ABC HFABC: Heart Failure & CardiomyopathyABC Heart Fail Cardiomyop0000-0000Sociedade Brasileira de Cardiologia - SBCabchf.2021000110.36660/abchf.20210001EditorialCardiovascular Burden of COVID-19 and the Post-Covid Era0000-0002-8155-2442MoscavitchSamuel D.1*VieiraJefferson L.2*LibbyPeter1Harvard Medical SchoolDepartment of MedicineBrigham and Women's HospitalBostonMAUSADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA - USA.Hospital de Messejana Dr. Carlos Alberto Studart GomesFortalezaCEBrazilHospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, CE - Brazil.Mailing Address: Peter Libby • Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA - USA. plibby@bwh.harvard.edu
Both authors contributed equally to this work
06072021Jul-Sep202111110280420203005202117052020This is an open-access article distributed under the terms of the Creative Commons Attribution LicenseKeywordsCoronavirus-19COVID-19Syndrome Respiratory Acute GravisSARS-19Betacoronavirus/complicationsPandemicsCardiovascular Diseases/complications
Coronavirus disease 2019, or COVID-19, rapidly became pandemic in 2020, causing hundreds of million cases and more than 2 million related deaths.1 This scourge has affected a wide range of people, from children to older adults, from healthy to high-risk individuals. Since December 2019, when the first cases of a virulent pneumonia of unknown etiology emerged in Wuhan, China, COVID-19 has not only become a major global health threat but has stretched health care systems and providers to the limits worldwide.2
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a variable clinical presentation, encompassing a wide range of symptoms similar to those of many infectious conditions, including fever, cough, and general malaise, now well known to most physicians worldwide.3,4 With disease progression, severe cases of COVID-19 can develop an acute lung injury with diffuse alveolar damage, producing the well-known bilateral infiltrates or ground glass opacities on chest x-ray or computed tomographic images.5-7 Although most cases are mild, patients with severe COVID-19 are more likely to have background comorbidities such as diabetes, hypertension, older age, airways disease, and obesity, risk factors frequently shared by several cardiovascular diseases.8
Why COVID-19 became an issue for cardiovascular specialists? SARS-CoV-2- related myocardial injury and myocarditis
Approximately 20-30% of hospitalized patients with COVID-19 have evidence of cardiac injury, as indicated by elevated levels of high-sensitivity troponins.9 The presence and magnitude of troponin elevation is associated with more severe disease and worse outcomes, even after adjusting for relevant risk factors. Myocardial injury portends a fatal outcome of COVID-19, while the prognosis of patients without myocardial injury, even with underlying cardiovascular disease, is more favorable.10
The pathophysiology of SARS-CoV-2-induced myocardial injury remains a topic of active research. COVID-19 can unfavorably affect the balance between myocardial oxygen supply and demand, as with other overwhelming viral or bacterial infections (Figure 1). Fever, metabolic stress, sympathetic activation, and tachycardia increase the energy expenditure and oxygen consumption of the myocardium.11,12 This imbalance can provoke type 2 (or “demand” type) myocardial infarction. Hypoxia from respiratory impairment can favor the production of reactive oxygen species and oxidative stress, acidosis, mitochondrial damage, and cell death.11,13,14 Other mechanisms of myocardial injury during COVID-19 include ischemia from microvascular thrombi and toxic levels of cytokines. Cardiac damage due to direct SARS-CoV-2 infection of cardiac myocytes appears uncommon.14-16 Indeed, the pericytes, smooth-muscle like cells that surround microvessels, express high levels of the receptor for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), while cardiac myocytes themselves have few, if any, of these portals of entry used by the virus.
A) This hypothetical diagram represents the spectrum of myocardial involvement in coronavirus disease 2019 (COVID-19). On the left, fulminant myocarditis due to direct myocardial infection. On the right, acute coronary syndrome developed from severe pre-existing lesions triggered by systemic inflammation from an active infection. B) Physiological changes associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that alter the balance between myocardial oxygen supply and demand to favor myocardial ischemia. Adapted with permission from Libby P. The Heart in COVID-19: Primary Target or Secondary Bystander? JACC Basic Transl Sci. May 2020;5(5):537-542. doi:10.1016/j.jacbts.2020.04.001.<xref ref-type="bibr" rid="B114"><sup>114</sup></xref>
Patients with COVID-19-related myocardial injury may present cardiac dysfunction and arrhythmias.10 A single center study used advanced cardiovascular magnetic resonance (CMR) and found a high prevalence of myocardial edema and fibrosis in patients recovering from COVID-19, which was independent of preexisting conditions and of severity and overall course of the acute illness.17 A subsequent multicenter study also used CMR to follow myocardial injury.18 During recovery after severe COVID-19 with troponin elevation, patients still can present a myocarditis-like injury, but it is limited and without important functional consequence. Nearly half of the evaluated patients had an abnormal CMR imaging, with 3 patterns of injury: non-infarct, myocarditis-pattern injury (27%), ischemic pathology (22%), and non-ischemic non-specific scar (5%).18
Although viral myocarditis appears uncommon in COVID-19, clinical conditions that may injure the myocardium include microvascular dysfunction and thrombosis, stress cardiomyopathy, and type 1 myocardial infarction. Heart failure in patients with COVID-19 may be precipitated by acute illness in patients with preexisting known or undiagnosed heart disease, acute hemodynamic stress, myocardial depression due to cytokines, or incident myocardial injury produced by the above-mentioned mechanisms.19
In the absence of obstructive epicardial coronary disease but evidence of myocardial injury (defined as positive troponin with or without wall motion abnormalities), physicians often consider the diagnosis of myocarditis as the underlying cause, using data such as clinical and imaging markers of myocyte injury.
Because the clinical presentation of myocarditis may vary, including vague or nonspecific symptoms such as fatigue, dyspnea, palpitations, and chest discomfort, the diagnosis of myocarditis in this setting is not straightforward. Indeed, most published cases of presumed myocarditis induced by COVID-19 infection were based on blood troponin levels or CMR, without biopsy confirmation.20,21 However, there have been few reported cases of histologically confirmed myocarditis, and viral myocarditis caused by SARS-CoV-2 has generally not been definitively demonstrated by histologic and viral genome analysis.19
From a pulmonary perspective to vascular and thromboembolic consequences
Initially conceived as a respiratory viral disease, the understanding of COVID-19 has broadened to encompass a heterogeneous and complex multi-organ condition.22,23 Emerging data indicates that COVID-19 patients have increased risk of broad systemic effects, including thrombosis,24-26 kidney failure,27,28 neurological events,29,30 and cardiovascular complications, such as heart failure31,32 and cardiogenic shock.33
A retrospective study comparing COVID-19 survivors and non-survivors showed that non-survivors had significantly higher levels of D-dimer and fibrin degradation products, as well as longer prothrombin time and activated partial thromboplastin time at clinical presentation.34 These differences increased during serial measurements, with 71.4% of non-survivors meeting the International Society on Thrombosis and Hemostasis (ISTH) diagnostic criteria for overt disseminated intravascular coagulation. The coexistence of coagulation abnormalities, hyperfibrinolysis, and large-vessel thrombosis in patients with severe COVID-19 has been linked to multiple organ dysfunction syndromes.35-37
COVID-19-related endothelial activation, dubbed endothelitis by some, explains systemic microcirculatory impairment in different vascular beds and its clinical sequelae in patients with SARS-CoV-2 infection (Figure 2).38-40 In addition to pericytes, arteriolar smooth muscle cells can express ACE2, and might act as target cardiac cells of SARS-CoV-2.41,42 SARS-CoV-2 and SARS-CoV-1 share almost identical receptor-binding domains. Some clinical features of COVID-19 resemble those of other coronavirus infections, including SARS-CoV-1, which emerged in 2002, and MERS-CoV, which threatened a pandemic in 2012.43 However, the SARS-CoV-2 binding site has a more compact and stable conformation, with structural features that enhance affinity for ACE2 and a furin cleavage site that increases the ability to infect target cells.43,44 The expression of ACE2 receptors on pericytes and microvascular smooth muscle cells, as well as findings of acute endothelitis in patients with COVID-19, provides a potential mechanism of direct viral injury through an infection-mediated vasculitis.38,41,45 Moreover, the presence of a furin cleavage site, which can be processed by near-ubiquitous furin-like proteases, sets SARS-CoV-2 apart from SARS-CoV-1 and other SARS-related coronaviridae that possess a monobasic cleavage site processed upon entry of target cells.46-48 Understanding the mechanisms and pathophysiology of SARS-CoV-2 infection and how it affects endothelial cells may provide useful insight on therapeutic and preventive strategies to avoid disease complications.
The left side of the diagram depicts a resting endothelial monolayer with the endothelial cells of squamous morphology resting on an intact basement membrane. When the endothelial cells undergo the cytopathic effect of a viral infection such as that caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or encounter pathogen-associated molecular patterns (PAMPs) derived from viruses or bacteria, such as lipopolysaccharide, proinflammatory cytokines such as interleukin (IL)-1 or tumor necrosis factor (TNF), or damage-associated molecular patterns (DAMPs) derived from dead or dying cells, the endothelial cells become activated. The endothelial cells display more columnar morphology. They can express adhesion molecules that attract leucocytes and chemokines that direct their migration into the subendothelial space. Sloughing of endothelial cells uncovers the thrombogenic basement membrane. Adherent neutrophils can undergo formation of neutrophil extracellular traps (NETs) that provide an amplifier for endothelial damage mediated in part by IL-1a. Inflammatory activation of endothelial cells can disrupt VE-cadherin largely responsible for the integrity of the endothelial barrier function. Activated endothelial cells can also express matrix metalloproteinases that can degrade the basement membrane and further interrupt endothelial barrier function. In small vessels, such as those that embrace alveoli in the lung, this impaired barrier function can lead to capillary leak. These various disturbances in endothelial function, depicted in the middle part of the diagram, lead to end organ damage, including adult respiratory distress syndrome (ARDS) and thrombosis in the lungs, predispose to plaque rupture and thrombosis in coronary arteries, and affect the microvasculature leading to myocardial ischemia and damage. The thrombotic diathesis provoked by endothelial dysfunction can also predispose towards strokes. Microvascular and macrovascular injuries can potentiate acute renal failure. Hepatic dysfunction can also result from microvascular thrombosis among other mechanisms. Deep venous thrombosis can occur as endothelial dysfunction represents an important part of Virchow's triad, and sets the stage for pulmonary embolism. Thus, loss of the endothelial protective function and unleashing of the mechanisms depicted can lead to multiorgan system failure that characterizes the advanced stages of coronavirus disease 2019 (COVID-19). Adapted with permission from Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 09 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623.<xref ref-type="bibr" rid="B39"><sup>39</sup></xref> uPA: urokinase-type plasminogen activator; tPA: tissue-type plasminogen activator; EDHF: endothelium-derived hyperpolarizing factor; PAI-1: plasminogen activator inhibitor 1; NADPH: nicotinamide adenine dinucleotide phosphate; ROS: reactive oxygen species; MI: myocardial infarction.
Recruitment of immune cells can cause widespread endothelial dysfunction associated with apoptosis.49,50 Pathologic data from patients with SARS-CoV-1 shows evidence of vasculitis with monocyte and lymphocyte infiltration, vascular endothelial cell injury, and stromal edema in the heart.51 Likewise, biopsies and post-mortem histological examination in patients with COVID-19 revealed lymphocytic endothelitis with apoptotic bodies and viral inclusion structures in multiple organs, including heart, lungs, kidneys, and intestine.7,38,52 The presence of viral elements within endothelial cells and accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death, suggests that SARS-CoV-2 infection yields endothelial activation in several organs, in addition to host's inflammatory response.53 Marked inflammation and endothelitis can also augment tissue factor expression, leading to a prothrombotic state.54-59 Analysis of pulmonary vessels in patients who died from COVID-19-related respiratory failure showed extensive thrombotic microangiopathy.52 Similar pathophysiology can apply to other organs affected by advanced COVID-19 as well.
Endothelial dysfunction resulting from infection and inflammation may lead to decreased coronary flow and destabilization of pre-existing atherosclerotic plaque, triggering a type 1 acute coronary event.60 Higher incidences of acute coronary syndromes, arrhythmias, heart failure-related events, and cardiovascular mortality observed during seasonal influenza outbreaks suggest a combination of systemic inflammation, vascular injury, and hypercoagulability.61,62 Additional reports of severe Kawasaki-like disease in children support the hypothesis of systemic hyperinflammation and widespread endothelial dysfunction in the pathogenesis of the most severe forms of COVID-19.63-65 The Kawasaki-like disease, also termed multisystem inflammatory syndrome in children, is characterized by persistent fever, gastrointestinal symptoms, rash, and conjunctivitis.63,64,66 Those children will typically present with 3-5 days of fever, followed by vasodilatory shock that is often refractory to volume resuscitation, requiring vasopressors and, occasionally, mechanical circulatory support.
Conceiving COVID-19 as a vascular disorder provides a rationale for endothelium-stabilizing therapies that can also impact viral replication, such as renin-angiotensin-aldosterone system inhibitors,38,67-70 statins,71-73 and anti-cytokine agents.74-76 These strategies could be particularly helpful in high-risk patients with preexisting endothelial dysfunction, such as those with hypertension, diabetes, obesity, and overt cardiovascular disease, all of which are associated with worse outcomes in COVID-19. Data available so far support the continuation of ACE inihibitor/angiotensin receptor blocker (ARB) and statins in patients taking them for pre-existing cardiovascular conditions.77 The blockade of interleukin (IL)-6, a cytokine produced by macrophages that induces a proinflammatory response and is often elevated in patients with COVID-19, has been recently studied, with contradictory results.78-83 We must await additional rigorously performed, properly powered, well-controlled, randomized trials before adopting or rejecting such therapies.
The clinical clouds gather: the heart may not resist a cytokine storm.
Massive cytokine release contributes to the most severe complications in COVID-19.53 Such an aggressive host inflammatory response commonly precipitates hemodynamic instability affecting all vessels, from veins to arteries of all calibers, and the microcirculation of many organs, as well as embolic phenomena, renal failure and shock. Acute heart failure with decrements of myocardial contractility can accompany this profound septic state.3,4,84
Intense inflammatory responses will involve overactivation of innate immunity, led by infections, or other stimuli, and will follow an uncontrolled rise in cytokines concentrations, causing collateral damage in tissues and multiple organs.85,86 The term “cytokine storm” first appeared in an article published in 1993 that describes the effects of graft-versus-host disease.87 It gained notoriety after being used to describe the effects of the avian H5N1 virus infection in 2005.88 Cytokine storm can complicate many infectious diseases, including SARS-CoV-1 and SARS-CoV-2,86,89 influenza virus,90 variola virus,91 cytomegalovirus,92 and group A streptococcus.93
In the case of COVID-19, from the entrance of SARS-CoV-2 into a host cell, an active innate immune system responds with a cascade of processes, leading to the release of cytokines, such as interferons type I/III, tumor necrosis factor alpha (TNF-α), IL-1β, IL-18, and IL-6. Conversely, proinflammatory cytokines will alter endothelial cell homeostatic functions in a manner that can lead to thrombosis and local tissue injury. Within this inflammatory microenvironment, endothelial cells and invading leukocytes will produce IL-1, which can elicit the production of chemoattractant molecules, stimulating migration and penetration of more inflammatory cells into local tissues.94 IL-1 can induce its own gene expression, triggering an amplification loop that can fuel a cytokine storm (Figure 3).95-97 IL-1 can also enhance the gene expression of other proinflammatory cytokines, including TNF-α.98 IL-1 potently sparks the production of another proinflammatory cytokine, IL-6.99,100 This induction of IL-6 production by IL-1 provides another strong contributor for the amplification loop that will maintain the overwhelming cytokines production that characterizes a cytokine storm. IL-6 will act by boosting, in the liver, the synthesis of fibrinogen (precursor of clots), of plasminogen activator inhibitor 1 (PAI-1) (major inhibitor of fibrinolysis), and of C-reactive protein, a biomarker that is consistently elevated in COVID-19.101 IL-6 plays a major role in acute lung injury and serves as a biomarker to predict the severity of COVID-19.102-105 Consistently, high levels of other inflammatory biomarkers, as C-reactive protein, IL-2, TNF-α, interferon-g, D-dimer, and ferritin, also correlate with severe manifestations and worse outcomes of patients with COVID-19. Lymphopenia and thrombocytopenia are frequent in this late phase of COVID-19.3,4,75,84,106,107 As components of the cellular immune response, natural killer (NK) cells and macrophages will undergo local activation, releasing cytokines to coordinate with activated T cells and other humoral responses in an attempt to resolve the infection rapidly.86 Severe COVID-19 can entail functional exhaustion of NK cells and CD8+ T lymphocytes, an evolution that favors virus persistence, macrophage activation, and further cytokine release.108,109 Antibody and cytotoxic T cell responses towards SARS-CoV can persist long after full recovery, with a moderate decline after one year from the onset of symptoms.110
Cytokine storm. Proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α) induce each other's gene expression, unleashing an amplification loop that sustains the cytokine storm. The endothelial cell is a key target of cytokines, as they induce action of a central proinflammatory transcriptional hub, nuclear factor kappa beta (NF-kB). IL-1 also causes substantial increases in production by endothelial and other cells of IL-6, the instigator of the hepatocyte acute phase response. The acute phase reactants include fibrinogen, the precursor of clot, and plasminogen activator inhibitor 1 (PAI-1), the major inhibitor of our endogenous fibrinolytic system. C-reactive protein (CRP), commonly elevated in coronavirus disease 2019 (COVID-19), provides a readily measured biomarker of inflammatory status. The alterations in the thrombotic/fibrinolytic balance due to the acute phase response promotes thrombosis in arteries, in the microvasculature, including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis (DVT) and predisposing towards pulmonary embolism (PE). Thus, the very same cytokines that elicit abnormal endothelial functions can unleash acute phase response, which, together with local endothelial dysfunction, can conspire to cause the clinical complications of COVID-19. The right side of this diagram aligns therapeutic agents that attack these mechanisms of the cytokine storm and may thus limit its devastating consequences. Adapted with permission from Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 09 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623.<xref ref-type="bibr" rid="B39"><sup>39</sup></xref> PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; RAAS: renin–angiotensin–aldosterone system.
Regarding cardiac dynamics, transient left ventricular dysfunction may occur during the acute phase of cytokine storm. A comparative echocardiographic study with SARS patients at the acute stage of infection and 30 days later showed a significantly higher left ventricular index of myocardial performance and a lower left ventricular ejection fraction, which characterized a subclinical diastolic impairment without systolic involvement at the acute phase. Furthermore, after 30 days, this impairment improved with clinical recovery.111 Patients who have recovered from cytokine storm syndrome may still bear long-lasting scars, such as pulmonary fibrosis, functional disability, and reduced quality of life.112 The long-term effect of myocardial injury sustained during acute COVID-19 will require careful attention in the coming years. Even in those who appear to recover fully from acute COVID-19, myocardial scarring could impair reserves required to withstand future insults. Fibrotic foci in the healed myocardium could nonetheless become substrates for reentrant arrhythmias as well as a long-term consequence of the acute SARS-CoV-2 infection.
At the level of the coronary arteries, the elevation of systemic cytokines can activate inflammatory cells resident in pre-existing atheroma and trigger a type 1 acute coronary syndrome due to plaque rupture.113 Cardiac ischemia can also arise from an imbalance between oxygen supply and demand. Even in the absence of epicardial atherosclerosis, the release of cytokines from a systemic or neighboring infection, such as pneumonitis, can activate the coronary microvascular endothelium and predispose to vasomotor abnormalities, augmented thrombosis, reduced fibrinolysis, increased leukocyte adhesion, and other aspects of dysfunction of heart microvessels.40,114
Perspectives
Is this pandemic ending or just beginning?
We are still learning about COVID-19 and new variants of SARS-CoV-2. Current evidence supports the use of remdesivir, glucocorticoids, prophylactic doses of anticoagulants, and anti-SARS-CoV-2 antibodies in certain hospitalized patients with COVID-19. We still need more evidence-based therapies for shortening the course of COVID-19 or reducing the need of mechanical ventilation or intensive care. The use of anticytokine agents might help to improve in more severe scenarios, in which there is dysfunction of biological systems and higher risk of fatalities. It is crucial to block an overwhelming wave of elevated cytokines, although we await the results of rigorous trials in this regard.74-76 There are few reports of reinfections following 50 days from recovery,115 and breakthrough infections can occur, albeit uncommonly, in those already vaccinated. Recovery from some symptoms, such as anosmia116 or fatigue,117 can also be incomplete.
Our current best approach to eradicate or, at least, control the SARS-CoV-2 threat is vaccination. There are many vaccines, based on different approaches, with results varying from reducing new cases to muting the advanced manifestations of COVID-19. The development of a variety of vaccines in rapid succession to confront the COVID-19 crisis represents a victory of medical science. We have reaped the benefits of decades of investment in basic research and in pharmaceutical development faced with this murderous pandemic. Since its recognition in December 2019, this pandemic has spurred many developments, strikingly altered most lives, disrupted daily routines, work, social gathering, exercising, with consequent challenges to both mental and physical health.
With the economic burden, strain on health systems, and urgent demand for vaccine, governments have struggled to accomplish the full vaccination of populations in a timely manner. We need to learn the durability of immunity conferred by the vaccines, and develop booster vaccinations that will prolong protection and broaden the spectrum of variants covered.
As a society, we must learn from this crisis to prepare ourselves to face future global health challenges in a more coherent and organized fashion. As professionals devoted to health care, we need to allow science rather than political considerations to lead our responses to public health disasters such as we have faced with COVID-19. To prepare for future outbreaks, investigators need to organize a priori to cooperate internationally to perform randomized, blinded, controlled, and adequately powered trials, rather than a scattershot of smaller observational or poorly controlled studies. Scientific rigor is the only proper way forward. Interventions based on anecdote and unproven plausibility delay progress and thus represent a threat to public health. We must confront the glaring inequities this pandemic has aggravated among less privileged segments of society. We have a chance to learn lessons from this grave situation. It is our duty to do so, to prevent the inevitable future pandemics from taking such a deadly toll on our society in upending so many lives.
Declaration of Competing Interest
Dr. Peter Libby: Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer, Sanofi-Regeneron. Dr. Libby is a member of scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr. Libby receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892), the American Heart Association (18CSA34080399), the RRM Charitable Fund, and the Simard Fund.
ReferencesDongEDuHGardnerLAn interactive web-based dashboard to track COVID-19 in real timeLancet Infect Dis0520202055335341. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 05 2020;20(5):533-4.ZhuNZhangDWangWLiXYangBSongJA Novel Coronavirus from Patients with Pneumonia in China, 2019N Engl J Med02202038287277332. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 02 2020;382(8):727-33.HuangCWangYLiXRenLZhaoJHuYClinical features of patients infected with 2019 novel coronavirus in Wuhan, ChinaLancet022020395102234975063. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 02 2020;395(10223):497-506.ZhouFYuTDuRFanGLiuYLiuZClinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort studyLancet03202039510229105410624. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 03 2020;395(10229):1054-62.LaxSFSkokKZechnerPKesslerHHKaufmannNKoelblingerCPulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a Prospective, Single-Center,Clinicopathologic Case SeriesAnn Intern Med05202017353503615. Lax SF, Skok K, Zechner P, Kessler HH, Kaufmann N, Koelblinger C, et al. Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a Prospective, Single-Center,Clinicopathologic Case Series. Ann Intern Med. May 2020;173(5):350-61.WölfelRCormanVMGuggemosWSeilmaierMZangeSMullerMAVirological assessment of hospitalized patients with COVID-2019Nature05202058178094654696. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Muller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 05 2020;581(7809):465-9.XuZShiLWangYZhangJHuangLZhangCPathological findings of COVID-19 associated with acute respiratory distress syndromeLancet Respir Med042020844204227. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 04 2020;8(4):420-2.Van LinthoutSKlingelKTschöpeCSARS-CoV-2-related myocarditis-like syndromes Shakespeare's question: what's in a name?Eur J Heart Fail0620202269229258. Van Linthout S, Klingel K, Tschöpe C. SARS-CoV-2-related myocarditis-like syndromes Shakespeare's question: what's in a name? Eur J Heart Fail. 06 2020;22(6):922-5.LalaAJohnsonKWJanuzziJLRussakAJParanjpeIRichterFPrevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 InfectionJ Am Coll Cardiol0820207655335469. Lala A, Johnson KW, Januzzi JL, Russak AJ, Paranjpe I, Richter F, et al. Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection. J Am Coll Cardiol. 08 2020;76(5):533-46.GuoTFanYChenMWuXZhangLHeTCardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)JAMA Cardiol0720205781181810. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 07 2020;5(7):811-8.VioliFCangemiRFalconeMTalianiGPieralliFVannucchiVCardiovascular Complications and Short-term Mortality Risk in Community-Acquired PneumoniaClin Infect Dis06201764111486149311. Violi F, Cangemi R, Falcone M, Taliani G, Pieralli F, Vannucchi V, et al. Cardiovascular Complications and Short-term Mortality Risk in Community-Acquired Pneumonia. Clin Infect Dis. Jun 2017;64(11):1486-93.TomasoniDItaliaLAdamoMInciardiRMLombardiCMSolomonSCOVID 19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new diseaseEur J Heart Fail05202022695796612. Tomasoni D, Italia L, Adamo M, Inciardi RM, Lombardi CM, Solomon S, et al. COVID 19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease. Eur J Heart Fail. May 2020; 22(6):957-66.WangDHuBHuCZhuFLiuXZhangJClinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, ChinaJAMA032020323111061106913. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 03 2020;323(11):1061-9.LippiGLavieCJSanchis-GomarFCardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysisProg Cardiovasc Dis03202063339039114. Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis. Mar 2020; 63(3):390-1.GiustinoGCroftLBStefaniniGGBragatoRSilbigerJJVicenziMCharacterization of Myocardial Injury in Patients With COVID-19J Am Coll Cardiol11202076182043205515. Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M, et al. Characterization of Myocardial Injury in Patients With COVID-19. J Am Coll Cardiol. 11 2020;76(18):2043-55.BavishiCBonowROTrivediVAbbottJDMesserliFHBhattDLSpecial Article - Acute myocardial injury in patients hospitalized with COVID-19 infection: A reviewProg Cardiovasc Dis2020Sep-Oct202063568268916. Bavishi C, Bonow RO, Trivedi V, Abbott JD, Messerli FH, Bhatt DL. Special Article - Acute myocardial injury in patients hospitalized with COVID-19 infection: A review. Prog Cardiovasc Dis. 2020 Sep-Oct 2020;63(5):682-9.PuntmannVOCarerjMLWietersIFahimMArendtCHoffmanJOutcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)JAMA Cardiol1120205111265127317. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffman J, et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Nov 2020;5(11):1265-73.KotechaTKnightDSRazviYKumarKVimalesvaranThorntonGPatterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonanceEur Heart J02202142191866187818. Kotecha T, Knight DS, Razvi Y, Kumar K, Vimalesvaran, Thornton G, et al. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur Heart J. Feb 2021;42(19):1866-78.KawakamiRSakamotoAKawaiKGianattiAPellegriniDNasrAPathological Evidence for SARS-CoV-2 as a Cause of Myocarditis: JACC Review Topic of the WeekJ Am Coll Cardiol01202177331432519. Kawakami R, Sakamoto A, Kawai K, Gianatti A, Pellegrini D, Nasr A, et al. Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis: JACC Review Topic of the Week. J Am Coll Cardiol. 01 2021;77(3):314-25.ZengJHLiuYXYuanJWangFXWuWBLiJXFirst case of COVID-19 complicated with fulminant myocarditis: a case report and insightsInfection04202048577377720. Zeng JH, Liu YX, Yuan J, Wang FX, Wu WB, Li JX, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection. Apr 2020;48(5):773-7.SalaSPerettoGGramegnaMPalmisanoAVillatoreAVignaleDAcute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infectionEur Heart J05202041191861186221. Sala S, Peretto G, Gramegna M, Palmisano A, Villatore A, Vignale D, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 05 2020;41(19):1861-2.BryceCGrimesZPujadasEAhujaSBeasleyMBAlbrechtRPathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experiencemedRxiv20202020.05.18.2009996022. Bryce C, Grimes Z, Pujadas E, Ahuja S, Beasley MB, Albrecht R, et al. Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv. 2020:2020.05.18.20099960.LangJPWangXMouraFASiddiqiHKMorrowDABohulaEAA current review of COVID-19 for the cardiovascular specialistAm Heart J052020226294423. Lang JP, Wang X, Moura FA, Siddiqi HK, Morrow DA, Bohula EA. A current review of COVID-19 for the cardiovascular specialist. Am Heart J. May 2020;226:29-44.BikdeliBMadhavanMVJimenezDChuichTDreyfusIDrigginECOVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-upJ Am Coll Cardiol04202075232950297324. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol. Apr 2020;75(23):2950-73.KlokFAKruipMJvan der MeerNJArbousMSGommersDAKantKMIncidence of thrombotic complications in critically ill ICU patients with COVID-19Thromb Res07202019114514725. Klok FA, Kruip MJ, van der Meer NJ, Arbous MS, Gommers DA, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 07 2020;191:145-7.PoissyJGoutayJCaplanMParmentierEDuburcqTLassalleFPulmonary Embolism in COVID-19 Patients: Awareness of an Increased PrevalenceCirculation042020142218418626. Poissy J, Goutay J, Caplan M, Parmentier E, Duburcq T, Lassalle F, et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation. Apr 2020; 142(2):184-6.DurvasulaRWellingtonTMcNamaraEWatnickSCOVID-19 and Kidney Failure in the Acute Care Setting: Our Experience From SeattleAm J Kidney Dis0420207614627. Durvasula R, Wellington T, McNamara E, Watnick S. COVID-19 and Kidney Failure in the Acute Care Setting: Our Experience From Seattle. Am J Kidney Dis. Apr 2020; 76(1):4-6.RoncoCReisTKidney involvement in COVID-19 and rationale for extracorporeal therapiesNat Rev Nephrol06202016630831028. Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat Rev Nephrol. 06 2020;16(6):308-10.AggarwalGLippiGHenryBCerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literatureInt J Stroke06202015438538929. Aggarwal G, Lippi G, Henry B. Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature. Int J Stroke. 06 2020;15(4):385-9.MaoLJinHWangMHuYChenSHeQNeurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, ChinaJAMA Neurol04202077668369030. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Apr 2020;77(6):683-90.DongNCaiJZhouYLiuJLiFEnd-Stage Heart Failure With COVID-19: Strong Evidence of Myocardial Injury by 2019-nCoVJACC Heart Fail0620208651551731. Dong N, Cai J, Zhou Y, Liu J, Li F. End-Stage Heart Failure With COVID-19: Strong Evidence of Myocardial Injury by 2019-nCoV. JACC Heart Fail. 06 2020;8(6):515-7.MehraMRRuschitzkaFCOVID-19 Illness and Heart Failure: A Missing Link?JACC Heart Fail0620208651251432. Mehra MR, Ruschitzka F. COVID-19 Illness and Heart Failure: A Missing Link? JACC Heart Fail. 06 2020;8(6):512-4.TavazziGPellegriniCMaurelliMBelliatoMSciuttiFBottazziAMyocardial localization of coronavirus in COVID-19 cardiogenic shockEur J Heart Fail05202022591191533. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 05 2020;22(5):911-5.TangNLiDWangXSunZAbnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumoniaJ Thromb Haemost04202018484484734. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 04 2020;18(4):844-7.TangNBaiHChenXGongJLiDSunZAnticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathyJ Thromb Haemost0520201851094109935. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 05 2020;18(5):1094-9.ZhuJJiPPangJZhongZLiHHeCClinical characteristics of 3,062 COVID-19 patients: a meta-analysisJ Med Virol04202092101902191436. Zhu J, Ji P, Pang J, Zhong Z, Li H, He C, et al. Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis. J Med Virol. Apr 2020;92(10):1902-14.PorfidiaAPolaRVenous thromboembolism in COVID-19 patientsJ Thromb Haemost0620201861516151737. Porfidia A, Pola R. Venous thromboembolism in COVID-19 patients. J Thromb Haemost. 06 2020;18(6):1516-7.VargaZFlammerAJSteigerPHabereckerMAndermattRZinkernagelASEndothelial cell infection and endotheliitis in COVID-19Lancet052020395102341417141838. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 05 2020;395(10234):1417-8.LibbyPLüscherTCOVID-19 is, in the end, an endothelial diseaseEur Heart J09202041323038304439. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 09 2020;41(32):3038-44.SiddiqiHKLibbyPRidkerPMCOVID-19 - A vascular diseaseTrends Cardiovasc Med0120213111540. Siddiqi HK, Libby P, Ridker PM. COVID-19 - A vascular disease. Trends Cardiovasc Med. 01 2021;31(1):1-5.ChenLLiXChenMFengYXiongCThe ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2Cardiovasc Res05202011661097110041. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 05 2020;116(6):1097-100.HeLMäeMAMuhlLSunYNaharKLiébanasEVPericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19bioRxiv20202020.05.11.08850042. He L, Mäe MA, Muhl L, Sun Y, Nahar K, Liébanas EV, et al. Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19. bioRxiv. 2020:2020.05.11.088500.ShangJYeGShiKWanYLuoCAiharaHStructural basis of receptor recognition by SARS-CoV-2Nature052020581780722122443. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 05 2020;581(7807):221-4.YanRZhangYLiYXiaLGuoYZhouQStructural basis for the recognition of SARS-CoV-2 by full-length human ACE2Science03202036764851444144844. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 03 2020;367(6485):1444-8.GuzikTJMohiddinSADimarcoAPatelVSavvatisKMarelli-BergFMCOVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment optionsCardiovasc Res042020116101666168745. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. Apr 2020;116(10):1666-87CoutardBValleCde LamballerieXCanardBSeidahNGDecrolyEThe spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same cladeAntiviral Res04202017610474210474246. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 04 2020;176:104742.WallsACParkYJTortoriciMAWallAMcGuireATVeeslerDStructure, Function, and Antigenicity of the SARS-CoV-2 Spike GlycoproteinCell042020181228192.e647. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 04 2020;181(2):281-92.e6.LiuTLuoSLibbyPShiGPCathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patientsPharmacol Ther09202021310758710758748. Liu T, Luo S, Libby P, Shi GP. Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients. Pharmacol Ther. 09 2020;213:107587.PagnouxCCohenPGuillevinLVasculitides secondary to infectionsClin Exp Rheumatol2006Mar-Apr2006242 Suppl 41S71S8149. Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol. 2006 Mar-Apr 2006;24(2 Suppl 41):S71-81.GuillevinLVirus-induced systemic vasculitides: new therapeutic approachesClin Dev Immunol2004Sep-Dec2004113-422723150. Guillevin L. Virus-induced systemic vasculitides: new therapeutic approaches. Clin Dev Immunol. 2004 Sep-Dec 2004;11(3-4):227-31.DingYWangHShenHLiZGengJHanHThe clinical pathology of severe acute respiratory syndrome (SARS): a report from ChinaJ Pathol072003200328228951. Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. Jul 2003;200(3):282-9.AckermannMVerledenSEKuehnelMHaverichAWelteTLaengerFPulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19N Engl J Med052020383212012852. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. May 2020; 383(2):120-8.SiddiqiHKMehraMRCOVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposalJ Heart Lung Transplant05202039540540753. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 05 2020;39(5):405-7.NakamuraSImamuraTOkamotoKTissue factor in neutrophils: yesJ Thromb Haemost0220042221421754. Nakamura S, Imamura T, Okamoto K. Tissue factor in neutrophils: yes. J Thromb Haemost. Feb 2004;2(2):214-7.van der PollTBüllerHRten CateHWortelCHBauerKADeventerSJActivation of coagulation after administration of tumor necrosis factor to normal subjectsN Engl J Med061990322231622162755. van der Poll T, Büller HR, ten Cate H, Wortel CH, Bauer KA, Deventer SJ, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med. Jun 1990;322(23):1622-7.de JongeEFriederichPWVlasukGPRoteWVroomMBLeviMActivation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjectsClin Diagn Lab Immunol05200310349549756. de Jonge E, Friederich PW, Vlasuk GP, Rote W, Vroom MB, Levi M, et al. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects. Clin Diagn Lab Immunol. May 2003;10(3):495-7.FrancoRFde JongeEDekkersPETimmermanJJSpekCAvan DeventerSJThe in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulationBlood07200096255455957. Franco RF, de Jonge E, Dekkers PE, Timmerman JJ, Spek CA, van Deventer SJ, et al. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood. Jul 2000;96(2):554-9.HendrenNSDraznerMHBozkurtBCooperLTDescription and Proposed Management of the Acute COVID-19 Cardiovascular SyndromeCirculation062020141231903191458. Hendren NS, Drazner MH, Bozkurt B, Cooper LT. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation. Jun 2020;141(23):1903-14.DingYQWangHJShenHLiZGengJHanHStudy on etiology and pathology of severe acute respiratory syndromeZhonghua Bing Li Xue Za Zhi06200332319520059. Ding YQ, Wang HJ, Shen H, Li Z, Geng J, Han H, et al. [Study on etiology and pathology of severe acute respiratory syndrome]. Zhonghua Bing Li Xue Za Zhi. Jun 2003;32(3):195-200.VallancePCollierJBhagatKInfection, inflammation, and infarction: does acute endothelial dysfunction provide a link?Lancet05199734990621391139260. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet. May 1997;349(9062):1391-2.NguyenJLYangWItoKMatteTDShamanJKinneyPLSeasonal Influenza Infections and Cardiovascular Disease MortalityJAMA Cardiol0620161327428161. Nguyen JL, Yang W, Ito K, Matte TD, Shaman J, Kinney PL. Seasonal Influenza Infections and Cardiovascular Disease Mortality. JAMA Cardiol. 06 2016;1(3):274-81.MadjidMSafavi-NaeiniPSolomonSDVardenyOPotential Effects of Coronaviruses on the Cardiovascular System: A ReviewJAMA Cardiol0320205783184062. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. Mar 2020; 5(7):831-40.RiphagenSGomezXGonzalez-MartinezCWilkinsonNTheocharisPHyperinflammatory shock in children during COVID-19 pandemicLancet052020395102371607160863. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 05 2020;395(10237):1607-8.LicciardiFPruccoliGDeninaMParodiETagliettoMRosatiSSARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in ChildrenPediatrics0520201462e2020171164. Licciardi F, Pruccoli G, Denina M, Parodi E, Taglietto M, Rosati S, et al. SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children. Pediatrics. May 2020; 146(2):e20201711.VinerRMWhittakerEKawasaki-like disease: emerging complication during the COVID-19 pandemicLancet062020395102391741174365. Viner RM, Whittaker E. Kawasaki-like disease: emerging complication during the COVID-19 pandemic. Lancet. 06 2020;395(10239):1741-3.ToubianaJPoiraultCCorsiaABajolleFFourgeaudJAngoulvantFKawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational studyBMJ062020369m209466. Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 06 2020;369:m2094.JarchoJAIngelfingerJRHamelMBD’AgostinoRBHarringtonDPInhibitors of the Renin-Angiotensin-Aldosterone System and Covid-19N Engl J Med052020382252462246467. Jarcho JA, Ingelfinger JR, Hamel MB, D’Agostino RB, Harrington DP. Inhibitors of the Renin-Angiotensin-Aldosterone System and Covid-19. N Engl J Med. May 2020; 382(25):2462-4.VaduganathanMVardenyOMichelTMcMurrayJJPfefferMASolomonSDRenin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19N Engl J Med042020382171653165968. Vaduganathan M, Vardeny O, Michel T, McMurray JJ, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 04 2020;382(17):1653-9.ReynoldsHRAdhikariSPulgarinCTroxelABIturrateEJohnsonSBRenin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19N Engl J Med052020382252441244869. Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. May 2020; 382(25):2441-8.ManciaGReaFLudergnaniMApoloneGCorraoGRenin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19N Engl J Med052020382252431244070. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. May 2020; 382(25):2431-40.LeeKCSewaDWPhuaGCPotential role of statins in COVID-19Int J Infect Dis0620209661561771. Lee KC, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis. Jun 2020; 96:615-7.CastiglioneVChiriacòMEmdinMTaddeiSVergaroGStatin therapy in COVID-19 infectionEur Heart J Cardiovasc Pharmacother0420206425825972. Castiglione V, Chiriacò M, Emdin M, Taddei S, Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. Apr 2020; 6(4):258-9.FedsonDSTreating influenza with statins and other immunomodulatory agentsAntiviral Res09201399341743573. Fedson DS. Treating influenza with statins and other immunomodulatory agents. Antiviral Res. Sep 2013;99(3):417-35.KangSTanakaTNarazakiMKishimotoTTargeting Interleukin-6 Signaling in ClinicImmunity0420195041007102374. Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity. 04 2019;50(4):1007-23.AgarwalSJuneCHHarnessing CAR T-cell Insights to Develop Treatments for Hyperinflammatory Responses in Patients with COVID-19Cancer Discov06202010677577875. Agarwal S, June CH. Harnessing CAR T-cell Insights to Develop Treatments for Hyperinflammatory Responses in Patients with COVID-19. Cancer Discov. 06 2020;10(6):775-8.XuXHanMLiTSunWWangDFuBEffective treatment of severe COVID-19 patients with tocilizumabProc Natl Acad Sci U S A05202011720109701097576. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 05 2020;117(20):10970-5.LopesRDMacedoAVSilvaPGMoll-BernardesRSantosTMMazzaLEffect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical TrialJAMA012021325325426477. Lopes RD, Macedo AV, Silva PG, Moll-Bernardes R, Santos TM, Mazza L, et al. Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA. 01 2021;325(3):254-64.RubinEJLongoDLBadenLRInterleukin-6 Receptor Inhibition in Covid-19 - Cooling the Inflammatory SoupN Engl J Med042021384161564156578. Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 - Cooling the Inflammatory Soup. N Engl J Med. 04 2021;384(16):1564-5.HermineOMarietteXTharauxPLRigonMRPorcherRRavaudPEffect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical TrialJAMA Intern Med0120211811324079. Hermine O, Mariette X, Tharaux PL, Rigon MR, Porcher R, Ravaud P. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 01 2021;181(1):32-40.SalvaraniCDolciGMassariMMerloDFCavutoSSavoldiLEffect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical TrialJAMA Intern Med0120211811243180. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 01 2021;181(1):24-31.GordonACMounceyPRAl-BeidhFRowanKMNicholADArabiYMInterleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19N Engl J Med042021384161491150281. Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 04 2021;384(16):1491-502.SalamaCHanJYauLReissWGKramerBNeidhartJTocilizumab in Patients Hospitalized with Covid-19 PneumoniaN Engl J Med0120213841203082. Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart J, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 01 2021;384(1):20-30.RosasIOBräuNWatersMGoRCHunterBDBhaganiSTocilizumab in Hospitalized Patients with Severe Covid-19 PneumoniaN Engl J Med042021384161503151683. Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 04 2021;384(16):1503-16.ShiSQinMShenBCaiYLiuTYangFAssociation of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, ChinaJAMA Cardiol0320205780281084. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. Mar 2020; 5(7):802-10.TisoncikJRKorthMJSimmonsCPFarrarJMartinTRKatzeMGInto the eye of the cytokine stormMicrobiol Mol Biol Rev032012761163285. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. Mar 2012;76(1):16-32.WangJJiangMChenXMontanerLJCytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy conceptsJ Leukoc Biol0620201081174186. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J Leukoc Biol. Jun 2020; 108(1):17-41.FerraraJLAbhyankarSGillilandDGCytokine storm of graft-versus-host disease: a critical effector role for interleukin-1Transplant Proc021993251 Pt 21216121787. Ferrara JL, Abhyankar S, Gilliland DG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc. Feb 1993;25(1 Pt 2):1216-7.YuenKYWongSSHuman infection by avian influenza A H5N1Hong Kong Med J06200511318919988. Yuen KY, Wong SS. Human infection by avian influenza A H5N1. Hong Kong Med J. Jun 2005;11(3):189-99.HuangKJSuIJTheronMWuYCLaiSKLiuCCAn interferon-gamma-related cytokine storm in SARS patientsJ Med Virol02200575218519489. Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. Feb 2005;75(2):185-94.LiuQZhouYHYangZQThe cytokine storm of severe influenza and development of immunomodulatory therapyCell Mol Immunol01201613131090. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. Jan 2016;13(1):3-10.JahrlingPBHensleyLEMartinezMJLeducJWRubinsKHRelmanDAExploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpoxProc Natl Acad Sci U S A10200410142151961520091. Jahrling PB, Hensley LE, Martinez MJ, Leduc JW, Rubins KH, Relman DA, et al. Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox. Proc Natl Acad Sci U S A. Oct 2004;101(42):15196-200.BarrySMJohnsonMAJanossyGCytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisitedBone Marrow Transplant09200026659159792. Barry SM, Johnson MA, Janossy G. Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited. Bone Marrow Transplant. Sep 2000;26(6):591-7.BisnoALBritoMOCollinsCMMolecular basis of group A streptococcal virulenceLancet Infect Dis0420033419120093. Bisno AL, Brito MO, Collins CM. Molecular basis of group A streptococcal virulence. Lancet Infect Dis. Apr 2003;3(4):191-200.WangJMSicaAPeriGWalterSPaduraIMLibbyPExpression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cellsArterioscler Thromb1991Sep-Oct19911151166117494. Wang JM, Sica A, Peri G, Walter S, Padura IM, Libby P, et al. Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. Arterioscler Thromb. 1991 Sep-Oct 1991;11(5):1166-74.DinarelloCAIkejimaTWarnerSJOrencoleSFLonnemannGCannonJGInterleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitroJ Immunol09198713961902191095. Dinarello CA, Ikejima T, Warner SJ, Orencole SF, Lonnemann G, Cannon JG, et al. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. Sep 1987;139(6):1902-10.WarnerSJAugerKRLibbyPHuman interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cellsJ Exp Med05198716551316133196. Warner SJ, Auger KR, Libby P. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. J Exp Med. May 1987;165(5):1316-31.WarnerSJAugerKRLibbyPInterleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cellsJ Immunol09198713961911191797. Warner SJ, Auger KR, Libby P. Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. J Immunol. Sep 1987;139(6):1911-7.WarnerSJLibbyPHuman vascular smooth muscle cells. Target for and source of tumor necrosis factorJ Immunol011989142110010998. Warner SJ, Libby P. Human vascular smooth muscle cells. Target for and source of tumor necrosis factor. J Immunol. Jan 1989;142(1):100-9.LoppnowHLibbyPAdult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1Cell Immunol091989122249350399. Loppnow H, Libby P. Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1. Cell Immunol. Sep 1989;122(2):493-503.LoppnowHLibbyPProliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6J Clin Invest031990853731738100. Loppnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. Mar 1990;85(3):731-8.WrightFLVoglerTOMooreEEMooreHBWohlauerMVUrbanSFibrinolysis Shutdown Correlation with Thromboembolic Events in Severe COVID-19 InfectionJ Am Coll Surg0820202312193203.e1101. Wright FL, Vogler TO, Moore EE, Moore HB, Wohlauer MV, Urban S, et al. Fibrinolysis Shutdown Correlation with Thromboembolic Events in Severe COVID-19 Infection. J Am Coll Surg. 08 2020;231(2):193-203.e1.AzizMFatimaRAssalyRElevated interleukin-6 and severe COVID-19: A meta-analysisJ Med Virol042020921122832285102. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol. Apr 2020; 92(11):2283-5.UlhaqZSSorayaGVInterleukin-6 as a potential biomarker of COVID-19 progressionMed Mal Infect062020504382383103. Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. 06 2020;50(4):382-3.MagroGSARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the ‘culprit lesion’ of ARDS onset? What is there besides Tocilizumab? SGP130FcCytokine X05202022100029100029104. Magro G. SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the ‘culprit lesion’ of ARDS onset? What is there besides Tocilizumab? SGP130Fc. Cytokine X. May 2020;2(2):100029.LiuBLiMZhouZGuanXXiangYCan we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?J Autoimmun072020111102452102452105. Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 07 2020;111:102452.QinCZhouLHuZZhangSYangSTaoYDysregulation of immune response in patients with COVID-19 in Wuhan, ChinaClin Infect Dis0320207115762768106. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. Mar 2020; 71(15):762-8.MehtaPMcAuleyDFBrownMSanchezETattersallRSMansonJJCOVID-19: consider cytokine storm syndromes and immunosuppressionLancet0320203951022910331034107. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 03 2020;395(10229):1033-4.ZhengMGaoYWangGSongGLiuSSunDFunctional exhaustion of antiviral lymphocytes in COVID-19 patientsCell Mol Immunol052020175533535108. Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 05 2020;17(5):533-5.DiaoBWangCTanYChenXLiuYNingLReduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)Front Immunol202011827827109. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827.LiTXieJHeYFanHBarilLQiuZLong-term persistence of robust antibody and cytotoxic T cell responses in recovered patients infected with SARS coronavirusPLoS One12200611e24110. Li T, Xie J, He Y, Fan H, Baril L, Qiu Z, et al. Long-term persistence of robust antibody and cytotoxic T cell responses in recovered patients infected with SARS coronavirus. PLoS One. Dec 2006;1(1):e24.LiSSChengCWFuCLChanYLeeMChanJWLeft ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up studyCirculation1020031081517981803111. Li SS, Cheng CW, Fu CL, Chan Y, Lee M, Chan JW, et al. Left ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up study. Circulation. Oct 2003;108(15):1798-803.CuiNZouXXuLPreliminary CT findings of coronavirus disease 2019 (COVID-19)Clin Imaging05202065124132112. Cui N, Zou X, Xu L. Preliminary CT findings of coronavirus disease 2019 (COVID-19). Clin Imaging. May 2020;65:124-32.MadjidMVelaDKhalili-TabriziHCasscellsSWLitovskySSystemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromesTex Heart Inst J20073411118113. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky S. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst J. 2007;34(1):11-8.LibbyPThe Heart in COVID-19: Primary Target or Secondary Bystander?JACC Basic Transl Sci05202055537542114. Libby P. The Heart in COVID-19: Primary Target or Secondary Bystander? JACC Basic Transl Sci. May 2020;5(5):537-42.SantosLAGoisPGFilhoSilvaAMSantosJVSantosDSAquinoMMRecurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workersJ Infect022021823399406115. Santos LA, Gois Filho PG, Silva AM, Santos JV, Santos DS, Aquino MM, et al. Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers. J Infect. Feb 2021;82(3):399-406.LechienJRChiesa-EstombaCMBeckersEMustinVDucarmeMJourneFPrevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patientsJ Intern Med012021116. Lechien JR, Chiesa-Estomba CM, Beckers E, Mustin V, Ducarme M, Journe F, et al. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. Jan 2021.WilliSLütholdRHuntAHanggiNVSejdiuDScaffCCOVID-19 Sequelae in adults aged less than 50 years: A Systematic ReviewTravel Med Infect Dis02202140101995101995117. Willi S, Lüthold R, Hunt A, Hanggi NV, Sejdiu D, Scaff C, et al. COVID-19 Sequelae in adults aged less than 50 years: A Systematic Review. Travel Med Infect Dis. Feb 2021;40:101995.EditorialSobrecarga Cardiovascular da COVID-19 e a Era Pós-COVID0000-0002-8155-2442MoscavitchSamuel D.1*VieiraJefferson L.2*LibbyPeter1BostonMAEUADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA - EUA.FortalezaCEBrasilHospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, CE - Brasil.Correspondência: Peter Libby • Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA - EUA. E-mail: plibby@bwh.harvard.edu
Os dois autores contribuíram igualmente para este trabalho
A doença do coronavírus 2019, ou COVID-19, rapidamente se tornou uma pandemia em 2020, causando centenas de milhões de casos e mais de 2 milhões de óbitos.1 Esse flagelo tem afetado uma ampla gama de pessoas, de crianças a idosos, de indivíduos saudáveis a grupos de alto risco. Desde dezembro de 2019, quando os primeiros casos de uma pneumonia virulenta de etiologia desconhecida surgiram em Wuhan, China, a COVID-19 tornou-se não apenas uma importante ameaça global à saúde, mas também sobrecarregou os sistemas e os prestadores de saúde até o limite em todo o mundo.2
A infecção pelo coronavírus associada a síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) tem uma apresentação clínica variável, abrangendo uma ampla gama de sintomas, semelhante a muitas condições infecciosas, incluindo febre, tosse e mal-estar geral, agora bem conhecidos da maioria dos médicos em todo o mundo.3,4 Com a progressão da doença, casos graves de COVID-19 podem desenvolver lesão pulmonar aguda com dano alveolar difuso, produzindo os conhecidos infiltrados bilaterais ou opacidades em vidro fosco na radiografia do tórax ou em imagens de tomografia computadorizada.5-7 Embora a maioria dos casos seja leve, pacientes com COVID-19 grave são mais propensos a ter comorbidades prévias, tais como diabetes, hipertensão, idade avançada, doença das vias aéreas e obesidade, que são fatores de risco frequentemente compartilhados com doenças cardiovasculares.8
Por que a COVID-19 tornou-se uma questão para especialistas cardiovasculares? Lesão miocárdica e miocardite relacionadas a SARS-CoV-2
Aproximadamente 20-30% dos pacientes hospitalizados com COVID-19 têm evidências de lesão cardíaca, conforme indicado pelos níveis elevados de troponinas de alta sensibilidade.9 A presença e a magnitude da elevação da troponina está associada a doença mais grave e pior prognóstico, mesmo após ajuste para fatores de risco relevantes. Lesão miocárdica prenuncia desfecho fatal da COVID-19, enquanto o prognóstico de pacientes sem lesão miocárdica, mesmo com doença cardiovascular subjacente, é mais favorável.10
A fisiopatologia da lesão miocárdica induzida pelo SARS-CoV-2 permanece um tema de pesquisa ativa. A COVID-19 pode afetar desfavoravelmente o equilíbrio entre a oferta e a demanda de oxigênio pelo miocárdio, assim como outras infecções virais ou bacterianas avassaladoras (Figura 1). Febre, estresse metabólico, ativação simpática e taquicardia aumentam o gasto energético e consumo de oxigênio do miocárdio.11,12 Esse desequilíbrio pode provocar infarto do miocárdio tipo 2. A hipóxia decorrente do comprometimento respiratório pode favorecer a produção de espécies reativas de oxigênio, estresse oxidativo, acidose, dano mitocondrial e morte celular.11,13,14 Outros mecanismos de lesão miocárdica durante a COVID-19 incluem isquemia decorrente de trombos microvasculares e níveis tóxicos de citocinas. O dano cardíaco devido à infecção direta dos miócitos cardíacos por SARS-CoV-2 parece ser incomum.14-16 De fato, os pericitos, células semelhantes células musculares lisas que circundam microvasos, expressam altos níveis do receptor para o SARS-CoV-2, a enzima conversora de angiotensina 2 (ECA2), enquanto os próprios miócitos cardíacos têm poucos receptores, ou talvez nenhum, utilizados pelo vírus como porta de entrada.
A) Este diagrama hipotético representa o espectro do envolvimento miocárdico na doença do coronavírus 2019 (COVID-19). À esquerda, miocardite fulminante devido a infecção miocárdica direta. À direita, síndrome coronariana aguda decorrente de lesões graves preexistentes desencadeadas por inflamações sistêmicas resultantes de infecção ativa. B) Mudanças fisiológicas associadas à infecção pelo coronavírus da síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) que alteram o equlíbrio entre a oferta e a demanda de oxigênio no miocárdio, favorecendo a isquemia miocárdica. Adaptada com permissão de Libby P. The Heart in COVID-19: Primary Target or Secondary Bystander? JACC Basic Transl Sci. May 2020;5(5):537-42. doi:10.1016/j.jacbts.2020.04.001.<xref ref-type="bibr" rid="B114"><sup>114</sup></xref>
Pacientes com lesão miocárdica relacionada à COVID-19 podem apresentar disfunção cardíaca e arritmias.10 Um estudo unicêntrico utilizou ressonância magnética cardiovascular (RMC) avançada e constatou uma alta prevalência de evidências de edema miocárdico e fibrose em pacientes que estavam se recuperando da COVID-19, independente de condições preexistentes e da gravidade e do curso geral da doença aguda.17 Um estudo multicêntrico subsequente também utilizou a RMC para acompanhar lesões miocárdicas.18 Durante a recuperação após COVID-19 grave com elevação da troponina, os pacientes ainda podem apresentar uma lesão semelhante a miocardite, mas esta é limitada e não acarreta consequências funcionais importantes. Aproximadamente metade dos pacientes avaliados apresentaram anormalidade na RMC, com 3 padrões de lesão: lesão não causada por infarto e com padrão de miocardite (27%), patologia isquêmica (22%) e cicatriz inespecífica não isquêmica (5%).18
Embora a miocardite viral seja aparentemente incomum na COVID-19, condições clínicas que podem lesar o miocárdio incluem disfunção microvascular e trombose, cardiomiopatia por estresse e infarto do miocárdio tipo 1. A insuficiência cardíaca em pacientes com COVID-19 pode ser precipitada por doença aguda em pacientes com cardiopatia preexistente, estresse hemodinâmico agudo, depressão miocárdica devido a citocinas, ou lesão miocárdica incidente produzida pelos mecanismos acima mencionados.19
Na ausência de doença coronária epicárdica obstrutiva mas com evidências de lesão miocárdica (definida como troponina positiva com ou sem anormalidades no movimento da parede), médicos costumam considerar o diagnóstico de miocardite como a causa subjacente utilizando dados como marcadores clínicos e por imagem de lesão miocítica. Visto que a apresentação clínica da miocardite pode variar e incluir sintomas vagos ou inespecíficos como fadiga, dispneia, palpitações e desconforto no peito, o diagnóstico de miocardite nesse contexto não é simples. De fato, a maioria dos casos publicados com suspeita de miocardite induzida na COVID-19 foram baseados nos níveis sanguíneos de troponina ou RMC, sem confirmação por biópsia.20,21 Entretanto, foram relatados poucos casos de miocardite evidenciada histologicamente. De forma geral, a miocardite viral causada pelo SARS-CoV-2 não foi demonstrada definitivamente por análise histológica e do genoma viral.19
De uma perspectiva pulmonar às consequências vasculares e tromboembólicas
Inicialmente concebida como uma doença respiratória viral, o entendimento da COVID-19 foi ampliado para abranger uma complexa condição heterogênea e multiorgânica.22,23 Dados emergentes indicam que os pacientes com COVID-19 apresentam maior risco de amplos efeitos sistêmicos, incluindo trombose,24-26 insuficiência renal,27,28 eventos neurológicos,29,30 e complicações cardiovasculares, tais como insuficiência cardíaca,31,32 e choque cardiogênico.33
Um estudo retrospectivo que comparou sobreviventes e não sobreviventes da COVID-19 demonstrou que os não sobreviventes apresentaram níveis significativamente mais elevados de D-dímero e de produtos da degradação da fibrina, além de maior tempo de protrombina e de tromboplastina parcial ativada na apresentação clínica.34 Essas diferenças aumentaram em medições seriadas, com 71,4% dos não sobreviventes preenchendo os critérios diagnósticos da Sociedade Internacional de Trombose e Hemostase (International Society on Thrombosis and Hemostasis, ISTH) para coagulação intravascular disseminada evidente. A coexistência de anormalidades na coagulação, hiperfibrinólise e trombose dos grandes vasos em pacientes com COVID-19 grave foi relacionada a inúmeras síndromes de disfunção de múltiplos órgãos.35-37
A ativação endotelial relacionada à COVID-19, chamada de endotelite por alguns, explica o comprometimento microcirculatório sistêmico em diferentes leitos vasculares e suas sequelas clínicas em pacientes com infecção pelo SARS-CoV-2 (Figura 2).38-40 Além dos pericitos, células musculares lisas arteriolares também podem expressar a ECA2, e atuar como células-alvo cardíacas do SARS-CoV-2.41,42 O SARS-CoV-2 e o SARS-CoV-1 compartilham domínios de ligação ao receptor quase idênticos. Algumas características clínicas da COVID-19 se assemelham àquelas de outras infecções por coronavírus, incluindo o SARS-CoV-1, que surgiu em 2002, e o MERS-CoV, que ameaçou desencadear uma pandemia em 2012.43 Entretanto, o sítio de ligação do SARS-CoV-2 apresenta uma conformação mais compacta e estável, com características estruturais que aumentam a afinidade à ECA2 e o local de clivagem da furina que aumenta a capacidade de infectar as células-alvo.43,44 A expressão dos receptores de ECA2 em pericitos e células musculares lisas microvasculares, assim como achados de endotelite aguda em pacientes com COVID-19, fornece um possível mecanismo de lesão viral direta através da vasculite mediada pela infecção.38,41,45 Além disso, a presença de um local de clivagem da furina, que pode ser processada por proteases quase ubíquas do tipo furina, distancia o SARS-CoV-2 do SARS-CoV-1 e de outros coronaviridae relacionados à SARS, que possuem um local de clivagem monobásico processado na entrada das células alvo.46-48 O entendimento dos mecanismos e da fisiopatologia da infecção por SARS-CoV-2 e da forma como esta afeta as células endoteliais pode fornecer perspectivas úteis sobre as estratégias terapêuticas e preventivas para evitar as complicações da doença.
O lado esquerdo do diagrama apresenta uma monocamada endotelial em repouso com as células endoteliais de morfologia escamosa repousando sobre uma membrana basal intacta. Quando as células endoteliais sofrem o efeito citopático de uma infecção viral como a causada pelo coronavírus da síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), ou encontram padrões moleculares associados a patógenos (pathogen-associated molecular patterns, PAMPs) derivados de vírus ou bactérias, tais como lipopolissacarídeos, citocinas pró-inflamatórias como interleucina (IL)-1 ou fator de necrose tumoral (tumor necrosis factor, TNF), ou padrões moleculares associados a danos (damage-associated molecular patterns, DAMPs), derivados de células mortas ou agonizantes, as células endoteliais tornam-se ativas. As células endoteliais apresentam uma morfologia mais colunar. Elas podem expressar moléculas de adesão que atraem leucócitos e quimiocinas que dirigem a sua migração para dentro do espaço subendotelial. A descamação (sloughing) das células endoteliais expõe a membrana basal trombogênica. Os neutrófilos aderentes podem ser submetidos a formação de armadilhas extracelulares dos neutrófilos (neutrophil extracellular traps, NETs), que amplificam o dano endotelial mediado em parte pela IL-1α. A ativação inflamatória das células endoteliais pode desfazer a VE-caderina, que é em grande parte responsável pela integridade da função endotelial de barreira. As células endoteliais ativadas também podem expressar metaloproteinases da matriz que podem degradar a membrana basal e posteriormente interromper a função endotelial de barreira. Nos vasos pequenos, como aqueles que envolvem os alvéolos pulmonares, esse comprometimento na função de barreira pode levar a vazamentos capilares. Esses vários distúrbios na função endotelial, representados na parte central do diagrama, levam a danos do órgão final, incluindo síndrome do desconforto respiratório do adulto (SDRA) e trombose nos pulmões, predispõem a ruptura da placa e trombose nas artérias coronárias, e afeta a microvasculatura, levando a isquemia e danos miocárdicos. A diátese trombótica provocada pela disfunção endotelial também pode predispor à acidente vascular cerebral (AVC). Lesões microvasculares e macrovasculares podem potencializar a insuficiência renal aguda. A disfunção hepática também pode ser decorrente da trombose microvascular, entre outros mecanismos. Pode ocorrer trombose venosa profunda, visto que a disfunção endotelial representa uma importante parte da tríade de Virchow e abre caminho para a embolia pulmonar. Portanto, a perda da função protetora do endotélio e o desencadeamento dos mecanismos apresentados pode resultar em falência sistêmica de múltiplos órgãos, a qual caracteriza os estágios avançados da doença do coronavírus 2019 (COVID-19). Adaptada com permissão de Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 09 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623.<xref ref-type="bibr" rid="B39"><sup>39</sup></xref> uPA: ativador do plasminogênio do tipo uroquinase (urokinase-type plasminogen activator); tPA: ativador do plasminogênio tecidual (tissue-type plasminogen activator); FHDE: fator hiperpolarizante derivado do endotélio; PAI-1: plasminogen activator inhibitor 1; NADPH: nicotinamida adenina dinucleótido fosfato (nicotinamide adenine dinucleotide phosphate); EROs: espécies reativas de oxigênio; IM: infarto do miocárdio.
O recrutamento das células imunes pode causar disfunção endotelial generalizada associada a apoptose.49,50 Dados patológicos de pacientes com SARS-CoV-1 evidenciam a presença de vasculite com infiltração de monócitos e linfócitos, lesão das células endoteliais vasculares e edema estromal no coração.51 Da mesma forma, biópsias e exames histológicos post-mortem em pacientes com COVID-19 revelaram endotelite linfocítica com corpos apoptóticos e estruturas de inclusão viral em múltiplos órgãos, incluindo coração, pulmões, rins e intestino.7,38,52 A presença de elementos virais dentro das células endoteliais e o acúmulo de células inflamatórias, com evidência de morte de células endoteliais e inflamatórias, sugere que a infecção por SARS-CoV-2 gera ativação endotelial em vários órgãos, além da resposta inflamatória do hospedeiro.53 Inflamação acentuada e endotelite também podem aumentar a expressão de fator tecidual, levando a um estado pró-trombótico.54-59 A análise dos vasos pulmonares em pacientes que faleceram de insuficiência respiratória relacionada a COVID-19 demonstrou microangiopatia trombótica extensa.52 Uma fisiopatologia semelhante também pode ser aplicada a outros órgãos afetados pela COVID-19 avançada.
A disfunção endotelial resultante de infecção e de inflamação pode acarretar a diminuição do fluxo coronário e a desestabilização de placas ateroscletóricas preexistentes, desencadeando um evento coronariano agudo tipo 1.60 A maior incidência de síndromes coronárias agudas, arritmias, eventos relacionados a insuficiência cardíaca e mortalidade cardiovascular observada durante os surtos sazonais de gripe sugere uma combinação de inflamação sistêmica, lesão vascular e hipercoagulabilidade.61,62 Relatos adicionais de uma doença “Kawasaki-like” grave em crianças suporta a hipótese de hiperinflamação sistêmica e disfunção endotelial generalizada na patogênese das formas mais graves da COVID-19.63-65 A doença de Kawasaki, também denominada síndrome inflamatória tipo A multissistêmica pediátrica, é caracterizada por febre persistente, sintomas gastrointestinais, exantema e conjuntivite.63,64,66 Normalmente, as crianças com essa doença apresentarão 3-5 dias de febre, seguida de vasodilatação que é muitas vezes refratária a ressuscitação volêmica, requerendo vasopressores e, ocasionalmente, suporte circulatório mecânico.
Conceber a COVID-19 como uma doença vascular fornece uma justificativa para terapias estabilizadoras do endotélio que também podem ter impacto na replicação viral, tais como inibidores do sistema renina-angiotensina-aldosterona,38,67-70 estatinas71-73 e agentes anticitocinas.74-76 Essas estratégias poderiam ser particularmente úteis em pacientes de alto risco com disfunção endotelial preexistente, tais como aqueles com hipertensão, diabetes, obesidade e doença cardiovascular evidente, todas associadas a piores desfechos na COVID-19. Os dados disponíveis até o momento apoiam a continuação de inibidores da ECA/bloqueadores do receptor de angiotensina (BRA) e das estatinas em pacientes que já utilizam para condições cardiovasculares preexistentes.77 O bloqueio da interleucina (IL)-6, uma citocina produzida por macrófagos que induz uma resposta pró-inflamatória e muitas vezes está elevada em pacientes com COVID-19, foi recentemente estudado, com resultados contraditórios.78-83 Devemos aguardar ensaios randomizados adicionais realizados de forma rigorosa, com poder adequado e bem controlados antes de adotar ou rejeitar essas terapias.
As nuvens clínicas se reúnem: o coração pode não resistir a uma tempestade de citocinas
A liberação massiva de citocinas contribui para as complicações mais graves na COVID-19.53 Uma resposta inflamatória tão agressiva do hospedeiro comumente precipita instabilidade hemodinâmica, afetando todos os vasos, de veias a artérias de todos os calibres, e a microcirculação de muitos órgãos, fenômenos embólicos, insuficiência renal e choque. Insuficiência cardíaca aguda com decréscimos da contratilidade miocárdica pode acompanhar esse estado séptico profundo.3,4,84
Respostas inflamatórias intensas envolverão hiperativação da imunidade inata, decorrente por infecções e medicamentos ou outros estímulos, e seguirão um aumento incontrolável da concentração de citocinas, causando danos colaterais nos tecidos e em múltiplos órgãos.85,86 O termo “tempestade de citocinas” apareceu pela primeira vez em um artigo publicado em 1993 que a descreve como efeito da doença do enxerto versus hospedeiro.87 Esse termo ganhou notoriedade após ser utilizado para descrever os efeitos da infecção pelo vírus aviário H5N1 em 2005.88 A tempestade de citocinas pode complicar diversas doenças infecciosas, incluindo SARS-CoV-1 e SARS-CoV-2,86,89 vírus da influenza,90 vírus da varíola,91 citomegalovírus92 e estreptocos do grupo A.93
No caso da COVID-19, a partir da entrada do SARS-CoV-2 em uma célula hospedeira, um sistema imune inato ativo responderá com uma cascata de processos, levando à liberação de citocinas, tais como interferons tipo I/III, fator de necrose tumoral alfa (TNF-α), IL-1β, IL-18 e IL-6. Em seguida, citocinas pró-inflamatórias alterarão as funções homeostáticas das células endoteliais de forma a gerar trombose e lesão tecidual local. Dentro desse microambiente inflamatório, as células endoteliais e leucócitos invasores produzirão IL-1, o que pode desencadear a produção de moléculas quimioatraentes, estimulando a migração e a penetração de mais células inflamatórias nos tecidos locais.94 A IL-1 induz sua própria expressão gênica, desencadeando um ciclo de amplificação em alça que pode fomentar uma tempestade de citocinas (Figura 3).95-97 A IL-1 também pode aumentar a expressão gênica de outras citocinas pró-inflamatórias, incluindo o TNF-α.98 A IL-1 potencialmente suscita a produção de outra citocina pró-inflamatória, a IL-6.99,100 Essa indução da produção de IL-6 pela IL-1 fornece outro forte estímulo para o ciclo de amplificação que manterá a produção esmagadora de citocinas característica da tempestade de citocinas. A IL-6 atuará estimulando, no fígado, a síntese de fibrinogênio (precursor de coágulos), do inibidor do ativador de plasminogênio tipo 1 (PAI-1) (principal inibidor da fibrinólise) e da proteína C reativa, um biomarcador que se encontra consistentemente elevado na COVID-19.101 A IL-6 tem importante papel na lesão pulmonar aguda e serve como um biomarcador para prever a gravidade da COVID-19.102-105 Consistemente, altos níveis de outros biomarcadores inflamatórios, tais como proteína C reativa, IL-2, TNF-α, interferon-γ, D-dímero e ferritina, também estão correlacionados a manifestações graves e piores desfechos em pacientes com COVID-19. Linfopenia e trombocitopenia são frequentes nessa última fase da COVID-19.3,4,75,84,106,107 Como componentes da resposta imune celular, as células natural killer (NK) e os macrófagos serão submetidos a ativação local, liberando citocinas para coordenar com células T ativadas e outras respostas humorais em uma tentativa de resolver rapidamente a infecção.86 A COVID-19 grave pode acarretar a exaustão funcional das células NK e dos linfocitos T CD8+, uma evolução que favorece a persistência do vírus, ativação de macrófagos e liberação adicional de citocinas.108,109 As respostas dos anticorpos e células T citotóxicas contra o SARS-CoV podem persistir por muito tempo após a recuperação completa, com declínio moderado 1 ano após o início dos sintomas.110
Tempestade de citocinas. Citocinas pró-inflamatórias, como a interleucina (IL)-1 e o fator de necrose tumoral alfa (tumor necrosis factor alpha, TNF-α), induzem a expressão gênica um do outro, desencadeando um ciclo de amplificação que sustenta a tempestade de citocinas. A célula endotelial é um alvo chave das citocinas, visto que estas induzem a ação de um eixo transcripcional central pró-inflamatório, o fator nuclear kappa beta (fator nuclear-kB). A IL-1 também causa aumentos substanciais da produção de IL-6 por células endoteliais e outras, o instigador da resposta dos hepatócitos na fase aguda. Os reagentes de fase aguda incluem fibrinogênio, o precursor de coágulos, e PAI-1, o principal de nosso sistema fibrinolítico endógeno. A proteína C-reativa (PCR), comumente elevada na COVID-19, fornece um biomarcador de estado inflamatório prontamente mensurado. As alterações no equilíbrio trombótico/fibrinolítico devido à resposta da fase aguda promovem trombose nas artérias, na microvasculatura, incluindo aquela de órgãos como o miocárdio e o rim, e nas veias, causando trombose venosa profunda (TVP) e predispondo a embolia pulmonar (EP). Portanto, as próprias citocinas que suscitam as funções endoteliais anormais podem desencadear a resposta da fase aguda, a qual, em conjunto com a disfunção endotelial local, pode colaborar para as complicações clínicas da doença do coronavírus 2019 (COVID-19). O lado direito desse diagrama alinha os agentes terapêuticos que atacam esses mecanismos da tempestade de citocinas e que, portanto, podem limitar as consequências devastadoras dessa tempestade. Adaptada com permissão de Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 09 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623.<xref ref-type="bibr" rid="B39"><sup>39</sup></xref> PAMPs: padrões moleculares associados a patógenos (pathogen-associated molecular patterns); DAMPs: padrões moleculares associados a danos (damage-associated molecular patterns); SRAA: sistema renina-angiotensina-aldosterona.
Quanto à dinâmica cardíaca, pode ocorrer disfunção ventricular esquerda transitória durante a fase aguda da tempestade de citocinas. Um estudo ecocardiográfico comparativo com pacientes com SARS no estágio agudo da infecção e 30 dias depois demonstrou um aumento significativo do índice do ventrículo esquerdo de desempenho miocárdico, além de uma menor fração de ejeção do ventrículo esquerdo, o que caracterizou comprometimento diastólico subclínico sem envolvimento sistólico na fase aguda. Além disso, após 30 dias, esse comprometimento melhorou com a recuperação clínica.111 Pacientes que se recuperaram da síndrome da tempestade de citocinas podem ainda apresentar cicatrizes duradouras, tais como fibrose pulmonar, incapacidade funcional e redução da qualidade de vida.112 O efeito a longo prazo da lesão miocárdica sustentada durante a COVID-19 aguda exigirá atenção especial nos próximos anos. Mesmo naqueles que aparentemente se recuperaram totalmente da COVID-19 aguda, as cicatrizes miocárdicas podem prejudicar as reservas necessárias para suportar futuros insultos. Focos fibróticos no miocárdio cicatrizado poderiam se tornar substratos para arritmias de reentrada, como consequência de longo prazo pós-infecção aguda por SARS-CoV-2.
No nível das artérias coronárias, a elevação das citocinas sistêmicas pode ativar as células inflamatórias residentes em um ateroma preexistente e desencadear uma síndrome coronariana aguda do tipo 1 devido à ruptura da placa.113 A isquemia cardíaca também pode ser decorrente de um desequilíbrio entre a oferta e a demanda de oxigênio. Mesmo na ausência de aterosclerose epicárdica, a liberação de citocinas de uma infecção sistêmica ou em local próximo, tais como pneumonite, pode ativar o endotélio microvascular coronariano e predispor a anomalidades vasomotoras, aumento da trombose, redução da fibrinólise, aumento da adesão dos leucócitos, e outros aspectos de disfunção dos microvasos do coração.40,114
Perspectivas
Essa pandemia está no fim ou apenas começando?
Ainda estamos aprendendo sobre a COVID-19 e sobre as novas variantes do SARS-CoV-2. As evidências atuais apoiam o uso de remdesivir, glicocorticoides, doses profiláticas de anticoagulantes e anticorpos contra o SARS-CoV-2 em certos pacientes hospitalizados com COVID-19. Ainda necessitamos de mais terapias baseadas em evidências para encurtar o curso da COVID-19 ou reduzir a necessidade de ventilação mecânica ou cuidados intensivos. A utilização de agentes anticitocinas pode auxiliar na melhoria dos cenários mais graves, nos quais há disfunção dos sistemas biológicos e maior risco de fatalidades, sendo crucial bloquear a onda avassaladora de citocinas elevadas, embora aguardemos por resultados de ensaios clínicos rigorosos.74-76 Existem relatos de reinfecções 50 dias após a recuperação,115 e podem ocorrer infecções pós-vacinação, apesar de incomuns, naqueles já vacinados. A recuperação de alguns sintomas, tais como anosmia116 ou fadiga,117 também pode ser incompleta.
Atualmente, nossa melhor abordagem para erradicar, ou pelo menos controlar, a ameaça do SARS-CoV-2 é a vacinação. Existem diversas vacinas, baseadas em diferentes abordagens, com resultados variando de redução de novos casos ao atenuamento de manifestações avançadas da COVID-19. O desenvolvimento de uma ampla variedade de vacinas em rápida sucessão para confrontar a crise da COVID-19 representa uma vitória da ciência médica. Colhemos os benefícios de décadas de investimentos em pesquisa básica e no desenvolvimento farmacêutico diante dessa pandemia assassina. Desde a sua identificação em dezembro de 2019, a pandemia impulsionou muitos desenvolvimentos, alterou significamente muitas vidas, abalou rotinas, o trabalho, a convivência social e a prática de exercícios, com consequentes desafios tanto para a saúde física quanto mental.
Com o ônus econômico, a pressão sobre os sistemas de saúde e a demanda urgente por vacinas, os governos têm lutado para alcançar a vacinação de populações inteiras em tempo hábil. Precisamos descobrir a durabilidade da imunização conferida pelas vacinas e desenvolver doses de reforço que prolongarão a proteção e ampliarão o espectro de cobertura de novas variantes.
Como sociedade, devemos aprender com essa crise e nos preparar para enfrentar futuros desafios globais de saúde de maneira mais coerente e organizada. Como profissionais devotados à atenção em saúde, precisamos permitir que a ciência, e não considerações políticas, lidere nossas respostas a desastres de saúde pública como o que estamos enfrentando com a COVID-19. A fim de se prepararem para surtos futuros, pesquisadores devem se organizar antecipadamente em uma cooperação internacional para a realização de ensaios clínicos randomizados, cegos, controlados e com poder adequado, em vez de estudos observacionais ou pouco controlados dispersos. O rigor científico é a única maneira apropriada de avançar. Intervenções baseadas em episódios anedóticos e sem comprovação plausível atrasam o progresso e, portanto, representam uma ameaça à saúde pública. Devemos confrontar as notórias desigualdades que essa pandemia agravou entre os segmentos menos privilegiados da sociedade. Temos a oportunidade de aprender com essa grave situação. Esse é nosso dever, a fim de evitar que inevitáveis pandemias futuras tenham um custo tão fatal para a nossa sociedade, alterando tantas e mais tantas vidas.
Declaração de Conflitos de Interesse
Dr. Peter Libby: O Dr. Libby é consultor não remunerado, ou está envolvido em ensaios clínicos, para as empresas Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer, Sanofi-Regeneron. O Dr. Libby é membro do comitê consultivo científico das empresas Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, e XBiotech, Inc. O laboratório do Dr. Libby's recebeu financiamento de pesquisa nos últimos 2 anos da Novartis. O Dr. Libby participa da Diretoria da XBiotech, Inc. O Dr. Libby tem interesses financeiros na Xbiotech, uma empresa que desenvolve anticorpos terapêuticos humanos. Os interesses do Dr. Libby foram revisados e são gerenciados pelas instituições Brigham and Women's Hospital and Partners HealthCare, de acordo com suas políticas de conflito de interesse. O Dr. Libby recebe apoio financeiro do Heart, Lung, and Blood Institute (1R01HL134892), da American Heart Association (18CSA34080399), do RRM Charitable Fund e do Simard Fund.