tachyarrhythmias, anemia, hypotension, and shock, can induce a myocardial damage due to the mismatch between oxygen supply and demand and results in type 2 myocardial infarction (MI). In addition, COVID-19 promotes atherosclerotic plaque instability and thrombus formation and may precipitate type 1 MI. Patients with severe disease often show decrease in platelets count, higher levels of d-dimer, ultralarge von Willebrand factor multimers, tissue factor, and prolongation of prothrombin time, which reflects a prothrombotic state. An endothelial dysfunction has been described as a consequence of the direct viral effects and of the hyperinflammatory environment. The expression of tissue factor, von Willebrand factor, thromboxane, and plasminogen activator inhibitor-1 promotes the prothrombotic status. In addition, endothelial cells generate superoxide anions, with enhanced local oxidative stress, and endothelin-1, which affects the vasodilator/vasoconstrictor balance and platelet aggregation. The optimal management of COVID-19 patients is a challenge both for logistic and clinical reasons. A deeper understanding of ACS pathophysiology may yield novel research insights and therapeutic perspectives in higher cardiovascular risk subjects with COVID-19.

BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19.

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.

PD-L1 Dysregulation in COVID-19 Patients.

The COVID-19 pandemic has reached direct and indirect medical and social consequences with a subset of patients who rapidly worsen and die from severe-critical manifestations. As a result, there is still an urgent need to identify prognostic biomarkers and effective therapeutic approaches. Severe-critical manifestations of COVID-19 are caused by a dysregulated immune response. Immune checkpoint molecules such as Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) play an important role in regulating the host immune response and several lines of evidence underly the role of PD-1 modulation in COVID-19. Here, by analyzing blood sample collection from both hospitalized COVID-19 patients and healthy donors, as well as levels of PD-L1 RNA expression in a variety of model systems of SARS-CoV-2, including in vitro tissue cultures, ex-vivo infections of primary epithelial cells and biological samples obtained from tissue biopsies and blood sample collection of COVID-19 and healthy individuals, we demonstrate that serum levels of PD-L1 have a prognostic role in COVID-19 patients and that PD-L1 dysregulation is associated to COVID-19 pathogenesis. Specifically, PD-L1 upregulation is induced by SARS-CoV-2 in infected epithelial cells and is dysregulated in several types of immune cells of COVID-19 patients including monocytes, neutrophils, gamma delta T cells and CD4+ T cells. These results have clinical significance since highlighted the potential role of PD-1/PD-L1 axis in COVID-19, suggest a prognostic role of PD-L1 and provide a further rationale to implement novel clinical studies in COVID-19 patients with PD-1/PD-L1 inhibitors.

Exercise Training and Cardiac Rehabilitation in COVID-19 Patients with Cardiovascular Complications: State of Art.

Recent scientific literature has investigated the cardiovascular implications of COVID-19. The mechanisms of cardiovascular damage seem to involve the protein angiotensin-converting enzyme 2 (ACE2), to which severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) binds to penetrate cells and other mechanisms, most of which are still under study. Cardiovascular sequelae of COVID-19 include heart failure, cardiomyopathy, acute coronary syndrome, arrhythmias, and venous thromboembolism. This article aims to collect scientific evidence by exploiting PubMed, Scopus, and Pedro databases to highlight the cardiovascular complications of COVID-19 and to define the physiotherapy treatment recommended for these patients. Exercise training (ET), an important part of cardiac rehabilitation, is a powerful tool in physiotherapy, capable of inducing significant changes in the cardiovascular system and functional in the recovery of endothelial dysfunction and for the containment of thromboembolic complications. In conclusion, due to the wide variety of possible exercise programs that can be obtained by combining intensity, duration, and speed in various ways, and by adjusting the program based on continuous patient monitoring, exercise training is well suited to the treatment of post-COVID patients with an impaired cardiovascular system of various degrees.

Role of multimodality imaging in evaluation of cardiovascular involvement in COVID-19.

The management of patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be difficult due to the need for dedicated in-hospital pathways, protective measures for healthcare professionals and isolated beds of intensive care, particularly in areas overwhelmed by wide viral spread. Although pneumonia is the most common clinical manifestation in coronavirus disease 2019 (COVID-19), a variety of cardiovascular complications have been reported. An integrated diagnostic algorithm in SARS-CoV-2-infected patients with suspected cardiac involvement (laboratory findings of myocardial injury and electrocardiographic changes) may help to avoid unnecessary examinations and minimize the risk of operator infection. Due to its mobility and bedside feasibility, echocardiography is the first-line imaging technique in this clinical setting. It quickly provides information on ventricular functions, pulmonary hypertension, valve disease and pericardial effusion. In case of ST-segment elevation (STE), urgent coronary angiography should be performed. Cardiac ultrasound helps distinguish between ischemic and non-ischemic myocardial disease and may detect pericardial disease. Transmural ischemic electrocardiographic changes, with or without early elevated troponin levels or echocardiographic wall motion abnormalities, will determine the need for early invasive coronary angiography. Computed tomography (CT) through its multiple applications (chest CT; CT pulmonary angiography and coronary CT angiography; late iodine enhancement CT) and cardiac magnetic resonance might be helpful in reinforcing or redirecting diagnostic hypothesis emerged by other clinical, electrocardiographic and echocardiographic findings. The current pandemic makes it challenging to perform serial invasive and non-invasive diagnostic testing in COVID-19 patients and high serum troponin level. Nevertheless, thoughtful and systematic use of an appropriate multimodality imaging strategy is clinically relevant to detect cardiac injury and distinguish myocardial infarction from, myocarditis, takotsubo syndrome and pulmonary embolism.

Cardiovascular risk factors and mortality in hospitalized patients with COVID-19: systematic review and meta-analysis of 45 studies and 18,300 patients.

BACKGROUND: A high prevalence of cardiovascular risk factors including age, male sex, hypertension, diabetes, and tobacco use, has been reported in patients with Coronavirus disease 2019 (COVID-19) who experienced adverse outcome. The aim of this study was to investigate the relationship between cardiovascular risk factors and in-hospital mortality in patients with COVID-19. METHODS: MEDLINE, Cochrane, Web of Sciences, and SCOPUS were searched for retrospective or prospective observational studies reporting data on cardiovascular risk factors and in-hospital mortality in patients with COVID-19. Univariable and multivariable age-adjusted analyses were conducted to evaluate the association between cardiovascular risk factors and the occurrence of in-hospital death. RESULTS: The analysis included 45 studies enrolling 18,300 patients. The pooled estimate of in-hospital mortality was 12% (95% CI 9-15%). The univariable meta-regression analysis showed a significant association between age (coefficient: 1.06; 95% CI 1.04-1.09; p < 0.001), diabetes (coefficient: 1.04; 95% CI 1.02-1.07; p < 0.001) and hypertension (coefficient: 1.01; 95% CI 1.01-1.03; p = 0.013) with in-hospital death. Male sex and smoking did not significantly affect mortality. At multivariable age-adjusted meta-regression analysis, diabetes was significantly associated with in-hospital mortality (coefficient: 1.02; 95% CI 1.01-1.05; p = 0.043); conversely, hypertension was no longer significant after adjustment for age (coefficient: 1.00; 95% CI 0.99-1.01; p = 0.820). A significant association between age and in-hospital mortality was confirmed in all multivariable models. CONCLUSIONS: This meta-analysis suggests that older age and diabetes are associated with higher risk of in-hospital mortality in patients infected by SARS-CoV-2. Conversely, male sex, hypertension, and smoking did not independently correlate with fatal outcome.

Timing of national lockdown and mortality in COVID-19: The Italian experience.

OBJECTIVE: To evaluate if the pandemic mitigation effects of lockdown in Italy have been influenced by the level of penetration of COVID-19 in Italian Regions at the onset of containment (March 9, 2020). METHODS: We collected data published day by daily from the first COVID-19 case until May 3, 2020, the end of lockdown, by Italy's Protezione Civile Department. Linear regression analyses were performed to evaluate possible correlations between the number of confirmed cases/100.000 residents and the number of new cases/100.000/day before lockdown, with the number of deaths/100.000 residents at sixty days, in each Italian region. RESULTS: We found a significant positive correlation between the number of confirmed cases before lockdown and mortality up to sixty days (p < 0.001; R2 = 0.57) as well as between the incidence rate of new cases per day and mortality up to sixty days (p < 0.001; R2 = 0.73). Regression coefficients indicated about two deaths up to sixty days for every new patient with confirmed COVID-19 before lockdown, and 37 deaths for every new infected subject per day until the lockdown decree of March 9, 2020. CONCLUSIONS: Every new infected subject before lockdown counted on the death toll of the COVID-19 pandemic in Italy.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19.

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.

Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study.

To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses.