key: cord-0933172-insb76x3
authors: Colombo, Claudia; Garatti, Laura; Ferrante, Giulia; Casadei, Francesca; Montalto, Claudio; Crimi, Gabriele; Cogliati, Chiara; Ammirati, Enrico; Savonitto, Stefano; Morici, Nuccia
title: Cardiovascular injuries and SARS-COV-2 infection: focus on elderly people
date: 2021-07-28
journal: J Geriatr Cardiol
DOI: 10.11909/j.issn.1671-5411.2021.07.001
sha: b13d35ade7da616a71368d4c9aac7fcb6a7a6ec2
doc_id: 933172
cord_uid: insb76x3

The novel coronavirus disease (COVID-19) has hit the healthcare system worldwide. The risk of severe infection and mortality increases with advancing age, especially in subjects with comorbidities such as cardiovascular disease, hypertension, diabetes, obesity and cancer. Moreover, cardiovascular complications such as myocardial injury, heart failure and thromboembolism are frequently observed in COVID-19 cases, and several biomarkers (troponin, NTproBNP and D-Dimer) have been identified as prognostic indicators of disease severity and worst outcome. Currently, there is no specific therapy against SARS-CoV-2, although many medications are under investigation. The aim of this review will be to explore the intertwined relationship between COVID-19 disease and the cardiovascular system, focusing on elderly population. The available supportive treatments along with the related concerns in elderly patients, due to their comorbidities and polypharmacotherapy, will be explored.

A number of studies suggest an association between pre-existing CVD and severe COVID-19, [3,5−7] but the viral infection leads itself to CV complications or exacerbation of pre-existing CVD. [6, 7] particularly in the geriatric population. [8] PATHOPHYSIOLOGY COVID-19 and Cardiovascular System: Hypothesis of Interaction and Mechanisms of Damage COVID-19 interacts with various systems, being responsible for a wide spectrum of clinical manifestations. Angiotensin converting enzyme-2 (ACE2) has been demonstrated to be the SARS-CoV-2 cell entry receptor, after activation of the viral surface spike protein S by transmembrane protease serine 2 (TMPRSS2). [9] ACE2 is highly expressed in the lung (principally type II alveolar cells), but has also been found in multiple tissues, including heart, intestinal epithelium, vascular endothelium and kidneys. [6] Relevantly, by cleaving angiotensin II (Ang II), ACE2 generates Ang 1-7, which counteracts the pro-inflammatory and pro-oxidant effects of Ang II. [10, 11] Beyond direct cell damage due to viral infiltration, SARS-CoV-2 seems to downregulate ACE 2 expression and Ang 1-7 production, leading to increased levels of Ang II. [12] Consequently, alveolar apoptosis and fibrosis together with cytokine storm and systemic inflammation can result in acute respiratory distress syndrome (ARDS) and multiorgan dysfunction. [13] Cardiovascular complications are often observed in patients with COVID-19, especially those with severe manifestations. The mechanisms of cardiac injury remain under investigation, but it has been supposed to involve three possible mechanisms: direct myocardial infection through ACE2 receptors expressed in myocardial tissue, indirect injury due to the systemic inflammatory response and increased cardiac stress due to hypoxemia (Figure 1 ). [14−16] Evidence suggests that ACE2 plays a double role in cardiovascular complication of COVID-19. First, ACE2 is largely expressed by myocardial pericytes, [17] therefore representing a potential portal of viral entry, resulting in cellular death and inflammation. On the other hand, viral replication seems to induce ACE2 downregulation. [18] This may alter the ACE/ACE2 balance leading to hyperactivation of the ACE/Ang II/AT1 system, responsible of vasoconstrictive, pro-inflammatory and pro-oxidant effects, potentially culminating in acute heart failure, endothelial dysfunction and intravascular coagulopathy. [19] The cardiovascular damage mediated by SARS-CoV-2 can also result from the immune-mediated pathway caused by activated T and B cells, leading to a cytokine storm (i.e., interleukin-1 (IL-1), IL-6, and TNF-a) [20] that can exert a negative inotropic ef- Figure 1 Possible mechanisms of cardiovascular injury due to COVID-19. ACE-2: angiotensin converting enzyme-2; ACS: acute coronary syndrome; AHF: acute heart failure; Ang II: angiotensin II; ARDS: acute respiratory distress syndrome; CS: cardiogenic shock; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; VTE: venous thromboembolism. fect, promote cardiomyocyte apoptosis and fibrosis and induce the release of pro-coagulant factors. [21−23] Generally, the rise in cardiac biomarkers tracks with inflammatory markers elevation, suggesting the relationship between cytokine storm and myocardial injury. [24] Even though Tavazzi, et al. [25] published a case of acute cardiac injury directly linked to SARS-CoV-2 myocardial localization, needs to be clarify if myocardial localization implies a viraemic phase or, alternatively, the migration of infected alveolar macrophages in extra-pulmonary tissues. Regardless the underlying mechanism, inflammatory infiltrates and necrosis were observed in cardiomyocytes of patients with COVID-19 and suspected myocarditis. [26, 27] In addition, prolonged hypoxia due to respiratory failure leads to cardiomyocytes apoptosis, [28] pulmonary hypertension, [29] and pressure overload of the right ventricle. Finally, the endothelial damage caused by SARS-CoV-2 causes vascular injury with severe consequences as acute release of cytokines, plasminogen activator (responsible for high levels of D-dimers) and von Willebrand factor, leading to a pro-thrombotic status and to a thrombotic microangiopathy. [30−33] Interestingly, older adults and subjects with diabetes and pre-existing CVD have lower levels of ACE2. [34, 35] The ACE2 downregulation with subsequent increased levels of Ang II and proinflammatory state predisposes older individuals with cardiovascular comorbidities to experience a more aggressive SARS-CoV2 infection, which can explain the higher CFR reported in the studies. [36] Moreover, aging leads to a disruption of the immune system and to a vascular pro-inflammatory state with dysregulated production of cytokines and other inflammatory mediators, that can further explain the worst outcome of patients affected by COVID-19 disease. [37, 38] 

Myocardial injury is generally defined by the elevation of cardiac troponin (cTn) above the 99 th percentile of its upper limit of normal (ULN). It can occur in the context of myocardial ischemia (type 1 or type 2 myocardial infarction according to fourth universal definition) or non-ischemic myocardial processes (myocarditis, stress-induced cardiomyopathy or cytokine release syndrome). [39] Irrespectively from the underlying mechanism, cTn elevation was observed in 7.2% to 17% of hospitalized patients with COVID-19. [6, 40] and has important prognostic implications. Indeed, as showed in several observational studies (Table 1 ) troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality, especially in elderly with an history of CVD. [41] The pattern in the rise of cTn levels is also significant: various reports from China showed that cTn values for survivors did not change significantly during follow-up, while they continued to rise until death in non-survivors. [6, 28] In absence of obstructive coronary artery disease, whether the myocardial injury is secondary to oxygen supply-demand imbalance (Type 2 MI), acute myocarditis, stress cardiomyopathy or cardiac involvement in cytokine release syndrome is a challenging issue. Despite some argued that up to 7% of COVID-19-related deaths were attributable to myocarditis, [42] the prevalence of acute myocarditis among COVID-19 patients is still unclear. [43] The Chinese National Health Commission firstly reports autopsy specimens characterized by degenerated and necrotized cardiomyocytes and monocytes, lymphocytes and/or neutrophils in the myocardium, [44] making a diagnosis of suspected myocarditis. Considering that in the clinical scenario of COVID-19 patients cardiac magnetic resonance or endomyocardial biopsy are rarely feasible, the diagnosis of myocarditis is mainly based on troponin elevation in association with echocardiographic abnormalities and ECG changes compatible with acute myocarditis. [45] Cases of acute cardiomyopathies with clinical, echocardiographic and ECG features of Tako-Tsubo syndrome have also been reported, especially in elderly individuals and in critically ill patients with prolonged mechanical ventilation. [46, 47] Acute Coronary Syndrome

Despite the effects of COVID-19 on acute coronary syndromes (ACS) is still under investigation, it is known that profound systemic inflammatory responses may contribute to destabilize plaques in COVID-19 patients. [48] In this regard, Kwong et al. 

Aquino [105] 73/254 (29%) Hs-cTnI > 99 th URL 53.8 ± 12.7

Multivariate cox proportional hazards analysis showed that primary endpoint (mortality) is determined by several variables including myocardial injury (OR = 3.764, 95% CI: 1.307-10.838; P = 0.014).

Arcari [106] 39/103 (38%) Hs-cTnI > URN 79 ± 13 In-hospital death is 11% in patients with Hs-troponine < URN and 31% in patients with Hs-Troponine > URN (P = 0.012).

Barman HA [27] 150/607 (24.7%) Hs-cTnI > 99 th percentile URL 68.5 ± 13.4 Mortality rate is higher in patients with cardiac injury vs. patients without myocardial injury (42% vs. 8%; P < 0.01).

Cipriani [107] 41/109 (38%) Hs-cTnI > 99 th URL 71 Compared with survivors, non-survivors presented with higher median levels of Hs-cTnI (64 vs. 6 ng/L, P < 0.001).

Du [108] NA/179 (NA) 57.6 ± 13.7

Univariate and multivariate logistic regression analysis revealed that cardiac troponin I ≥ 0.05 ng/mL (OR = 4.077, 95% CI: 1.166-14.253; P < 0.001) is associated with an increase in risk of mortality.

Guo [ Li [24] 181/2 068 (9%) Hs-cTnI > 99 th URL 63 (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) When compared to non-critically ill patients critically ill have more frequent cardiac injury on admission (30.3% vs. 2.3%, P < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, P < 0.001).

Lombardi [110] 278 Karbalai [112] 118/386 (30%) Hs-cTnI > 99 th URL 59 ± 16

The development of cardiac injury is significantly associated with a higher inhospital mortality rate compared to those with normal troponin levels (40.9% vs. 11.1%, P < 0.001).

Majure [113] 1821/6 247 (29%)

Hs-cTnI > 99th URLTnT > 99 th percentile URLHs-cTnI > 99th URL 66 Patients with elevated troponin have significantly increased odds of death for mildly elevated compared with normal troponin (adjusted OR = 2.06; 95% CI: 1.68-2.53; P < 0.001).

Nie [114] 103/311 (33%) TnI > 99 th percentile URL 63 (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) Multivariable logistic regression analysis identified cTNI concentration (OR = 1.92 [95% CI: 1.41-2.59]) as one of the independent risk factors for death in patients with COVID-19.

Qin [115] 95/1 462 (6.5%) Hs-cTnI > 99 th percentile URL 57 Elevation of hs-cTnI is associated with increased 28 days mortality (adjusted HR 7.12 ([95% CI: 4.60-11.03]; P < 0.001).

Stefanini [116] 90/397 (23%) Hs-TnI > 99 th percentile URL 67 The rate of mortality is higher in patients with elevated hs-TnI (22.5%, OR = 4.35, 95% CI: 1.72 to 11.04).

Shi [ Woo [120] NA/415 (NA) Hs-cTnI > 99 th URLHs-cTnI > 99 th URL 66 Elevated troponin is associated with a higher rate of mortality (37.2% vs. 14.8%, P < 0.001).

Yang [ demonstrated that patients with acute respiratory infections are more prone to develop acute MI after influenza and after non-influenza viral illnesses including other coronavirus species. [49] Moreover, inflammation promotes a prothrombotic state, which could further increase the risk of microangiopathy [50] and coronary thrombosis at sites of plaque disruption. [51] As already mentioned, although reports suggest that cTn elevation in COVID-19 may be related more to myocardial injury or type 2 MI than to type 1 MI, more data are needed to properly understand all mechanisms that may induce ACS in SARS-CoV-2 infection. [52] On the other hand, as a side effect of COVID-19, the ongoing pandemic has stressed the public opinion and the emergency system to the point that activation of the Emergency Services and reperfusion therapy have been systematically delayed in STEMI, leading to increased rates of out of hospital cardiac arrest [53] and increased mortality across the ACS spectrum. [54] Arrhythmia Viral infections are associated with metabolic dysfunction, myocardial inflammation, and activation of the sympathetic nervous system, all of which predispose to cardiac arrhythmia. In a report on 138 hospitalized COVID-19 patients, the incidence of arrhythmia is about 17%, which ranked only second among serious complications after ARDS. [40] Arrhythmia was observed in 7% of patients who did not require ICU treatment and in 44% of subjects who were admitted to an ICU. [50] A study from Bhatla, et al. [55] concluded the cardiac arrests and arrhythmias are likely the consequence of systemic illness and not solely the direct effects of COVID-19 infection.

In the setting of supraventricular arrhythmias, as assessed by Colon et al, compared with patients without atrial tachyarrhythmias, those with atrial fibrillation, flutter, or tachycardia tended to be older with higher concentrations of CRP and D-dimer (55 ± 17 vs. 64.6 ± 12.8, P = 0.028). [56] Heart Failure Although few data exists on incidence of heart failure in COVID-19 patients, as reported by Zhou, et al., [6] acute heart failure (AHF) was observed in 23.0% of infected patients and was more common in patients who died compared to survivors (51.9% vs. 11.7%). Similar rates were observed in other studies. [57] Whether AHF is most commonly due to exacerbation of pre-existing cardiovascular disease or to new cardiomyopathy (such as myocarditis or stress cardiomyopathy) is not clear. In elderly individuals with left ventricular (LV) dysfunction, coronary artery disease, hypertension or diabetes, AHF is more likely to result from the exacerbation of these conditions, sometimes previously undiagnosed. [58] Moreover, diastolic LV dysfunction is a common condition related to senescence, [59] particularly in patients with hypertension, overweight and chronic obstructive pulmonary disease (COPD). These patients are prone to develop heart failure with preserved ejection fraction (HFpEF), triggered by fever, tachycardia and impaired renal function. [58] Routine monitoring of N-terminal pro-brain natriuretic peptide (NTproBNP) or BNP levels may be helpful to timely detection of patients with LV systolic or diastolic dysfunction, which is essential to avoid aggressive fluid replacement. [42] However, since natriuretic peptides circulation levels are significantly influenced by age, [60, 61] their diagnostic and prognostic accuracy may be limited in the elderly population. [61, 62] Therefore, diagnostic age-adjusted cutoff values have been proposed [62, 63] and should be taken into account in the management of these patients.

COVID-19 patients are at increased risk of thrombotic complications such as venous and arterial thromboembolism and microvasculature thrombosis. Data suggests that rates of thrombotic complications may involve almost 1/3 of critically ill patients. [64] Hypercoagulability in COVID-19 is primary the results of direct effects of the virus able to infect endothelial cells and cause perturbation of the cellular homeostasis, [65] leading to plasminogen activator release, and high molecular size multimeric von Willebrand factor causing thrombotic microangiopathy. [30] Furthermore, severe inflammatory response, critical illness, and underlying traditional risk factors may all predispose to thrombotic events, similar to prior coronavirus outbreaks. [66] Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in critically ill patients with COVID-19, especially when admitted to ICU (Table 2 ). Case series of hospitalized patients with COVID-19 reported VTE in 20% to 85% of ICU-patients and in 2% to 15% of non-ICU patients. [67−72] In some studies, VTE was associated with an increased mortality rate [73, 74] and longer duration of mechanical ventilation. [75] Whereas prophylactic anticoagulation is generally effective in preventing DVT, many patients experienced PE despite adequate prophylaxis, usually without evidence of DVT. [64] This evidence, together with autopsy studies descriptions of thrombotic microangiopathy in pulmonary and systemic vessels, [33] suggest that pulmonary thrombi, rather than emboli from peripheral veins, may be the hallmark of severe COVID-19. [76, 77] Arterial thrombosis was also reported as a complication of COVID-19. A large case series from New York, including 3 334 patients, reported stroke in 1.6%, myocardial infarction in 8.9% and other arterial thrombotic events (i.e., acute limb ischemia, upper extremity arterial thrombosis, renal and splenic infarcts) in 1%. As predictable, arterial thrombotic events were associated with increased mortality (adjusted HR = 1.99; 95% CI: 1.65−2.40). [73] The most common laboratory test abnormalities found in COVID-19 patients are thrombocytopenia and increased D-dimer levels, which are associated with a higher risk of requiring mechanical ventilation, ICU admission, or death. [66] In a multicenter retrospective cohort study from China, elevated Ddimer levels (> 1 g/L) were strongly associated with in-hospital death, even after multivariable adjustment. [6] As assessed by Tang, et al. [78] in a retrospective study of 183 COVID-19 patients, those who died presented levels of D-dimer and fibrin degradation products significantly increase (3.5-and ~1.9fold increase, respectively) and PT prolongation. In addition, 71% of patients who died fulfilled the International Society on Thrombosis and Hemostasis criteria for DIC, compared with only 0.6% among survivors.

Currently, there is no specific therapy against SARS-CoV-2, although many medications are under investigation. Therefore, we focused our review on supportive treatments and the related concerns in elderly COVID-19 patients, due to their comorbidities and polypharmacotherapy.

Glucocorticoids are indicated for severely ill patients receiving respiratory support, as they counteract the immune system hyperactivation and mitigate the inflammatory multiorgan damage due to COVID-19. [79] This recommendation originates from several clinical trials, especially the RECOVERY Trial, [80] which showed that treatment with dexamethasone at a dose of 6 mg once daily reduced mortality in COVID-19 patients on supplemental oxygen or ventilatory support. Data are lacking about the possible role of glucocorticoids in preventing and treat-ing the cardiovascular complications of COVID-19, which may constitute a supplemental indication to this treatment. Of note, in elderly patients, the benefits of a steroid therapy may be outweighed by higher risk of superinfections, induction or worsening of underlying psychiatric disorder and metabolic side effects (i.e., fluid retention, hypertension and hyperglycemia), which can precipitate pre-existing comorbidities including cardiovascular disease. [81] Caution should be used about corticosteroid administration in elderly STEMI patients with subacute admission, not a rare case during the current pandemic, due to the increased risk of myocardial rupture. [82] Anticoagulants Due to the high rate of venous and arterial thromboembolism, anticoagulation is a cornerstone in the management of COVID-19 patients. According to current guidelines, [83] all hospitalized patients should receive low-molecular-weight heparin (LMWH) at doses registered for prevention of venous thromboembolism, the only which have demonstrated an association with reduced risk of death. [84] LMWH is also known to exert anti-inflammatory and immunomodulant properties, by protecting glycocalyx from shedding. [85] Anticoagulant interventions at increased doses (intermediate or therapeutic) have been proposed and used in patients hospitalized for COVID disease, [64] based on the hypothesis that higher dose of heparin could reduce mortality and morbidity by improving anti-inflammatory activity and decreasing the incidence of local thrombosis in vital organs, therefore preventing their disfunction.

Comparisons between different anticoagulant dosing strategies are under investigation in several randomized controlled trials (RCTs), which have been described in a recent scoping review. [86] Of note, in three trials (REMAP-CAP, ACTV-4 and AT-TAC) investigating therapeutic doses of anticoagulant drugs in COVID-19 patients, enrollment of ICU patients has been recently paused because of futility and safety concerns. [87] Since high-quality data from randomized controlled trials will provide consistent evidence, any different approach compared to a thromboprophylaxis regimen, should be avoided in patients without a clear indication to full dose anticoagulant therapy.

An algorithm for the antithrombotic management of patients with SARS-CoV2 infection, with and without pre-existing indications to antithrombotic treatment, is suggested in Figure 2 .

Currently, there is no sufficient evidence to recommend for or against intermediate and therapeutic dose regimens, which are obviously affected by a higher risk of bleeding.

Several clinical trials on antiviral and immunomodulant agents are currently ongoing. Ad-vanced age is generally not an exclusion criterion per se, but patients with severe comorbidities (i.e., advanced liver, heart, or kidney disease) are usually excluded. Potential interactions of these therapies with the cardiovascular system and with other cardiovascular medications are summarized in (Table 3) .

Besides the cardiovascular effects of SARS-COV-2 treatments, early concern had been raised about the potential involvement of some cardiovascular drugs in the natural history of COVID-19. In particular, since ACEi and ARBs have been shown to upregulate ACE2 expression in animal models, [88] it had been supposed that these drugs might cause a higher susceptibility and/or a more aggressive course of COVID-19. [89, 90] On the other hand, RAAS inhibitors could exert a beneficial effect by counteracting the pro-inflammatory role of Angiotensin II, as previously discussed, despite lack of evidence from clinical studies. Based on available data, [90−92] major cardiology scientific societies recommend the continuation or initiation of ACEi/ARBs when indicated. [93, 94] Therapeutic Antibodies

Antibodies taken from the blood of recovered patients serve as a therapeutic alternative that is currently under study. One of the first studies on the use of plasma in the treatment of patients with SARS-CoV2 infections was conducted on 5 COVID-19 patients [95] and followed by other studies, mostly on a small number of patients. [96] The main results of the observational studies conducted reported clinical and survival improvement in all patients after the end of the additional intervention with plasma and hyperimmune immunoglobulins. However, as recently demonstrated by RCTs, the use of convalescent plasma therapy in addition to standard treatment in patients with moderate to severe pneumonia due to COVID-19 did not reduce mortality or improve other clinical outcomes as compared with placebo. [97, 98] Vaccine Several observations support the concept that vaccination has the potential to prevent SARS-CoV-2 infection. In non-human primate studies, infection with wild-type SARS-CoV-2 virus protected against subsequent reinfection, indicating that infection can result in protective immunity. [99] Vaccination of primates also protected against viral challenge allowing development of functional neutralizing antibodies correlated with protection. [100] Epidemiologic studies in humans have also suggested that neutralizing antibodies are associated with protection from infection. [101] SARS-CoV-2 vaccines are being developed using several different platforms. [102] Some of these are traditional approaches, such as inactivated virus or live attenuated viruses. Other approaches employ newer platforms, such as recombinant proteins and vectors. [102] Some platforms, such as RNA and DNA vaccines, have never been employed in a licensed vaccine. Recently mRNA vaccines BNT162b2 (Pfizer-BioNTech COVID-19 Vaccine) and 1 273 (Moderna COVID-19 Vaccine) have been granted emergency use authorization (EUA) for prevention of COVID-19. Of note, responses in participants ≥ 65 years old to mRNA vaccine (BNT162b2 Pfizer-BioNTech) were generally lower than in younger subjects, but still comparable to titers in convalescent plasma. [103] As well as mRNA 1 273 (Moderna COVID-19 Vaccine) vaccination in adults older than 55 years also elicited immune responses that were comparable to those seen in the younger populations. [104] CONCLUSIONS From the beginning of the COVID-19 outbreak, the scientific world devote attention to the cardiovascular implication of SARS-COV-2 infection. Since cardiovascular biomarkers are recognized as prognostic indicators, the effort to complete understand the mechanisms of this interaction is still crucial. Despite current evidence of several interaction between viral infection and cardiovascular disease, the consideration for treatments, including ACEI or ARB, immunosuppression/modulation and anti-coagulation continue to evolve. Elderly people have been the proportion with worst outcome among those affected by SARS-CoV-2 infection. However, the need of turn off the effects of the immune system hyperactivation by therapy should adequately counterbalance the excess of adverse effects in the elderly population.

WHO Coronavirus Disease

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Clinical characteristics of 2019 novel coronavirus infection in China

Factors Associated With All-Cause 30-Day Mortality in Nursing Home Residents With COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

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

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Cardiovascular involvement during COVID-19 and clinical implications in elderly patients. A review

SARS-CoV-2 Cell Entry Depends on ACE2 and TM-PRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research

Angiotensin converting enzyme 2: a double-edged sword

Evidence for Use or Disuse of Renin-Angiotensin System Modulators in Patients Having COVID-19 With an Underlying Cardiorenal Disorder

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

COVID-19 and the Heart

Cooper Leslie T. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

COVID-19 and Cardiovascular Disease

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

Replicationdependent downregulation of cellular angiotensinconverting enzyme 2 protein expression by human coronavirus NL63

Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

COVID-19: consider cytokine storm syndromes and immunosuppression

Innate immunity and the failing heart: the cytokine hypothesis revisited

The NLRP3 inflammasome in acute myocardial infarction

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches

Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area

COVID-19 and the cardiovascular system

Right ventricle dimensions and function in response to acute hypoxia in healthy human subjects

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Role of von Willebrand Factor and ADAMTS-13 in the Pathogenesis of Thrombi in SARS-CoV-2 Infection: Time to Rethink

Coronavirus and Cardiovascular Disease, Myocardial Injury, and Arrhythmia: JACC Focus Seminar

Age-and gender-related difference of ACE2 expression in rat lung

The reality of getting old

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making

Immunosenescence: emerging challenges for an ageing population

Universal Definition of Myocardial Infarction

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic

Recognizing COVID-19 -related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management

Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment

SARS-CoV-2 inflames the heart. The importance of awareness of myocardial injury in COVID-19 patients

The Variety of Cardiovascular Presentations of COVID-19

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

Acute Infection and Myocardial Infarction

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection

The Science Underlying COVID-19: Implications for the Cardiovascular System

Acute respiratory tract infections: a potential trigger for the acute coronary syndrome

Acute Coronary Syndromes and Covid-19: Exploring the Uncertainties

Out-of-Hospital Cardiac Arrest during the Covid-19 Outbreak in Italy

Impact of COVID-19 pandemic on mechanical reperfusion for patients with STEMI

COVID-19 and cardiac arrhythmias

Atrial Arrhythmias in COVID-19 Patients

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

COVID-19 Illness and Heart Failure: A Missing Link?

Trends in prevalence and outcome of heart failure with preserved ejection fraction

Influence of age on natriuretic peptides in patients with chronic heart failure: a comparison between ANP/NT-ANP and BNP/NT-proBNP

Reference intervals and decision limits for B-type natriuretic peptide (BNP) and its precursor (Nt-proBNP) in the elderly

NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study

NT-proBNP prognostic value is maintained in elderly and very elderly patients with chronic systolic heart failure

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

COVID-19 is, in the end, an endothelial disease

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

COVID-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome

Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: a systematic review and metaanalysis

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019

Extremely High Incidence of Lower Extremity Deep Venous Thrombosis in 48 Patients With Severe COVID-19 in Wuhan

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients

Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome

Prevalence of venous thromboembolism in critically ill patients with COVID-19

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

High rates of pulmonary artery occlusions in COVID-19. A metaanalysis

Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology

Information on COVID-19 Treatment, Prevention and Research. COVID-19 Treatment Guidelines

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Corticoid-associated complications in elderly

Relation between use of anti-inflammatory agents and left ventricular free wall rupture during acute myocardial infarction

Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

The role of heparin in sepsis: much more than just an anticoagulant

Anticoagulant interventions in hospitalized patients with COV-ID-19: A scoping review of randomized controlled tri

COVID-19 Anticoagulation Trials 'Paused ' for Futility

Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2

SARS-CoV2: should inhibitors of the renin -angiotensin system be withdrawn in patients with COVID-19?

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease

at a glance: focus on COVID-19, quality of life and comorbidities

Scientific statement of the Chinese Society of Cardiology (CSC) on using of renin angiotensin system blockers in patients with cardiovascular disease and COVID-19

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques

Development of an inactivated vaccine candidate for SARS-CoV-2

Neutralizing Antibodies Correlate with Protection from SARS-CoV-2 in Humans during a Fishery Vessel Outbreak with a High Attack Rate

A systematic review of

SARS-CoV-2 vaccine candidates

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273

Vaccine in Older Adults

Implications of myocardial injury in Mexican hospitalized patients with coronavirus disease 2019 (COVID-19)

Incidence and determinants of high-sensitivity troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients

Cardiac injury and mortality in patients with Coronavirus disease 2019 (COVID-19): insights from a mediation analysis

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study

Myocardial injury determination improves risk stratification and predicts mortality in COVID-19 patients

The association between cardiac injury and outcomes in hospitalized patients with COVID-19

Usefulness of Elevated Troponin to Predict Death in Patients With COVID-19 and Myocardial Injury

Cardiac Troponin I Is an Independent Predictor for Mortality in Hospitalized Patients With COVID-19

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

Early detection of elevated cardiac biomarkers to optimise risk stratification in patients with COVID-19

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

Development a Nomogram to Predict Prognosis in Severe and Critically Ill

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis

Development and Validation of a Web-Based Severe COVID-19 Risk Prediction Model

Risk factors for critical ill events of patients with COVID-19 in Wuhan, China: a retrospective cohort study

Venous thromboembolism in SARS-CoV-2 patients: only a problem in ventilated ICU patients, or is there more to it? Published online first

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels

Imageproven thromboembolism in patients with severe COVID-19 in a tertiary critical care unit in the United Kingdom

Pulmonary embolism and screening for concomitant proximal deep vein thrombosis in noncritically ill hospitalized patients with coronavirus disease 2019

Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Clinical characteristics of acute lower extremity deep venous thrombosis diagnosed by duplex in patients hospitalized for coronavirus disease 2019

Venous thromboembolism in critically Ill patients with COVID-19: Results of a screening study for deep vein thrombosis

Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis

Incidence of venous thromboembolism in hospitalized patients with COVID-19

Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19)

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

Factors Associated With Pulmonary Embolism Among Coronavirus Disease

Multicenter Study Among 375 Patients

Thrombotic events in SARS-CoV-2 patients: an urgent call for ultrasound screening

Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom

Analysis of Risk Factors for the Thromboembolic Events from 88 Patients with COVID-19 Pneumonia in Wuhan, China: A Retrospective Report

Cardiovascular injuries and SARS-COV-2 infection: focus on elderly people