key: cord-0709616-0zfmrbd9
authors: Kite, Thomas A.; Pallikadavath, Susil; Gale, Chris P.; Curzen, Nick; Ladwiniec, Andrew
title: The Direct and Indirect Effects of COVID-19 on Acute Coronary Syndromes
date: 2022-03-23
journal: Cardiol Clin
DOI: 10.1016/j.ccl.2022.03.002
sha: 16fcad13c0548b5450d9c41e19cd68cfc856f4f1
doc_id: 709616
cord_uid: 0zfmrbd9

The novel SARS-CoV-2 virus has directly and indirectly impacted patients with acute coronary syndrome (ACS). The onset of the COVID-19 pandemic correlated with an abrupt decline in hospitalizations with ACS and increased out-of-hospital deaths. Worse outcomes in ACS patients with concomitant COVID-19 have been reported, and acute myocardial injury secondary to SARS-CoV-2 infection is recognized. A rapid adaptation of existing ACS pathways has been required such that overburdened healthcare systems may manage both a novel contagion and existing illness. As SARS-CoV-2 is now endemic, future research is required to better define the complex interplay of COVID-19 infection and cardiovascular disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the most significant infectious disease outbreak and public health emergency for a century. Declared a pandemic by the World Health Organization in March 2020, coronavirus disease 2019 (COVID-19) has infected millions and caused excess mortality and morbidity across the world.

Healthcare systems have been required to restructure and adapt to an entirely novel disease entity, while providing routine and emergency care for existing illness.

Patients with acute coronary syndrome (ACS) provide one such example in which these challenges intersected (Figure 1) . The diagnosis and treatment of acute myocardial infarction (MI) has attracted much scientific attention during the COVID-19 pandemic by virtue of several critical issues:

It rapidly became apparent that the SARS-CoV-2 virus would have wide-reaching consequences for patients with cardiovascular disease, because such risk factor profiles were recognized to portend an increased risk of hospitalization and mortality following infection. 7 Yet perhaps more unexpected was the sudden and unheralded decline in cases of heart attack observed at the outset of the COVID-19 pandemic. For example, in one of the first such reports, De Filippo et al documented a 25% reduction in hospital admissions for all ACS in Northern Italy. 2 These data that have since been replicated in larger and more robust analyses that also show preponderance for greater decreases in non-ST elevation acute coronary syndrome (NSTE-ACS) presentations. 1, 8 Moreover, increases in of out-of-hospital cardiac arrest and death at home when compared with pre-pandemic periods were described, suggesting that many patients were forgoing medical attention. 9, 10 Where did all the heart attacks go? Viral respiratory infections are well recognized to increase risk of acute myocardial infarction, 11 so why was this not reflected in greater hospital attendances during the initial waves of the pandemic? Proposed theories comprised; 1) a desire from patients to self-manage symptoms at home (perhaps compounded by societal pressures to quarantine), 2) a reduction in activity levels that may provoke MI, or 3) a fear of COVID-19 contagion in healthcare settings. 12 Against the backdrop of falling heart attack case rates, a story of the complex interplay between SARS-CoV-2 infection and cardiovascular disease developed, fuelled by rapid dissemination of knowledge via social media platforms. 13 Case series described spontaneous and excess micro-and macrothrombi development in multiple vascular beds, 14 myocarditis J o u r n a l P r e -p r o o f masquerading as ST elevation myocardial infarction (STEMI), 15 and elevated rates of myocardial injury in patients with COVID-19 infection. 16 However, the exact degree and frequency of acute myocardial injury in patients with COVID-19, and its relationship with the cardiovascular system, has been difficult to accurately define.

In perhaps the most robust study to investigate its prevalence, Lala et al reported acute myocardial injury by means of cardiac troponin elevation in 36% of 2,736 patients hospitalized with COVID-19. 17 Elevated levels correlated with disease severity, as troponin concentrations three times the upper reference limit were associated with a three-fold increased risk of mortality. 17 Multiple hypotheses have been presented for the direct impact of SARS-CoV-2 on the cardiovascular system, ranging from supply-demand mismatch-mediated ischemia, intravascular thrombosis and endotheliitis, systemic hypoxia, or direct viral insult and injury -each a result of a systemic inflammatory cascade as the SARS-CoV-2 viral spike protein binds to angiotensin-converting enzyme 2 receptors. 18, 19 Indeed, discrimination between COVID-19-related and non-COVID-19-related myocardial injury has been intensely debated and acknowledged to present significant diagnostic and therapeutic uncertainty for frontline clinicians. 20 An important group comprises those patients who present with ACS while concurrently infected with COVID-19. Such cases were documented in early observations to experience greater rates of adverse outcomes. 21 The worse clinical courses may be explained by: It became clear that descriptive and mechanistic observational studies were required to better understand this multifaceted disease process.

The International COVID-ACS Registry was designed to evaluate characteristics and outcomes of ACS patients with concurrent COVID-19 infection. 23 As it became clear that this population represented a unique challenge, 24 the study was established in March 2020 to elucidate potential mechanisms that may account for the adverse outcomes observed.

The International COVID-ACS Registry has provided a pragmatic means of investigatorinitiated data collection via an online web-hosted portal. Lead investigators were cognisant of increased clinical demands, redeployed research personnel, and redistributed funding streams during this period. The criteria for study inclusion were: 1) COVID-19 positive (or high index suspicion according to clinical status and chest imaging findings 25 ) and, 2) invasive coronary angiography undertaken for suspected ACS.

A consortium of international investigators collected data from 144 STEMI and 121 NSTE-ACS patients with concomitant COVID-19 infection. The key findings of the study were consistent regardless of ACS subtype ( Table 1) . 23 Table 2) . 28,29 Furthermore, elevated rates of unfavourable presenting characteristics such as out-of-hospital cardiac arrest, heart failure, and cardiogenic shock in COVID-19 positive STEMI patients have consistently been described in the literature. 23,28-30

The principal mechanistic finding of the International COVID-ACS Registry was that time taken for patients to render the hospital was prolonged when compared with pre-COVID controls, and that this was associated with poorer clinical outcomes (symptom onset to admission: suggesting that pathways and well-established systems of care struggled to adapt to the obligatory organizational changes, screening of patients, and preparation of personnel in the catheter laboratory. Such insights in STEMI patients, irrespective of COVID-19 status, provide valuable information and add credence to early hypotheses that deferment in seeking and receiving medical care may, in part, explain the excess mortality rates observed. Public health communications that requested the public "stay at home", alongside a perceived fear of COVID-19 contagion, appear to have impacted patterns of healthcare-seeking behaviour.

Studies to date have often focused on COVID-19 positive patients with STEMI. The unique scope of the International COVID-ACS registry also afforded insights into patients with NSTE-ACS that underwent an invasive strategy. A striking observation existed that magnitude increases of cardiogenic shock and in-hospital mortality compared to pre-pandemic controls were similar across both COVID-19 positive ACS subgroups ( Table 1) . It is well-established that superior outcomes following STEMI are driven by a time-critical concept dependant on expeditious mechanical reperfusion of an occluded coronary artery. For NSTE-ACS, however, the underlying pathophysiology differs and the association with time from symptom onset to angiography (with or without revascularisation) is not nearly as strong when compared with STEMI. 33 Although limited by a small number of events in the NSTE-ACS group, acceptance pandemic continues to indirectly impact on mortality and morbidity. Specifically, healthcare system reorganization, together with changes in patient and clinician behaviour, have resulted in restricted access to previously established care pathways, with suggestions that this has led to an increase in deaths from cardiovascular disease. 36 In particular, reduced availability of intensive care unit support for procedures such as To the best of our knowledge, the UK-ReVasc Registry is the only prospective study that has collected data on this specific and novel patient cohort who were required to undergo an alternative mode of revascularization due to the impact of the COVID-19 pandemic. It affords examination of contemporary PCI techniques in a group of patients with high rates of multivessel disease (96%) and left main stem disease (52%), that according to international guidelines should primarily be reserved for CABG. 41 Even so, only short-term outcomes have been reported and initial findings perhaps generate more questions than answers. In a population with anatomically complex CAD, does revascularization with contemporary PCI techniques provide comparable and durable longer-J o u r n a l P r e -p r o o f term results that are comparable to CABG surgery? Have calcium modification techniques and newer generation drug eluting stents evolved such that historical revascularization trials require updating to best inform current practice? Longer term follow up is required, and ongoing, to inform these important discussions.

As we enter the next stages of the COVID-19 pandemic, with decreasing rates of mortality driven by improved therapeutics and mass vaccination strategies, now seems an appropriate juncture to reflect on the impact of this unprecedented crisis. Focus must now shift away from COVID-19 itself and examine the consequences of the SARS-CoV-2 virus on other areas of health service delivery and care.

Cardiovascular disease remains the leading cause of morbidity and mortality globally and is associated with 17.8 million deaths annually. 42 Patients with cardiovascular disease have been one of hardest hit groups during the pandemic period, directly because of SARS-CoV-2 predilection to cause severe infection and death in people with such co-morbidities, but also indirectly because of restricted availability and access to routine and urgent healthcare provision that is recognized to improve clinical outcomes. 6 These two effects are well illustrated by the International COVID-ACS and UK-ReVasc registries. 23, 39 Governments and public health institutions mandated their citizens to stay at home and reduce social interaction to avoid contagion, particularly those of older age and at high risk of complications following SARS CoV-2 infection. 43 Yet, it is this group of individuals, in whom cardiovascular disease is most prevalent, 44 that will have been disadvantaged the most from J o u r n a l P r e -p r o o f delays in receiving timely diagnosis and treatment. 45 For instance, surges in mechanical complications following ACS have been described during the pandemic, with reports of ventricular septal and free wall rupture, 46,47 acute functional mitral regurgitation, 48 and cardiogenic shock not seen in such frequency since prior to the establishment of primary PCI networks. 49 Perhaps the most noteworthy impact of the pandemic has yet to be quantified. Concerns regarding provision of care for non-communicable diseases such as cardiovascular disease and cancer have been raised, but arguably overlooked due to the imminent threat of COVID-19 positive patients overwhelming acute hospitals. While some patients were able to undergo an alternative treatment strategy, many have been left struggling to access timely and appropriate healthcare. Analyses from electronic health record and mortality in England estimate that up to 100,000 excess deaths from indirect effects of the COVID-19 pandemic have occurred in patients with cardiovascular disease, predominantly due to reduced supply of, and demand for, cardiac services. 50 Beyond this, we are only beginning to see the repercussions of delayed and suboptimal revascularization in patients with ACS that will lead to larger infarct size, adverse ventricular remodelling, heart failure and arrhythmias. 51 Despite the immeasurable suffering caused by COVID-19, it remains remarkable that in the face of adversity health care systems and professionals have remained resilient despite these • Due to the indirect effect of the COVID-19 pandemic on healthcare delivery, many patients with ACS have undergone alternative revascularization strategies (e.g., PCI rather than CABG). Short-term outcomes are robust but follow up of such cohorts is necessary to establish whether long term clinical outcomes are acceptable. 

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England

Reduced Rate of Hospital Admissions for ACS during Covid-19 Outbreak in Northern Italy

Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Cardiac Troponin for Assessment of Myocardial Injury in COVID-19: JACC Review Topic of the Week

Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK

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

Impact of COVID19 Pandemic on the Incidence and Management of Out of Hospital Cardiac Arrest in Patients Presenting with Acute Myocardial Infarction in England

Place and causes of acute cardiovascular mortality during the COVID-19 pandemic

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection

Where have all the heart attacks gone? New York Times

Social media in the era of COVID-19

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

Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes

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

Prevalence and Impact of Myocardial Injury in 30

In-hospital outcomes of COVID-19 ST-elevation myocardial infarction patients

Impact of COVID-19 Pandemic on Mechanical Reperfusion for Patients With STEMI

Management and Outcomes of Patients With STEMI During the COVID-19 Pandemic in China

Delay from symptom onset to hospital presentation for patients with non-ST-segment elevation myocardial infarction

Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI

Clinical features of patients with acute coronary syndrome during the COVID-19 pandemic

Papillary Muscle Rupture Due to Delayed STEMI Presentation in a Patient Self-Isolating for Presumed COVID-19

Collateral Damage: Medical Care Avoidance Behavior Among Patients With Myocardial Infarction During the COVID-19 Pandemic

Excess deaths in people with cardiovascular diseases during the COVID-19 pandemic

Left ventricular remodeling after myocardial infarction: pathophysiology and therapy

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