key: cord-0763092-u8agxs8d
authors: Napoli, Claudio; Tritto, Isabella; Benincasa, Giuditta; Mansueto, Gelsomina; Ambrosio, Giuseppe
title: Cardiovascular involvement during COVID-19 and clinical implications in elderly patients. A review
date: 2020-08-05
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2020.07.054
sha: dbdd3f14a564b6545cf95d025cbe36af1ca4fea3
doc_id: 763092
cord_uid: u8agxs8d

SARS-CoV-2 betacoronavirus is responsible for the Corona Virus Disease 2019 (COVID-19), which has relevant pathogenic implications for the cardiovascular system. Incidence and severity of COVID-19 syndrome are higher in the elderly population (65 years and older). This may be due to higher frequency of comorbidities, but increased frailty and immunosenescence linked with aging may also contribute. Moreover, in elderly individuals, SARS-CoV-2 may adopt different molecular strategies to strongly impact on cardiac aging that culminate in exacerbating a pro-inflammatory state (cytokine storm activation), which, in turn, may lead to pulmonary vascular endothelialitis, microangiopathy, diffuse thrombosis, myocarditis, heart failure, cardiac arrhythmias, and acute coronary syndromes. All these events are particularly relevant in elderly patients, and deserve targeted cardiovascular treatments and specific management of repurposed drugs against COVID-19. We discuss current evidence about the cardiovascular involvement during COVID-19, and elaborate on clinical implications in elderly patients.

Aging and senescence are complex processes [1, 2] . Aging is associated with increased frailty of the body functions, particularly of the cardiovascular system [3, 4] , increased oxidative stress [5] , and decreased endogenous protective mechanisms [6] [7] [8] . Moreover, increasing age is associated with reduced efficiency of thrombolysis [9] , lower protection afforded by physical exercise against myocardial ischemia [7, 10] , as well as increased incidence of heart failure [11] .

Many pathogens are more aggressive and prevalent in the elderly population [12] . SARS-CoV-2 betacoronavirus (large RNA virus) is the virus responsible for Corona Virus Disease 2019 , a respiratory infection, with relevant effects on the cardiovascular system [13, 14] .

Furthermore, patients with pre-existing cardiovascular conditions represent a relevant subset of elderly patients with symptomatic form of the disease and consequent worse outcomes [13, 15] . Table 1 shows clinical studies regarding COVID-19 that have stratified cardiac vs non-cardiac patients according to increasing age and gender [16] [17] [18] [19] [20] .

Here, we describe the pathogenic events occurring in the cardiovascular system of elderly patients affected by COVID-19 and their possible clinical management.

J o u r n a l P r e -p r o o f Older age, D-dimer levels greater than 1 μg/mL, and higher SOFA score on admission were associated with higher in-hospital death [20] Abbreviations: CHD: Coronary Heart Disease; COPD: Chronic Obstructive Pulmonary Disease; HF: Heart Failure; SOFA: Sequential Organ Failure Assessment.

Patients suffering of COVID-19 infection can present cardiac arrhythmias, heart failure, myocarditis, pericarditis, and vasculitis [21, 22] with increased troponin release [13, 23, 24] . The structure of the SARS-CoV-2 binding site shows enhanced affinity for the angiotensin I converting enzyme 2 (ACE2) receptor which is expressed mainly in the lung and other tissues including vascular endothelial cells [25, 26] . Patients with cardiovascular diseases are more prone to respiratory virus illness, thus constituting a high-risk group [27] [28] [29] . Viral entry into the myocardium and artery vessels through ACE2 receptor can enhance the risk for myocardial injury and inflammatory response (Figure 1 ) [30] . However, it remains to be established whether a higher rate of cardiac injury with increasing age is due to a direct viral injury or an overwhelming immunological response within myocardium and microvasculature, or both [31] [32] [33] [34] .

ACE2 has been confirmed as the SARS-CoV-2 internalization receptor [26, 35, 36] together with the TMPRSS2 membrane protease that primes the spike S protein of the virus [37] and significantly enhances viral shedding [38] . In heart failure, expression of ACE2 is downregulated, though its function may be upregulated [39] , reflecting increased ACE2 activity. Relevantly, ACE2

is an immune modulator interacting with macrophages in the setting of inflammation [40] , and it also reduces the levels of angiotensin II which is pro-inflammatory and pro-oxidant, while increasing angiotensin 1-7 concentrations that exert opposite effects [41] . In terms of cardiac manifestations of COVID-19, the spectrum is similar to a general viral myocarditis [42] .

Infected subjects with robust immune response can manifest acute myocarditis with heart failure, accompanied by elevations of cytokines and inflammatory cell infiltration of the heart [43] .

Lymphopenia occurs in over 80% of patients with marked reductions in circulating levels of CD4 + and CD8 + T lymphocytes, and relative prevalence of mononuclear cells (monocytes and macrophages) in target injury tissues [43] (Figure 1) . Thus, decreased capacity to phagocytose J o u r n a l P r e -p r o o f apoptotic cells by senescent macrophages may induce a vascular pro-inflammatory state. The immune system imbalance is typical of aging and is exacerbated upon SARS-CoV-2 infection leading to further depletion of CD4 + T cells and macrophage response [34] . Thus, elderly subjects may have a natural tendency to have reduced virus clearance, which in turn generates an inappropriate cytokine storm, with inadequate immune response and immunologic memory.

Another pathogenetic hallmark of COVID-19, which distinguishes it from most infectious diseases, is the ability of the virus to directly infect endothelial cells and cause their perturbation and injury, leading to a pro-inflammatory status as well as plasminogen activator release (responsible for very high levels of D-dimers) and high molecular size multimeric von Willebrand factor levels which cause thrombotic microangiopathy [30, 43] . In a very recent study, Ackermann et al. [44] have analyzed the up-regulation of genes regulating the "intussusceptive angiogenesis" process by using direct multiplexed measurements in the autopsy of COVID-19 patients compared to H1N1 and healthy lungs. An "attachment of lymphocytes to the vascular wall", a feature called "endothelialitis" or "endothelitis", has been initially documented in liver biopsies [45] and arteriosclerosis in heart transplant recipients [46] . COVID-19 induces reduction of lymphocytes, mainly CD4 + and CD8 + T cells, and secondary viral sepsis [47] . Viral particles and SARS-CoV2

RNA have been detected in T lymphocytes from peripheral blood, spleen, and lymph nodes, suggesting that SARS-CoV2 infects T cells directly [47] . The master gene hypoxia-inducible factor (HIF) regulates genes of adaptive response including modulators of inflammation but also of angiogenesis suggesting novel potential therapeutic strategies [48] . Further studies will determine whether differences in angiogenesis and endothelialitis represent distinct points in a similar process of pneumonia or a true endotype occurring selectively during the cytokine storm seen in COVID-19

patients (Figure 1) .

Patients with clinical evidence of vasculitis, or laboratory indicators of thrombotic risk, such as higher D-dimer levels, should be considered with no doubt for early treatment with J o u r n a l P r e -p r o o f antithrombotic drugs. Moreover, many of these patients should be considered also for full anticoagulation, such as heparin, depending on individual risk versus benefit, especially in elderly individuals [49] . (Figure 1) (Figure 1) . In elderly patients with potential dysfunctional immune responses there are early warning signals, such as lymphopenia, troponin release, elevated BNP, rising inflammatory markers such as cRP, IL-1β and IL-6 [56] . These aging patients should be followed closely and monitored for early evidence of organ failure, with efforts made to restore immunosenescence and cellular-mediated response [34] .

If viral proliferation is still continuing, strategies to attenuate the virus may be critical. However, the intervention will need to be instituted early, before the immune amplification process is fully underway.

Furthermore, obesity which is common among elderly subjects represents another independent risk factor linked to severe COVID-19 illness and its complications [57] . Indeed, obesity triggers a chronic pro-inflammatory state characterized by elevated levels of IL-6, CRP, and adipokine which are further increased upon viral infection leading to the dangerous cytokine storm J o u r n a l P r e -p r o o f [57] . Besides, elderly patients with chronic obstructive pulmonary disease (COPD) were at high risk of the involvement of the severe and critical clinical forms of COVID-19 resulting in high mortality rate [58] .

Whereas the release of troponin is relatively modest during COVID-19, this may be an indication of either viral or immune-mediated cardiac injury. The release of "danger signals" from myocytes in patients with heightened immune response can further amplify myocardial injury [16] [17] [18] 23, 59] . Thus, patients with cardiac injury and/or stress marker release warrant more careful monitoring and institution of cardioprotective agents to minimize ongoing damage [16] [17] [18] 23, 59] . In patients with suspected acute myocarditis, inflammatory cardiomyopathy, and pericarditis, appropriate investigations, such as magnetic resonance imaging where feasible and safe to perform, can be helpful [60, 61] . Moreover, electrocardiographic abnormalities reflecting cardiovascular dysfunction have been reported in elderly patients affected by severe COVID-19 [62] . Furthermore, chest X-ray plays a relevant role in the early diagnosis and treatment for patients with suspected or confirmed COVID-19 [63] as well as lung computed tomography is recommended during hospitalization to monitor COVID-19 and heart failure [64] . A great attention should also be devoted to pulmonary and cardiac rehabilitation of COVID-19 survivors [65] .

Multiple clinical trials are currently in progress using drug interventions to treat COVID-19 [66] and many others are under development. Down-regulation of ACE2 with viral infection may predispose to relatively unopposed angiotensin II effects, such as hypertension, enhanced inflammation, and thrombosis [41] . Most patients with cardiovascular diseases are treated with

ACEi or ARB therapy [67] . Since both ACEI and ARB could significantly increase the amount of cardiac ACE2 mRNA, it has been hypothesized that these drugs might impact the cardiac transcriptome, contributing to the aggressive course of COVID-19 [68] . However, major J o u r n a l P r e -p r o o f cardiology scientific associations, such as ESC Hypertension Council, HFSA, ACC, and AHA have rejected this correlation hypothesis concluding that there is no significant evidence to stop therapeutic treatment with these drugs [61, 69] . Indeed, as there are no definitive data on the risk versus benefit of ACE inhibitors or ARBs in COVID-19, most professional organizations have recommended continuation of RAS inhibitors in patients who have been prescribed them [61, 69] .

Actually, emerging data suggests that benefits may outweigh risks in patients with COVID-19 and hypertension when prescribed ACE inhibitors or ARBs [67] [68] [69] [70] . Ongoing randomized trials will help providing definitive answers. In patients with heart failure, appropriate medications, including RAS inhibitors, should be considered [61] . The risk/benefit of statin use is still controversial in patients affected by COVID-19, except for patients with diabetes, history of stroke or acute coronary syndrome, and familial hypercholesterolemia [71, 72] . However, a molecular docking study has suggested that statins may act as SARS-CoV-2 Mpro inhibitors (a protein of the viral envelope); clinical investigations are needed to clarify whether statins could exert beneficial effects in the treatment of COVID-19 disease [73] .

Low resting heart rate (RHR) is associated with health and longevity, and conversely, high RHR associated with disease and adverse events [74] [75] [76] [77] [78] . Advances in technology have provided new insights into genetic factors related to RHR as well as insights into whether elevated RHR is a risk factor or risk marker [79] . Besides, genome-wide association studies in the general population using

Mendelian randomization have demonstrated a causal link between RHR and longevity [74] . Since the COVID-19 pandemic was a global disaster, many repurposed drugs are being tested.

Chloroquine or hydroxychloroquine may interfere with cellular endocytosis of the virus [80] ;

however, these drugs may prolong QT and, thus, ECG monitoring needs to be performed [81] . In this regard, data from Wuhan, China, has indicated that arrhythmias and acute cardiac injury are among the most prevalent heart complications in hospitalized patients (16.7% and 7.2%, respectively) [50] . Recent studies have questioned the benefit of hydroxychloroquine or chloroquine J o u r n a l P r e -p r o o f in the treatment of patients affected by COVID-19 owing to serious side effects disturbing the heart rhythm when prescribed at high doses or combined with azithromycin [82, 83] . Abnormal QT prolongation, defined as a prolongation to a QTc >500 msec, has been documented for 10%-25% of COVID-19 patients treated with hydroxychloroquine/azithromycin. Many of these patients were elderly and had comorbidities increasing the risk of drug-induced long QTS. Physicians should pay particular attention to elderly females, patients with structural heart disease, baseline QT interval on ECG, concomitant use of other QT-prolonging drugs, potassium or magnesium abnormalities, and recorded episodes of bradycardia [84] . However, only results from ongoing randomized trials will provide definitive answers raising the issue of needing more rigorous data during COVID-19

pandemic [85] .

The ability to restore immune balance, with approaches such as type I interferon,

immunoglobulin, and recovered serum, may be considered. Among the most important cells of primary immunity that causes cytokine storm there are mast cells that reside in all vascularized tissues generating pro-inflammatory cytokines such as IL-1 and IL-6 [86] [87] [88] [89] . Remarkably, suppression both of IL-1 and IL-6 have been shown to have a therapeutic effect in patients with immune system suppression and advanced form of COVID-19 [86] [87] [88] [89] . Anti-inflammatory strategies, whether anti-IL-1 or anti-IL-6 approaches (such as tocilizumab), will be determined in randomized trials. Preliminary studies indicated some beneficial effects of tocilizumab, a IL-6 receptor antagonist, in the clinical management of COVID-19 [90] [91] [92] .

Many antivirals have been administered to COVID-19 patients. A recent trial with Lopinavir-Ritonavir gave disappointing results [93] . Viral proliferation can be blocked at multiple stages, including inhibition of RNA polymerase with remdesivir. Preliminary data seems to indicate that remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 [94, 95] . Among the regions of the S protein (S1, S2, RBD), RBD is one accessible target for vaccine. Nevertheless, RBD is a genomic variable region [96] with a risk for J o u r n a l P r e -p r o o f immunologic "escape" [97] . The immunogenic role of the N protein, a more conserved region of the genome, is still poorly understood in immune response to SARS-CoV-2 both in adult and elderly patients [96, 97] . Vaccine development is the best successful approach for reducing viral diseases, including COVID-19. Until now, there are 70 active clinical trials related to a SARS-CoV2 vaccine (see ClinicalTrials.gov). Overall, people who have more than 60 years are believed to have lesser protective effects by vaccines due to age-related declines in immune function [98] .

Thus, even when a vaccine for SARS-CoV2 will become available, particular attention will be due to elderly subjects.

Elderly patients, particularly those with underlying structural heart disease, are among the highest risk group for severe COVID-19 illness and its complications. Currently, diagnostics and personalized therapy of severe and critically ill patients remain the major challenges. In the early stage of the disease, we need to avoid "fever phobia" [99] . The greatest benefit would be seen when drugs are administered 30 hours before severe symptom onset, especially in elderly subjects [100] .

In this regard, network medicine [101, 102] and precision medicine [103] would be helpful in the clinical evaluation of these patients. Cardiovascular dysfunction, cytokine storm, and lymphocytopenia are hallmarks of COVID-19 disease associated with a poor clinical outcome;

however, the precise mechanistic basis is unknown. Despite several clinical trials are ongoing to assess the effectiveness of repurposed drugs, no definitive therapies are currently available. Only dedicated prospective trials in patients of different ages will provide definitive answers to the precise role of aging in COVID-19 therapy. Among gender-related differences, females seem to have a higher susceptibility to Sars-CoV-2 but lower severity and mortality [104, 105] . However, further investigations are required to better understand the gender-specific difference in the development of COVID-19. Much advance in the knowledge of SARS-CoV-2 pathogenic mechanisms is coming from network-oriented analysis which provides maps of human proteins J o u r n a l P r e -p r o o f interacting with SARS-CoV-2 proteins suggesting putative candidate repurposed drugs and potential combination therapies [106] . The elderly population residing in long-term care facilities suffering from multiple comorbidities [107] and thus more prone to COVID-19 related sequelae.

The Italian National Institute of Health COVID-19 mortality group showed that elderly adults (≥ 65 years) had a higher number of comorbidities compared to those aged <65 years [108] . Interestingly, the prevalence of CHD, atrial fibrillation, heart failure, hypertension, COPD, was higher in older patients (≥ 65 years). Thus, cardiovascular aging needs to be evaluated carefully in the context of COVID-19.

The authors declare they have no conflict of interest.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Not commissioned, externally peer reviewed. 

To help aging populations, classify organismal senescence

The hallmarks of aging

Isik AT. Inflammation, frailty and cardiovascular disease

Novel pathogenic insights in the primary prevention of cardiovascular disease

Age-related decrease in cardiac tolerance to oxidative stress

Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart?

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients

Warm-up" phenomenon detected by electrocardiographic ambulatory monitoring in adult and older patients

Efficacy of thrombolysis in younger and older adult patients suffering their first acute q-wave myocardial infarction

Six-minute walking test but not ejection fraction predicts

Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality

China Novel Coronavirus I and Research T. A novel coronavirus from patients with pneumonia in China

Characteristics of COVID-19 infection in Beijing

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy

Association of clinical and radiographic findings with the outcomes of 93 patients with COVID-19 in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

A current review of COVID-19 for the cardiovascular specialist

Coronavirus disease 2019 (COVID-19) and cardiovascular disease

Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis

High-sensitivity cardiac troponin can be an ally in the fight against COVID-19

Structural basis of receptor recognition by SARS-CoV-2

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Correlation between herpes and Epstein-Barr viruses and acute myocardial infarction

Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis

Acute myocardial infarction after laboratory-confirmed influenza infection

Measuring multimorbidity in older adults: comparing different data sources

Immunosenescence of ageing

The influence of age on T cell generation and TCR diversity

Immunosenescence exacerbates the COVID-19

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Enhanced isolation of SARS-CoV-2 by TMPRSS2 expressing cells

New perspectives in the renin-angiotensin aldosterone system (RAAS) IV: circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure

Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse

Angiotensin converting enzyme 2: a double edged sword

Clinical and immunologic features in severe and moderate Coronavirus Disease

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

Clinicopathological study of lymphocyte attachment to endothelial cells (endothelialitis) in various liver diseases

Accelerated arteriosclerosis in heart transplant recipients is associated with a T-lymphocyte mediated endothelialitis

Bin Cao. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet Online. 2020

Targeting the HIF pathway in inflammation and immunity

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence

Clinical and epidemiological characteristics of 320 deceased Covid-19 patients in an Italian Province: a retrospective observational study

Molecular mechanisms of ischemic preconditioning with cardiovascular aging in elderly patients with arterial hypertension

SARS-CoV-2 and viral sepsis: observations and hypotheses

Lille Intensive Care COVID-19 and Obesity study group. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

Concerns about COVID-related collateral damage for patients with COPD

Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)

Cardiac involvement in recovered COVID-19 patients identified by magnetic resonance imaging

Management of Heart Failure Patients with COVID-19. A Joint Position Paper of the Chinese Heart Failure Association & National Heart Failure Committee and the Heart Failure Association of the European Society of Cardiology

Characteristic electrocardiographic manifestations in patients with COVID-19

Portable chest X-ray in coronavirus disease-19 (COVID-19): A pictorial review

CT Features of coronavirus disease 2019 (COVID-19) pneumonia in 62 Patients in Wuhan, China

Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?

Coronavirus puts drug repurposing on the fast track

Renin-angiotensin-aldosterone system blockers and the risk of Covid-19

Coronavirus Disease 2019 (COVID-19): do angiotensin-converting enzyme inhibitors/angiotensin receptor blockers have a biphasic effect?

Outcomes in patients with COVID-19 infection taking ACEI/ARB

Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality

COVID-19: A personalized cardiometabolic approach for reducing complications and costs. The role of aging beyond topics

May statins and PCSK9 inhibitors be protective from COVID-19 in familial hypercholesterolemia subjects? Nutr Metab Cardiovasc Dis

Statins and the COVID-19 main protease: in silico evidence on direct interaction

Resting heart rate and relation to disease and longevity: past, present and future

Bradyarrhythmias in the elderly

Age-related changes in human left and right atrial conduction

Influence of advancing age on fractionated right atrial endocardial electrograms

Resting heart rate and the risk of heart failure in healthy adults: the Rotterdam Study

Genome-wide association analysis identifies multiple loci related to resting heart rate

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Chloroquine-induced QTc prolongation in COVID-19 patients

An updated systematic review of the therapeutic role of hydroxychloroquine in Coronavirus Disease-19 (COVID-19)

Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in

Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin

Balancing the need for rapid and rigorous scientific data during early phase of the COVID-19 pandemic: a further role for the scientific community

Induction of proinflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1

Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2

SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and antiinflammatory cytokines

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in

Management and treatment of COVID-19: the chinese experience

A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19

GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19

ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19-Preliminary Report

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19)

Detection and control of influenza outbreaks in well-vaccinated nursing home populations

COVID-19: Do not be phobic from fever

Interventions to restore appropriate immune function in the elderly

Molecular networks in network medicine: development and applications

Strengths and opportunities of network medicine in cardiovascular diseases

Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics

Age-dependent gender differences of covid-19 in mainland china: comparative study

Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Coronavirus disease 2019 in geriatrics and long-term care: the ABCDs of COVID-19

Italian National Institute of Health COVID-19 mortality group. Clinical characteristics of hospitalized individuals dying with COVID-19 by age group in Italy