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Abstract

Although COVID-19 is viewed primarily as a respiratory disease, cardiovascular risk factors and disease are prevalent among infected patients and are associated with worse outcomes. In addition, among multiple extra-pulmonary manifestations, there has been an increasing recognition of specific cardiovascular complications of COVID-19. Despite this, in the initial stages of the pandemic there was evidence of a reduction in patients presenting to acute cardiovascular services. In this masterclass review, with the aid of 2 exemplar cases, we will focus on the important therapeutic implications of COVID-19 for interventional cardiologists. We summarize the existing evidence base regarding the varied cardiovascular presentations seen in COVID-19 positive patients and the prognostic importance and potential mechanisms of acute myocardial injury in this setting. Importantly, through the use of a systematic review of the literature, we focus our discussion on the observed higher rates of coronary thrombus burden in patients with COVID-19 and acute coronary syndromes.

Keywords

COVID-19 ST-segment elevation myocardial infarction primary percutaneous coronary intervention thrombosis myocardial injury

Introduction

Coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has, to date, infected more than 57 million people globally leading to more than 1.3 million deaths and an unprecedented impact on healthcare services.¹ Since the initial presentation of COVID-19 in Wuhan, China, much has been learnt about the pathophysiology and specific cardiovascular manifestations of the disease. Early in the pandemic, there was evidence that those with pre-existing cardiovascular conditions were over-represented in cases of severe infection.² Since that time, it has become clear that COVID-19 appears to have several unique cardiovascular manifestations that cardiologists must understand, including myocardial injury and importantly a propensity for thrombosis.

Cardiovascular Disease (CVD) Is a Risk Factor for COVID-19

There has been recognition from early patient cohorts that cardiovascular risk factors and disease are prevalent among patients with COVID-19 and are associated with worse outcomes. In hospitalized patients in Wuhan who either died or were discharged by the end of January 2020 hypertension was the most common comorbidity, followed by diabetes and coronary artery disease (CAD) with their presence being associated with in-hospital death.² A raised high-sensitivity troponin was also identified as a risk factor for mortality.² Among patients with COVID-19 admitted to ITU in the Lombardy region, hypertension followed by a combined demographic of cardiomyopathy and heart failure were the most common co-morbidities.³ Of particular note is the observation that the prevalence of hypertension was higher among patients who died than those discharged.³ Subsequent larger cohort studies have continued to note CVD as an independent risk factor for fatal outcome with COVID-19.^4,5

Cardiovascular Manifestations of COVID-19

While COVID-19 predominantly causes respiratory disease, including pneumonia and acute respiratory distress syndrome, a number of detrimental effects outside of the lung and affecting the majority of organ systems have been observed, although the mechanisms are not yet fully understood.⁶ However, what we do know is that the spike protein of SARS-CoV-2, much as other SARS viruses although with a 4-fold higher affinity,⁷ binds to the membrane bound glycoprotein angiotensin-converting enzyme 2 (ACE2),⁸ leading to fusion of the viral and host cell membranes and thus endocytosis and entry into cells. ACE2 is expressed across numerous extra-pulmonary tissues including cells of the heart, thereby making regional direct viral toxicity possible. Endothelial cell damage and thrombo-inflammation, dysregulation of the immune response, and dysregulation of the renin–angiotensin–aldosterone system (RAAS) have all been proposed to contribute to the pathophysiology of multi-organ injury.^6,9 A range of cardiovascular manifestations of COVID-19 have now been observed, including myocardial injury, acute coronary syndromes (ACS), arrhythmia, myocarditis and stress-induced cardiomyopathy.^10

-13 Our group recently highlighted a high thrombus burden in patients with COVID-19 presenting with ST-segment elevation myocardial infarction (STEMI).¹⁴ In this review we focus on the implications of COVID-19 for interventional cardiologists, with a particular emphasis on the evidence, and reported mechanisms, for high thrombus burden in patients with COVID-19 presenting with ACS.

Myocardial Injury and COVID-19

Myocardial injury, most commonly defined as an elevated troponin above the 99th percentile upper reference limit (URL),¹⁵ is both common and associated with poor outcome in patients with COVID-19. However, the exact mechanisms underlying the troponin elevation, and whether the presence of acute myocardial injury itself results in long-term adverse outcomes independent of type of myocardial infarction are not clear.

The first cohort demonstration of the link between myocardial injury and COVID-19 came from a study of 191 patients from Wuhan where myocardial injury among hospitalized COVID-19 patients was shown to be 17%, which was significantly higher (46% vs 1%) among those who died than survivors.² Subsequently Guo et al, in a cohort of 187 patients, highlighted the worse outcome for those with underlying CVD (such as hypertension, coronary artery disease (CAD) and cardiomyopathy) coupled with myocardial injury (present in 27.8% of their patients) in COVID-19.¹⁶ Patients with CVD were more likely to have myocardial injury, and in those where both were present this was associated with significantly increased mortality. In contrast, those with underlying CVD but a normal troponin had more favorable outcomes. Interestingly, the investigators also found that troponin elevation correlated positively with high sensitivity C-reactive protein levels suggesting a link between myocardial injury and the inflammatory process of COVID-19.¹⁶ Further cohort studies from China have reported rates of myocardial injury between 15%-20%; it occurred more frequently in older patients with comorbidities, correlated with inflammatory markers, and was associated with poor outcomes with mortality rates up to 4 times that of patients with normal troponin levels.^17
-19

Two large cohorts from New York have confirmed the above findings. Lala et al, in a cohort of 2736 patients reported a myocardial injury rate of 36% among patients hospitalized with COVID-19 and that larger troponin rises (>3 times the URL) was associated with a 3-fold increase in mortality.²⁰ Majure et al (6,247 patients) reported an incidence of myocardial injury of 29% in hospitalized patients, that troponin levels correlated with inflammatory markers (high sensitivity C-reactive protein and procalcitonin), and that there was increased risk of mortality up to 4.5 times that of patients with a normal troponin level.²¹

A detailed overview of the postulated mechanisms of myocardial injury in COVID-19 is beyond the scope of this review and is covered elsewhere.^22,23 However, there are several mechanisms to explain troponin rise in COVID-19 infection which include coronary plaque rupture (Type 1 myocardial infarction), oxygen supply-demand imbalance (Type 2 myocardial infarction) due to hypoxia due to severe respiratory infection, direct viral invasion via ACE2 receptors in the myocardium, cardiac inflammation due to cytokine storm, stress-cardiomyopathy,¹³ myocarditis,¹² and de novo coronary or microvascular thrombosis and dysfunction.²⁴

For the cardiologist the contribution of each aspect must be judged on a case by case basis with careful use of appropriate investigations such as electrocardiography, echocardiography, angiography and, in some cases, cardiac magnetic resonance imaging. Some reports suggest that, in view of the increased mortality observed in patients with myocardial injury, these patients should be treated in a more aggressive manner with targeted treatment.^16,18 However, given the variety of mechanisms, and potential difficulty in discriminating between them in critically ill patients, outside of type 1 myocardial infarction the correct “targeted” treatment may not always be clear. It is suggested elsewhere that direct infection of the myocardium and subsequent myocarditis is a less common cause of myocardial injury compared to other non-ischemic causes (e.g. severe hypoxia, systemic inflammation, cytokine storm etc).²³ While individual case reports have suggested good outcomes of patients with diagnoses of COVID-19 associated myocarditis these patients have been treated with different combinations of steroids, intravenous immunoglobulin and antivirals making it difficult to draw conclusions on optimal management strategies.^12,25 The predominant focus of this review is on the management of patients with COVID-19 with myocardial injury secondary to type 1 myocardial infarction with intra-coronary thrombus. It should be noted that myocardial injury predicting increased mortality is present across a variety of conditions, however these known associations have not yet impacted on management.^26,27

The Impact of COVID-19 on Primary Percutaneous Coronary Intervention (PCI)

Prior to the first wave of the pandemic an increase in STEMI activations was expected at primary PCI centers due to the combination of STEMI induced by viral illness (similar to that seen with influenza), STEMI mimics such as COVID-19 myopericarditis, and the potential psychological stressors.²⁸ With concerns regarding the ability to safely deliver primary PCI in this setting there was international debate as to whether thrombolytic therapy should be recommended for patients with confirmed or suspected COVID-19. Indeed, there has been increased use of thrombolysis in China, although European and American guidelines advocate continuation of primary PCI as the default strategy.^29

-32 Subsequently, there were multiple reports of decreased activity of primary PCI during the initial phase of the pandemic. In the United States, analysis from 9 high volume cardiac catheterization laboratories showed an estimated 38% reduction in STEMI activations in March 2020, compared to the average figure for the preceding 14 months.³³ Similarly in England insights from the British Cardiovascular Intervention (BCIS) registry suggested that nationally there was a decline in the number of primary PCI procedures of 43% in April 2020 compared with the average monthly procedures during 2017-2019, although these patients had an increased symptom-to-hospital and door-to-balloon time.³⁴ These reports were supported by an international survey by the European Society of Cardiology of 3101 cardiovascular specialists from across 6 continents, where the majority of respondents reported a reduction in STEMI presentations of more than 40%, with patients presenting later after symptom onset.³⁵ A number of explanations have been suggested for this observation, including a possible reluctance among patients to seek medical attention for fear of contracting COVID-19 or overburdening the healthcare system. In light of a potential second wave, with further lockdowns currently taking place across Europe, it remains to be seen whether the trend of decreased STEMI presentations will continue. Excess mortality over the course of the pandemic will include the indirect impact of patients with cardiovascular disease choosing not to, or not being able to, access appropriate services.

Case Studies

In order to highlight the potential influence of COVID-19 on ACS, Figures 1 and 2 outline 2 STEMI patients, one with a history of ischemic heart disease and one without traditional risk factors, who presented to Barts Heart Centre (treated by the authors) at the height of the pandemic (1st wave). Both cases presented via the primary PCI pathway, denied any prior overt symptoms of COVID-19, and were taken immediately for angiography with catheter laboratory staff all wearing full personal-protective equipment (PPE). In both cases RT-PCR on admission subsequently (48 hours later) returned as positive for SARS-CoV-2 RNA.

Figure 1.

A 51-year-old male with previous PCI to the LAD presented with an anterior STEMI. The patient had impaired left ventricular (LV) function with thrombus on life-long warfarin (therapeutic INR on admission). There were no prior reported COVID-19 symptoms. The patient received clopidogrel 600 mg and aspirin 300 mg along with intra-procedural heparin and underwent emergency coronary angiography shown in left panels A and C. This demonstrated (A) appearance of thrombus in the proximal and distal RCA; (C) simultaneous thrombotic occlusion of the LAD stent. He underwent multiple runs of aspiration thrombectomy and PCI to the LAD. CXR post procedure confirmed COVID-19 related changes alongside positive PCR. He received 12 hours of glycoprotein IIb/IIIa inhibitor and underwent re-study several days later shown in right panels (B) and (D). This demonstrated (B) resolution of the RCA thrombus; (D) widely patent LAD stent. The patient was discharged home on triple therapy (DAP and a novel oral anticoagulant). D-dimer 1.71mg/L (0-0.5), Fibrinogen 4.54g/L (2.0-4.0).

Figure 2.

A 46-year-old male with no significant risk factors presented with an infero-lateral STEMI. The patient reported diarrhea and mild myalgia on the day of presentation. He underwent emergency coronary assessment. This demonstrated (A) thrombotic occlusion of the obtuse marginal branch of the circumflex; (C) Thrombotic occlusion of the distal LAD. The patient underwent aspiration thrombectomy and balloon angioplasty improving flow in the (B) obtuse marginal branch; (D) distal LAD. On restoration of flow, there was minimal coronary atheroma (confirmed by OCT) and the patient received 12 hours of glycoprotein IIb/IIIa inhibitor. COVID-19 was confirmed, and a bubble study for paradoxical embolism was negative. The patient had an uneventful recovery and was discharged on DAP. D-dimer 0.37mg/L (0-0.5), Fibrinogen 6.08g/L (2.0-4.0).

Coronary Thrombus in COVID-19

Our exemplar cases highlight STEMI with high thrombus burden as a presentation in patients with concurrent COVID-19 infection. COVID-19 has been noted to predispose patients to venous and arterial thrombosis, which has been attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis.^36,37 The most commonly observed thrombotic complication is pulmonary embolism, however arterial thrombosis is thought to affect approximately 4% of severe/critically ill intensive care unit-admitted COVID-19 patients and can affect multiple arteries.³⁸ One Italian cohort found ACS to occur in 1.1% of 388 hospitalized patients with COVID-19.³⁹ A larger Spanish cohort of 1419 hospitalized COVID-19 patients observed a lower incidence of arterial thrombotic events at 1%, with a 0.2% incidence of ACS.⁴⁰

In order to better assess the available evidence for, and management of, increased coronary thrombus in COVID-19 patients with ACS we conducted a systematic review of the literature to identify all relevant articles. The search strategy and subsequent literature review was performed by an experienced medical reference librarian. The EMBASE, MEDLINE, and Pubmed databases were searched on 19th October 2020 for English language articles. The search returned 34 articles. After excluding reviews, duplicates and unrelated articles, 15 were deemed relevant. Reference lists of relevant articles were screened for further potential citations, identifying a further 8 articles. These are summarized in Table 1. There was no randomized controlled trial evidence regarding this question. Patients were deemed to initially present either with typical COVID-19 (i.e. shortness of breath/respiratory failure, fever, cough), ACS presentations (i.e. chest pain as the predominant feature) or a mixed picture. Presentation of ACS was classified as either on admission or developing while an inpatient.

Table 1.

Studies of COVID-19 Patients and Coronary Thrombosis/Acute Coronary Syndromes.

Study	Sample	Age (years) sex (M/F)	Initial presentation: COVID/ACS/Mixed	Evidence of COVID	Presentation of ACS: admission/ inpatient (day)	CV risk factors	ECG	Coronary thrombus (single/multivessel)	Treatment	Intensive care	Mortality	Key observation/conclusions
Cohort Studies/Case Series
Bangalore et al ⁴¹(USA)April 2020	18 with COVID-19 & STE	63y (median)M 83%	Cough, SOB-83%Chest pain-33%	“Confirmed”	Admission 56%	CAD 18%DM 35%HLD 41%HTN 65%	Focal STE 78%	Obstructive CAD 67% of those who underwent angiography	PCI in 83% with MI	–	72%	10/18 (56%) diagnosed to have noncoronary myocardial injury on basis of non-obstructive disease on angiography or normal wall motion on echo if no angiogram.
Hamadeh et al⁴² (Italy, Lithuania, Spain and Iraq)June 2020	78 with COVID-19 & STEMI	65y (median)M 63%	–	RT-PCR	–	CAD 78%DM 27%HLD 92%HTN 73%	–	Of 19 treated with PCI:-No coronary artery obstruction 5%-LAD most common culprit 44%-Stent thrombosis 21%	19 (24.3%) treated primary PCI59 (75.7%) thrombolysis-85% success	18% (mechanical ventilation)	9/7812%	High rate of comorbidity (55% had at least 4 comorbidities), of thrombotic complications, and high mortality rate in largest series to date of COVID-19 patient presenting with STEMI.Stent thrombosis in 21% patients treated with PCIHemorrhagic stroke in 9% treated with thrombolysis
Stefanini et al ⁴³ (Italy) June 2020	28 with COVID-19 and STEMI	68y (mean)M 71.4%	ACS-78.6%	RT-PCR	Admission 85.7%	DM 32.1%HLD 42.9%HTN 71.4%PCI 14.3%	Localized STE 89.3%	Culprit lesion 60.7%No obstructive CAD 39.3%	–	–	39.3%	STEMI may represent first clinical manifestation of COVID-19Thrombolysis strategy not justified given significant proportion (39.3%) without thrombus on angiography
Choudry et al¹⁴ (UK)July 2020	39 COVID-19 & STEMI/115 total STEMI admissions	61.6y (mean)M 85%	ACS (STEMI)	RT-PCR orSymptoms +CXR/CT	Admission	DM 46.2%HLD61.6%HTN 71.8%PCI 23.1%Smoker 61.6%	STE-Anterior (61.6%)-Inferior (28.2%)-Lateral (7.7%)-Posterior 1 (2.6%)	COVID vs non-COVID:Multivessel 17.9% vs 0%Stent thrombosis 10.3% vs 1.2%Modified thrombus grade 4/5 75% vs 31.4%**= P < .05	COVID vs non-COVID:PCI 97.4% vs 97.3%TA-17.9% vs 1.3%GPI-59.0% vs 9.2%*= P < .05	COVID vs non-COVID:28.2% vs 6.6%	COVID vs non-COVID:17.9% vs 6.5%	“In patients presenting with STEMI and concurrent COVID-19 infection, there is a strong signal toward higher thrombus burden and poorer outcomes. This supports the need for establishing COVID-19 status in all STEMI cases”
Prieto-Lobato et al⁴⁴ (Spain) July 2020	4	49yM	ACS	CXRAntibody	Admission	DM	Lateral STE	Single vessel (LCx)Acute stent thrombosis	PCI-DES CxRepeat angio: POBA of DESGPI	N	0/1	Noted a higher than expected incidence of stent thrombosis in COVID-19 patients. Increase in incidence from 1.1% of PCI at this center in 2019 to 13% of PCI between March 15-April 5 2020.
		71yM	ACS	Symptoms + CXR	Admission	PCI 2007	Inferior STE	Single vessel (RCA)Late stent thrombosis	TAGPIPCI-DES	N	0/1
		86yM	ACS	RT-PCR	Admission	DMPCI 2018	Anterior STE	Single vessel (LAD)Late stent thrombosis	PCI-DES	N	0/1
		85yM	ACS	Antibody	Admission	PCI 2005	Anterior STE	Single vessel (LAD)Late stent thrombosis	POBATAGPI	N	0/1
Alaarag et al⁴⁵ (Egypt) Oct 2020	26 patients with STEMI and COVID-19	57.7y (mean)M 69.2%	ACS (chest pain) 57.7%STEMI as first presentation 69.2%	RT-PCR	Admission	DM 38.5%HLD 38.5% HTN 42.3%PCI 3.8%Smoker 50%	STE-Inferior 42.4$-Anterior 34.6%-Lateral 7.7%	Non-obstructive coronaries-30.8%Acute stent thrombosis-15.4%Thrombus grade 4/5-46%	Primary PCI	–	15.4%	Take home: STEMI may be initial presentation, non-obstructive in 30.8%, in patients with total occlusion thrombus grade was high. “Adjunctive anticoagulation and antiplatelet therapy may need to be revised.”
Case Reports
Yolcu et al⁴⁶ (Turkey) April 2020	1	55yM	COVID	RT-PCRCT	Inpatient (D9)Chest pain	DMHTN, PCI	Anterior & Inferior STE	Multivessel (LAD & RCA)	PCI-DES LAD, PCI-BMS RCADAP	Y	0/1	Multivessel thrombus-increased stress and metabolic demand?
Lacour et al⁴⁷ (France) April 2020	1	68yM	ACS	RT-PCR	Admission	DM	Anterior STE	Single vessel (LAD)Early stent thrombosis x2	ThrombolysisRescue PCI LADRepeat angio:TA & POBAFurther angio:TA but no reflow	Y	1/1	Two episodes of acute stent thrombosis following initial thrombolysis strategy with rescue PCI in patient asymptomatic COVID-19. Raises concerns of increased risk of stent thrombosis in COVID-19 patients.Consider GPI inhibitors in every patient with STEMI and COViD-19
Harari et al⁴⁸ (USA)May 2020	1	40yF	Mixed	RT-PCRCXR	Inpatient D2Chest pain	DM,HLD, HTN	Anterior, lateral and inferior STE	Single vessel (LAD)	TAIC-TPCI-DESGPIDAP	Y	1/1	Increased thrombotic risk of COVID-19. Management of AMI with extensive thrombus unclear.
Hinterseer et al⁴⁹ (Germany)May 2020	1	65yM	COVID	RT-PCRCXR	Inpatient (D3)Respiratory deterioration	DM, HLD, HTN, PCI	Acute RBBB, STE aVR	Single vessel (LAD)In-stent	PCI-DESDAP	Y	1/1	Sudden respiratory deterioration may be due to ischemia
Dominguez-Erquicia et al⁵⁰ (Spain)May 2020	1	64yM	ACS	RT-PCR	Admission(although same day as discharge for COVID-19)	Nil	–	Multivessel (RCA & LAD)	TAPCI-DES RCADAPLMWH 7/7	–	0/1	OCT revealed no underlying atheroma. Increasing D-dimer and platelets suggestive of in situ thrombosis as mechanism for multivessel obstruction
Seif et al⁵¹ (UK) May 2020	1	58yF	ACS	RT-PCR (prior to admission)	Admission	–	Inferior/posterior STE	Single vessel (RCA)	TAGPIPOBAIV HeparinDAP	Y	1/1	No-reflow despite mechanical and pharmacological approaches. Plan to repeat angio after 48 hrs heparin & GPI but patient died. Suggested PPCI, potent P2Y12 inhibitors, upstream GPI and infusion post PPCI.
Zendjebil et al⁵² (France)June 2020	1	42yM	ACS	RT-PCR	Admission	Ex-smoker	Anterior STE	Multivessel (LAD & RCA)	PCI-DESGPI	N	0/1	STEMI with a high thrombus burden can appear as the first and only onset of COVID-19 symptoms. Therefore suggest ruling out in patients with unusual/severe ischemic events
Setia et al⁵³ (USA)June 2020	1	59yM	Mixed	RT-PCRCXR, CT	Admission	DM, HLD, HTN	Inferior STE, complete heart block	Multivessel (LCx and RCA)	Initial thrombolysisTA PCI-DES LCx 48 hrsNil RCA (q waves)Heparin	Y	0/1	“Thrombolytic therapy alone may not be adequate in patients with STEMI and COVID-19”
Rey et al⁵⁴ (Spain)June 2020	1	59yM	ACS	RT-PCRCXR	Admission	DM, HTN	Inferolateral STE, anterior STD	Multivessel (RCA & LAD)	TA, PCI-DESGPIDAP	N	1/1	SARS-CoV2 infection may increase risk of plaque rupture, plaque rupture likely given obstructive coronary lesions.
Cardenes et al⁵⁵ (Spain)June 2020	1	74yM	Mixed	RT-PCRCXR	Admission	CVA, DM, HTN	Inferior STE, anterior ST depression	Single vessel (RCA)	PCI-DESDAPHeparin	Y	1/1	Mixed shock. Multiple arterial thrombosis
Al-Sadawi et al⁵⁶ (USA) June 2020	1	57F	ACS	RT-PCR	Admission	HLD	Inferior STE	Single vessel (RCA)	PCI-DESDAP + Rivaroxaban 2.5 mg BD (1 month)	N	0/1	Extrapolated data from ATLAS ACS 2-TIMI to add Rivaroxaban⁵⁷
Tedeschi et al⁵⁸ (Italy)July 2020	1	60yM	COVID	RT-PCRCXR	Inpatient (D7)Chest pain	Nil	Inferolateral STE	Single vessel (RCA)	TAGPIPCI DESDAP	Y	1/1	Coronary thrombosis unresponsive to GPI and PCI
Shams et al⁵⁹ (Qatar)July 2020	1	28yM	COVID	RT-PCRCXR	Inpatient (D9)Chest pain	Nil	Anterior STE	Single vessel (LAD)	TAPCI-DESGPIDAP	N	0/1	Coronary thrombus in young patient without risk factors
Kirresh et al⁶⁰ (UK)July 2020	1	43yM	COVID	RT-PCRCXR	Inpatient D1Cardiac arrest	Ex-smoker	Inferior STE	Single vessel (RCA)	TAGPIIC-TPCI-POBA	Y	1/1	“High thrombus burden may be driven by significant cytokine storm, endothelial dysfunction, increase risk of coronary plaque rupture and hypercoagulability”
Dancy et al⁶¹ (UK)July 2020	1	51yM	COVID	RT-PCRCXR	Inpatient D4Chest pain	DM, HLD, HTN	Inferior STE	Single vessel (RCA)	TAPCI	Y	–	IVUS revealed no plaque rupture. First reported case of COVID-19 related in situ thrombosis imaged using intravascular imaging techniques
Antuna et al⁶² (Spain)July 2020	1	81yM	COVID	RT-PCRCXR	Inpatient D10	HTN,PCI (3 months prior)	Anterior STE	Single vessel (LAD stent thrombosis)	TAPOBAGPIDAP	N	0/1	OCT revealed large occlusive mixed thrombus. Likely multifaceted: mechanical factors & COVID-19
Kurdi et al⁶³ (UK)July 2020	1	54yM	ACS	Symptoms + CXR, CT(RT-PCR negative)	Admission	Obesity	Inferolateral STE	Multivessel (RCA & LAD)	TAGPIPOBA RCAPCI-DES LADDAP&DOAC	N	0/1	COVID-19 confirmed with CT chest after multiple negative RT-PCR swabs, high index of suspicion should remain

ACS, acute coronary syndrome; BMS, bare-metal stents; CAD, coronary artery disease; CXR, chest x-ray; CT, computed tomography scan; CVA, cerebrovascular accident; DAP, dual antiplatelet; DES, drug-eluting stent; DOAC, direct oral anti-coagulant DM, diabetes mellitus; GPI, glycoprotein IIb/IIIa inhibitors; HLD, hyperlipidemia; HTN, hypertension; IC-T, intra-coronary thrombolysis; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCx, left circumflex artery; MI, myocardial infarction; OCT, optical coherence tomography; RCA, right coronary artery; PCI, percutaneous coronary intervention; POBA, plain old balloon angioplasty; STE, ST-elevation; TA, thrombus aspiration.

Case series of patients with COVID-19 and ST-elevation from New York and Lombardy early in the pandemic painted a bleak picture, with mortality rates of 72% and 39% respectively.^41,43 The high rates of non-obstructive CAD, 56% and 39% respectively (although only half the New York patients underwent coronary angiography), highlighted the importance of considering non-coronary diagnoses (type 2 myocardial infarction/myocarditis).^41,43 A more recent Egyptian cohort of 26 patients reported a rate of non-obstructive CAD of 31% among patients with COVID-19 and STEMI.⁴⁵ Persistent high rates of non-obstructive diagnoses among COVID-19 patients with ST-elevation highlights the potential risks of pursuing a strategy based on thrombolysis. This risk was emphasized in an international registry of 78 patients, where among the 59 patients who received thrombolysis there was a hemorrhagic stroke rate of 9%.⁴⁵

The Lombardy series also gave one of the earliest insights of STEMI being a presenting feature of COVID-19, in 86% STEMI was the first manifestation of COVID-19, with 79% presenting with typical chest pain.⁴³ This was then repeated throughout the literature. STEMI was the first presentation of COVID-19 in 69% of the Egyptian cohort.⁴⁵ Of the 21 (17 case reports and a 4 patient series) individual cases 11 had a predominant ACS presentation, with a further 3 presenting in a mixed fashion with symptoms of ACS and COVID-19.

Our study,¹⁴ describing a high thrombus burden among COVID-19 patients, is replicated throughout the series and case reports summarized in Table 1.^42,44,45 Our study reported a 10.3% stent thrombosis rate, Prieto-Lobato et al describe a stent thrombosis rate (13%) more than 10 times their centers historical comparator, while Hamadeh et al noted an acute stent thrombosis rate of 21%, with a further 3 cases of stent thrombosis reported in the literature.^{42,44,47,49,62} Multivessel thrombus occurred in 17.9% of patients in our study and in 6 case reports.^{46,50,52
-54,63}

It can be seen in Table 1 that a high proportion of patients with COVID-19 who presented with STEMI had traditional cardiovascular risk factors. As noted above, we know these patients are at increased risk of mortality from COVID-19 infection. Conversely there are also multiple reports of patients without traditional risk factors, but with COVID-19, presenting with STEMI with a high thrombus burden.^{50
-52,56,58
-60} This observation underlies our suggestion that in patients without, or with few, risk factors presenting with high thrombus burden STEMI, there should be a high index of suspicion for COVID-19.⁶³ This suspicion should remain even if initial PCR testing is negative given the high false negative rates.⁶⁴

More recently 2 larger scale studies have been presented of ACS in COVID-19. First, the Global COVID-ACS registry which was an anonymized collection of data on 316 COVID-19 patients from 85 centers around the world.⁶⁵ All patients underwent coronary angiography with 265 confirmed ACS, consisting of 144 STEMI and 121 NSTEMI patients. Compared to previous MINAP and BCIS data there were significantly increased rates of cardiogenic shock (22.9% in the STEMI subgroup, and 5.0% in the NSTEMI subgroup) compared with pre-COVID-19 data of 8.7% for STEMI and 1.4% for NSTEMI with a similar signal for in-hospital mortality. Overall, there was a high rate of in-hospital mortality (15.5%), and repeat MI (4.9%), heart failure (21.5%) and prolonged hospital stay (6.6 days) and required greater use of ventilation, pressor support, and (for STEMI) mechanical circulatory support.

The second registry to recently report is the North American COVID-19 STEMI registry that has enrolled 594 STEMI patients at 64 sites: 171 of whom were confirmed COVID-19 positive.⁶⁶ Similarly, higher rates of cardiogenic shock, in-hospital mortality were found along with longer hospital stays. There were also clear racial disparities found with Black, Asian, and Hispanic patients representing 27%, 7%, and 24%, respectively, of the COVID-19 group, making up only 11%, 6%, and 6% of the non-COVID-19 group. Together the findings of these 2 registries alongside our own single center study highlights the poor outcomes associated with the presence of COVID-19 infection in patients with ACS, whether related to respiratory complications, greater thrombotic complications or thrombus burden.

Procedural Management

Use of intracoronary imaging could be helpful in cases where COVID-19 related thrombosis is the presumed underlying etiology of the ACS rather than due to underlying coronary disease, as described in case 2 above. Imaging use has also been reported in 3 cases, with optical coherence tomography (OCT) twice and intravascular ultrasound (IVUS) once.^50,61,62 In 2 cases this helped identify that there was no underlying atheroma in coronary arteries with thrombosis, therefore increasing the probability that the patient’s presentation was due to COVID-19.^50,61 In the third case, where OCT was used in the setting of acute stent thrombosis, the OCT helped determine that the presentation was likely due to a combination of mechanical factors related to the stent and COVID-19 infection.⁶²

A key strategy in light of high thrombus burden is thrombus aspiration. This was utilized in 17.9% of COVID-19 patients in our study and in 14/21 individual cases.¹⁴ ESC guidelines for STEMI advise “routine thrombus aspiration is not recommended, but in cases of large residual thrombus burden after opening the vessel with a guide wire or a balloon, thrombus aspiration may be considered.”⁶⁷ Given the higher thrombus burden reported, the select use of thrombus aspiration in COVID-19 patients with STEMI may be reasonable and consistent with guidelines.

Procedural and Post-Procedural Pharmacology

High thrombus burden during primary PCI is difficult to manage resulting in technical considerations, poor procedural outcomes and important long-term prognostic implications. To date, in the absence of clinical studies, no consensus exists on the optimal antiplatelet and antithrombotic regimens in patients with COVID-19.

All patients with individual data reported above were loaded on dual antiplatelet therapy (DAP). Recommendations from individual case reports were made for the use of potent P2Y₁₂ inhibitors⁵¹ or for the use of DAP (Aspirin and Clopidogrel) and low-dose Rivaroxaban 2.5 mg BD⁵⁶ based on extrapolation from the ATLAS ACS 2-TIMI trial.⁵⁷ Although there is currently no trial evidence to direct which antiplatelet/anticoagulant regime should be used in COVID-19 patients undergoing PCI, we suggest it is reasonable to use potent P2Y₁₂ inhibitors (prasugrel or ticagrelor) along with aspirin, in keeping with IA ESC recommendations for STEMI,⁶⁷ irrespective of the PCI indication. Shorter durations could be used i.e. 1 month prior to downgrading to less potent P2Y₁₂ inhibitors, if bleeding concerns exist or if NSTEMI/elective indications. The additional use of a DOAC could be considered on a case by case basis through a shared decision-making process, acknowledging the lack of evidence. There is an ongoing clinical trial (NCT04333407) assessing the impact on mortality of the use of Aspirin, Clopidogrel, Rivaroxaban (2.5 mg BD), Atorvastatin and Omeprazole in hospitalized COVID-19 patients, although this study excludes patients with a clear need for ACS treatment.⁶⁸

Our study cohort showed signs of heparin resistance in patients with COVID-19, which were maintained when we performed analysis with weight adjusted doses i.e. COVID-19 patients required higher doses of heparin to achieve therapeutic ACTs. Although only hypothesis generating, these changes are supported by other small case series suggesting heparin resistance among intensive care COVID-19 patients (unfractionated and low molecular weight heparin)⁶⁹ Alternatives to unfractionated heparin such as enoxaparin or bivalirudin could be considered however concerns around both exist. It is likely that use of enoxaparin, despite holding a class IIa recommendation in current STEMI guidelines may demonstrate similar findings to unfractionated heparin.⁶⁷ Furthermore, the increased risk of stent thrombosis associated with bivalirudin as a heparin alternative in PCI is not ideal in the prothrombotic state associated with COVID-19.⁷⁰ It appears from the literature and our study that a combination of unfractionated heparin and GPIIbIIIa inhibition is safe in supporting primary PCI in the COVID-19 cohort but regular ACT monitoring to maintain therapeutic levels is needed. Our study reported the use of GPIIbIIIa inhibitors in 59% of COVID-19 patients compared to 9.2% of the non-COVID STEMI comparator,¹⁴ and they were used in 12/21 cases with one of these recommending routine upstream administration and post-procedure infusion.⁵¹ A further article, where they were not used and the patient died from early stent thrombosis, also recommended their use.⁴⁷ The use of GPIIbIIIa inhibitors in the setting of COVID-19 associated STEMI, although lacking any RCT data, therefore appears reasonable and consistent with the ESC guidelines regarding their use in STEMI where they are given a IIa recommendation and “should be considered for bailout if there is evidence of no-reflow or a thrombotic complication.”⁶⁷ Finally the local administration of thrombolysis has been described in isolated case series and should/could be reserved as a last resort with limited data to support its use.⁴⁸

Possible Mechanisms of Coronary Thrombus

The mechanisms underlying arterial thrombosis, in the setting of COVID-19 are unclear. One hypothesis that may have relevance is that the severe inflammatory response induced by COVID-19, as well as the virus itself, results in a consequent endothelial dysfunction that in combination with underlying comorbidities leads to worse outcome in COVID-19, and also might predispose patients to a hypercoagulable state.^71,72 A key characteristic of cardiovascular disease and risk factors such as diabetes, hypertension, aging and obesity, is that they are all characterized by chronic endothelial dysfunction and it is possible that this contributes to the severity of COVID-19 disease.

In health the endothelium has an array of anticoagulant and antithrombotic properties that act to prevent and attenuate intravascular clot formation.⁷³ The endothelium binds antithrombin III,⁷⁴ expresses thrombomodulin⁷⁵ and a tissue factor pathway inhibitor⁷⁶ as well as release of the soluble mediators nitric oxide^77,78 and prostacyclin⁷⁹ that inhibit platelet activation.⁸⁰ However, in both CVD and infection as well as a loss of these protective anti-thrombotic factors endothelial cells can also promote thrombus formation and inflammation⁸¹ through generation of pro-thrombotic factors that include endothelin-1, and pro-thrombotic prostaglandins.

As mentioned above COVID-19 is thought to lead to endothelial dysfunction across the circulation through 2 pathways. Firstly direct invasion by COVID-19 into engineered human blood vessel organoids⁸² has been demonstrated. This is further supported by histological reports documenting increased ACE2 expression in endothelial cells coupled with viral expression of the pulmonary⁸³ and renal⁸⁴ vasculature of patients that were COVID-19 positive. Although, it is important to note there is some uncertainty regarding the methods used for recording intracellular viral expression⁸ and further peer-reviewed evidence in support of these observations is needed. Secondly indirect via the effects of the potent systemic cytokine storm characterized by an amplification loop of transcription of proinflammatory cytokines IL-1, IL-6 and TNF-a.^85
-87 The endothelial dysfunction that ensues is thought to lead to recruitment of leukocytes, particularly neutrophils and the induction of neutrophil extracellular traps,⁸⁸ and thereby the immune response and tissue injury as well as platelet activation. In the coronary circulation this may lead to destabilization of coronary plaque. Here, activated macrophages secrete collagenases that degrade collagen within the fibrous cap leading to plaque rupture and also secrete tissue factor, a potent procoagulant that triggers thrombus formation when the plaque ruptures.⁸⁹ Activation of platelets leads to increased thromboxane synthesis,⁹⁰ VWF expression,⁹¹ Gp1b expression,⁹² activation of coagulation cascade and increased thrombin activation and fibrin production.

It is worth noting that in many patients STEMI is the first manifestation of COVID-19 infection¹⁴ suggesting that COVID-19 can cause ACS even in the absence of substantial systemic inflammation. Therefore, direct endothelial or vascular injury caused by SARS-CoV-2 infection might be a major contributory factor leading to STEMI in these cases⁸⁴ and targeted inhibition of endothelial infection may offer unique opportunities to prevent and treat COVID-19 infection.

Conclusion

During the global COVID-19 pandemic interventional cardiology has seen a significant reduction in activity of primary PCI pathways with increased rates of cardiac arrest, cardiogenic shock and mortality. Early reports of patients with myocardial injury and severe COVID-19 infection without obstructive coronary thrombus lead to the recommendation for routine primary PCI over thrombolysis. Accumulating data now suggests that type 1 myocardial infarction is an extrapulmonary manifestation of COVID-19 and indeed may be the initial presentation of the disease. STEMI in COVID-19 patients has been shown to be associated with increased thrombus burden and poorer outcomes than in non-COVID-19 groups.

Footnotes

Acknowledgments

Evidence search: Coronary Thrombus OR Intracoronary thrombus AND COVID-19 OR Coronavirus. Ms Assad Lahlou. (19th October, 2020). LONDON, UK: Barts Health Knowledge and Library Services.

Author Contributions

All authors contributed to the preparation of this manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Jones is funded from The Barts Charity. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

ORCID iD

Daniel A. Jones

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Therapeutic Implications of COVID-19 for the Interventional Cardiologist

Abstract

Keywords

Introduction

Cardiovascular Disease (CVD) Is a Risk Factor for COVID-19

Cardiovascular Manifestations of COVID-19

Myocardial Injury and COVID-19

The Impact of COVID-19 on Primary Percutaneous Coronary Intervention (PCI)

Case Studies

Coronary Thrombus in COVID-19

Procedural Management

Procedural and Post-Procedural Pharmacology

Possible Mechanisms of Coronary Thrombus

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References