*Editorial* **COVID-19 Severity and Cardiovascular Disease: An Inseparable Link**

**Michael Y. Henein 1,2,\*, Matteo Cameli 3, Maria Concetta Pastore <sup>3</sup> and Giulia Elena Mandoli <sup>3</sup>**


The COVID-19 pandemic is a global health issue that has so far affected over 250 million people worldwide. Having completed the first three waves of SARS-CoV2 infection, the world is currently facing the fourth wave, with significant consequences on overall global morbidity and mortality. The only effective proven weapons against COVID-19 are currently the vaccines and optimum prevention, in the form of personal protection, immune system strengthening with supplements, and personal isolation when tested positive. With this background, a thorough understanding of the viral mechanism of spread and underlying risk factors for critical disease is pivotal in order to limit COVID-19 detrimental consequences.

This Special Issue of the *Journal of Clinical Medicine* (JCM) entitled "Advances in Cardiology" offers four articles that contribute to the general physician and cardiologist's knowledge on the role of cardiovascular risk factors and angiotensin-converting enzyme-2 (ACE-2) in COVID-19 severity.

It is known that the presence of cardiovascular diseases (CVDs) is associated with worse clinical conditions and higher mortality in patients who contract COVID-19. Data analysis of 44,672 patients with COVID-19 found that a history of CVD provided a nearly fivefold increase in fatality rates when compared with patients without CVD (10.5 vs. 2.3%) [1]. Among approximately 9000 patients hospitalized for COVID-19 in North America, Europe, and Asia, 30.5% had hyperlipidemia, 26.3% had arterial hypertension, 14.3% had diabetes mellitus, 16.8% were former smokers, and 5.5% were current smokers. Additionally, 11.3% had coronary artery disease, and 2.1% had congestive heart failure [2]. A meta-analysis of 48,317 patients with COVID-19 confirmed that CVD and cardiovascular risk factors are closely associated with fatal outcomes, irrespective of age [3]. Other meta-analyses have also shown that the prevalence of arterial hypertension or cardiac disease was >15% and was associated with a higher need for critical care management. Hypertension has been shown to induce a pre-activation of the immune cells, with raised inflammatory cytokines, which led to a surging immune response in patients in contact with SARS-CoV2 and delayed viral clearance. Moreover, patients with diabetes mellitus and COVID-19 infection were at a higher risk of admission to the ICU and mortality due to hyperglycemia-associated vascular endothelial cell dysfunction [4]. Obesity has also been shown to have a key role in COVID-19 infection severity, because of its known associated inflammation that contributes to the weakening of the immune system by augmenting adipose tissue production of pro-inflammatory cytokines and downregulating anti-inflammatory immune cells.

Two of the studies published in this issue deal with a social category of people who are particularly at a high risk of exposure to SARS-CoV2 infection, i.e., clergy, because of the close inter-personal contact required during liturgies. Additionally, probably due to their special lifestyle, clergies are at significant risk because of the significantly high prevalence of

**Citation:** Henein, M.Y.; Cameli, M.; Pastore, M.C.; Mandoli, G.E. COVID-19 Severity and Cardiovascular Disease: An Inseparable Link. *J. Clin. Med.* **2022**, *11*, 479. https://doi.org/10.3390/ jcm11030479

Received: 10 January 2022 Accepted: 13 January 2022 Published: 18 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**<sup>\*</sup>** Correspondence: michael.henein@umu.se

CV risk factors they carry, including hypertension, diabetes, and obesity. The two published studies are part of our multicenter "COVID-CVD study", which sought to investigate the importance of the various CV risk factors among Coptic clergies from Europe, the USA, and Egypt, in increasing their vulnerability to catching COVID-19, with its clinical consequences. In a group exceeding 1,600 clergies, the prevalence of SARS-CoV2 infection was 16.2%. Additionally, a model combining CV risk factors (hypertension, i.e., systolic blood pressure (SBP) ≥160 mmHg, diabetes mellitus, obesity, and history of coronary heart disease) was the most powerful independent predictor of COVID-19-related mortality, OR 3.991 ((1.919 to 6.844); *p* = 0.002) and the need for mechanical ventilation (OR 1.501 ((0.809 to 6.108); *p* = 0.001) [5]. In the second analysis, we found that obesity was the highest prevalent CV risk factor among Coptic clergies (above all, among Egyptians) and was the most powerful independent predictor of major COVID-19-related adverse events in the form of death or mechanical ventilation (OR = 4.180; 2.479 to 12.15; *p* = 0.01) [6]. These findings highlight the need for special attention to be given to clergy as a social category example for optimum protection from COVID-19 complications, with a serious need for lifestyle optimization and immune system support. Additionally, a well-designed education program for clergies is highly recommended, in order to optimally adhere to SARS-CoV2 contagion preventive measures and optimum control of CV risk factors according to available guidelines.

The Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine for the Management of Patients with Vascular Disease or CV risk factors and COVID-19 suggested that lock-down policies for epidemic waves should target, in particular, patients with underlying CVD who should also undergo regular medical followup. They also recommended encouraging the use of telemedicine whenever possible, to improve adherence to antihypertensive, lipid-lowering, and hypoglycemic treatment according to current guidelines. It also recommends patients with underlying CVD and non-severe COVID-19 receive medical care at home, close follow-ups, and be prioritized for hospital admission when needed.

With respect to anti-hypertensive treatment, the role of ACE-inhibitors has been extensively sought during the pandemic, since the aminopeptidase angiotensin-converting enzyme 2 (ACE2) has been identified as a receptor for SARS-CoV2, due to its binding to the spike protein of the virus. The review by Triposkiadis et al. [7], included in this issue, elucidates the role of ACE2 in COVID-19 progression and severity, reassuring the scientific community on the safety of continuing the use of ACE inhibitors.

In fact, ACE2 is highly expressed in many organs such as cardiomyocytes, enterocytes, renal tubular cells, and sinonasal cavity cells, whereas in the lungs, the ACE2 expression is minimum. However, the expression of ACE2 depends on the immune responses; therefore, binding of ACE2 with SARS-CoV2 may amplify inflammatory signaling and ACE2 expression, as well as promote virus replication, its entrance into the host cell, and its spread throughout the organism with the contribution of inflammatory M1 macrophages, which, in turn, have marked upregulation of ACE2 on their surface. Therefore, each action promoting the expression of ACE2 instead of its inhibition may be harmful to COVID-19 progression in the organism after SARS-CoV2 infection. The authors of this article also illustrate, in detail, the peculiar impact of COVID-19 and the role of the renin–angiotensin– aldosterone system in specific populations, such as patients with cancer, renal failure, and chronic obstructive pulmonary disease. Mechanism and disease-specific risk factors are described, such as tumor stage, disease progression, and type of cancer (above all thoracic), which are high-risk factors for disease severity in cancer patients. Again, the role of CV risk factors is highlighted with obesity and diabetes mellitus, resulting in an imbalance in the renin–angiotensin–aldosterone system, with higher ACE2 expression, which leads to slower viral clearance. In the end, emerging therapies targeting transmembrane protease, serine 2 (TMPRSS2), and ACE2 co-factor involved in the SARS-CoV2 binding and internalization are introduced, which represent new therapeutic frontiers against COVID-19.

The fourth article addresses an important in-hospital issue, which is the outcome of STelevation myocardial infarction, hence impacting the national health services and national

health systems. Our hospital admission analysis showed a trend toward a reduction in acute coronary syndromes incidence, with a substantial increase in STEMI fatality rate and complications during the pandemic, compared with 2019 [8]. This was explained by the decrease in percutaneous coronary intervention (PCI) procedures [9], with an annual 634 PCI patients falling by 25.7% during the COVID-19 period (mean 30.0 ± 4.01 vs. 40.4 ± 5.3 case/month) and prolongation of the time from first medical contact to needle (125.0 ± 53.6 vs. 52.6 ± 22.8 min, *p* = 0.001). Such significant change in practice was interpreted on the basis of patients' fear of visiting the hospital, lack of organized emergency pathways for acute coronary syndromes during the COVID-19 period, and occasional misdiagnosis in patients with respiratory symptoms. The last finding was higher in-hospital mortality (7.4 vs. 4.6%, *p* = 0.036), incidence of reinfarction (12.2 vs. 7.7%, *p* = 0.041), and the need for revascularization (15.9 vs. 10.7%, *p* = 0.046) during the COVID-19 pandemic. In fact, a dramatic increase in hospitalization for subacute myocardial infarction >72 h has been described worldwide, with increasing incidence of malignant arrhythmias and severe heart failure resistant to conventional therapy and often requiring inotropic or mechanical support. Untreated myocardial infarction is known to increase left ventricular maladaptive remodeling and the long-term incidence of dilated cardiomyopathy and heart failure. This would unavoidably constitute a clinical challenge and result in a poor prognosis. Possible solutions rely on optimal organization of healthcare services during the pandemic, social education, and alternative methods of follow-up to balance between the prevention of COVID-19 and acute coronary syndromes, such as the aforementioned telemedicine.

Beyond coronary heart disease, since many cases were described as due to SARS-CoV2 infection or vaccine induced (the former with a 40-fold higher incidence than the latter), which may also be a potential confounder of an acute coronary syndrome—namely, acute myocarditis. In severe cases, these may cause life-threatening ventricular arrhythmias; therefore, arrhythmia monitoring may be crucial for these patients. Peretto G. et al. [10] conducted a study in 104 adult patients with biopsy-proven active myocarditis and de novo ventricular arrhythmias, who underwent prospective monitoring by both sequential 24 h Holter ECGs and continuous arrhythmia monitoring (CAM), including either implantable cardioverter defibrillator (ICD) (60%) or loop recorder (40%). The authors found that nearly half of the patients developed ventricular arrhythmias over long-term follow-up, CAM was more accurate in the identification of patients with ventricular arrhythmias, and histological signs of chronically active myocarditis (70%) and anteroseptal late gadolinium enhancement (25%) were significantly associated with the occurrence of ventricular tachycardia. These important findings may help the decision-making processes in patients presenting with acute myocarditis.

Another consequence of myocarditis is the development of dilated cardiomyopathy (DCM), a complex disease for its variable etiology, complications, and management, irrespective of the etiology of DCM, primary, congenital/hereditary, or secondary, often a consequent to ischemic heart disease, myocarditis, infective or peripartum cardiomyopathy. Primary or secondary DCM may be complicated by valvular heart disease, chronic heart failure, arrhythmias, leading to sudden cardiac death; however, there are some primary forms that are particularly prone to develop arrhythmias, often presenting with sudden cardiac death, such as those deriving from LMNA gene (encoding for laminin A/C) mutation. The article by Ferradini et al. included in this issue [11] describes, among 77 families with DCM referred for genetic counseling and molecular screening, how they found 18 patients with heterozygotes mutation for laminin A/C with 2 new variants of the gene. Interestingly, 44.5% of patients presented with ventricular arrhythmias as the first symptom. These results highlight the importance of genetic analysis when laminin A/C mutation may be suspected in order to provide a good risk stratification of sudden cardiac death. In fact, there is currently a lack of targeted therapy for the treatment of LMNA variants-associated cardiomyopathy and the only therapy to consider is the prevention with ICD, also in these cases, because of the high risk of SCD in these patients.

It should be highlighted that ICD implantation is not free of risks. It carries a risk of pocket infection and leads to endocarditis with possible systemic infection, pneumothorax, or bleeding. It may also require new intervention either years after the first implantation, for example, to replace the battery, or earlier in the case of lead dislodging or for infections/malfunctions. While battery replacement without lead extraction is an almost simple procedure with only a few potential complications, transvenous lead extraction (TVE) is a challenging procedure that carries a high risk of life-threatening complications, such as superior vena cava tear, pericardial effusion, tamponade, and embolization. Therefore, a reconsideration of ICD indications is often operated when TVE should be performed, as recommended by the guidelines [12]. In this issue, D'Angelo et al. reported a study on 223 patients undergoing TVE, in 14.8% of whom no reimplantation was performed. At a median follow-up of 41 months, 11.8% received a new ICD after 17–84 months due to arrhythmic events. While hospitalization for device revision (in the reimplantation group) or late reimplantation (in the no-reimplantation group) was similar (11.1% vs. 12.1%, *p* = 0.771), as was short-term survival, five-year survival was significantly lower in the no-reimplantation group (78.3% vs. 94.7%, *p* = 0.014), and death occurred mostly for non-cardiac causes [13]. The absence of atrioventricular blocks in the primary indication and higher left-ventricular ejection fraction represented independent predictors favoring no-reimplantation. Therefore, these two elements may help therapeutic decisions, as these results recommend careful consideration of ICD reimplantation when TVE should be performed.

Finally, the eighth article in this Special Issue of Advances in Cardiology concerns a new but still important and timely topic, since the traditionally known non-alcoholic fatty liver disease, currently called metabolic-dysfunction fatty live disease (MAFLD), remains a challenging hepatic syndrome. Although its association with CV risk factors is well known, the mechanisms of its direct/indirect link with the CV system are still to be ascertained. In their article, Ismaiel et al. [14] investigated the association between adipokines, peptides product of the adipose tissue, and CV ultrasound parameters in 80 patients with hepatic steatosis evaluate by both hepatic ultrasonography and SteatoTestTM (40 patients with MAFLD diagnosis, 40 controls), who all underwent echocardiography and carotid Doppler ultrasound and adipokines analysis. The authors found that adiponectin and visfatin levels were not significantly different in MAFLD vs. controls. Visfatin was associated with mean carotid intima-media thickness, while adiponectin was associated with left ventricular ejection fraction and early/late diastolic waves (E/A) ratio in controls. A significant direct proportional association was found between adiponectin and E/A ratio in the univariate linear regression analysis but was lost in multivariate models. Conversely, although left ventricular ejection fraction was not significantly associated with adiponectin in univariate analysis, a significant inversely proportional association was demonstrated after adjustment using multivariate regression models, according to similar previous studies. These results may generate interesting hypotheses on the relationship between MAFLD and the CV system, but this needs to be further tested.

In conclusion, the articles in this issue are expected to assist the readers confronted by COVID-19 patients and guide them to pay particular attention to CV risk factors and lifestyle. They also highlight the relationship between the COVID-19 pandemic and other cardiac syndromes, as well as its potential cardiovascular clinical consequences and their predictors, which, in some cases, could be avoided.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Article* **The Impact of COVID-19 on In-Hospital Outcomes of ST-Segment Elevation Myocardial Infarction Patients**

**Sherif Ayad 1,\*, Rafik Shenouda <sup>2</sup> and Michael Henein <sup>3</sup>**


**Abstract:** Primary percutaneous coronary intervention (PPCI) is one of the important clinical procedures that have been affected by the COVID-19 pandemic. In this study, we aimed to assess the incidence and impact of COVID-19 on in-hospital clinical outcome of ST elevation myocardial infarction (STEMI) patients managed with PPCI. This observational retrospective study was conducted on consecutive STEMI patients who presented to the International Cardiac Center (ICC) hospital, Alexandria, Egypt between 1 February and 31 October 2020. A group of STEMI patients presented during the same period in 2019 was also assessed (control group) and data was used for comparison. The inclusion criteria were established diagnosis of STEMI requiring PPCI.A total of 634 patients were included in the study. During the COVID-19 period, the number of PPCI procedures was reduced by 25.7% compared with previous year (mean 30.0 ± 4.01 vs. 40.4 ± 5.3 case/month) and the time from first medical contact to Needle (FMC-to-N) was longer (125.0 ± 53.6 vs. 52.6 ± 22.8 min, *p* = 0.001). Also, during COVID-19, the in-hospital mortality was higher (7.4 vs. 4.6%, *p* = 0.036) as was the incidence of re-infarction (12.2 vs. 7.7%, *p* = 0.041) and the need for revascularization (15.9 vs. 10.7%, *p* = 0.046). The incidence of heart failure, stroke, and bleeding was not different between groups, but hospital stay was longer during COVID-19 (6.85 ± 4.22 vs. 3.5 ± 2.3 day, *p* = 0.0025). Conclusion: At the ICC, COVID-19 pandemic contributed significantly to the PPCI management of STEMI patients with decreased number and delayed procedures. COVID-19 was also associated with higher in-hospital mortality, rate of re-infarction, need for revascularization, and longer hospital stay.

**Keywords:** ST segment elevation myocardial infarction; COVID-19; primary percutaneous intervention

#### **1. Introduction**

Currently, primary percutaneous coronary intervention (PPCI) is the best management strategy for patients presenting with ST-segment elevation myocardial infarction (STEMI) according to the latest guidelines [1]. Studies have shown that time delay in PPCI has negative impact on the clinical outcomes of STEMI patients [2,3].

COVID-19 affected many aspects of human life since its start in early 2020, one of which is prioritizing clinical management of various medical conditions including coronary artery disease, particularly acute coronary syndrome and urgent interventions required for STEMI, a potential life-threatening condition. The WHO classifiesCOVID-19 cases into four categories based on clinical history, presentation, and laboratory findings: confirmed (COVID-19 +), suspected (COVID-19 +/−), contact (COVID-19 C), or non-suspected (COVID-19 NS) [4].

COVID-19 has significantly impacted conventional management of STEMI patients, resulting in practice variabilities between countries. Some countries have changed their reperfusion strategy to fibrinolytic therapy [5–7], others still follow the guidelines in performing PPCI to all STEMI patients [8–11]. The delay in seeking medical advice during

**Citation:** Ayad, S.; Shenouda, R.; Henein, M. The Impact of COVID-19 on In-Hospital Outcomes of ST-Segment Elevation Myocardial Infarction Patients. *J. Clin. Med.* **2021**, *10*, 278. https://doi.org/10.3390/ jcm10020278

Received: 1 December 2020 Accepted: 11 January 2021 Published: 14 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the lockdown periods, the time needed for screening for COVID-19 infection, and the fear of healthcare providers regarding cross-infection are the main causes behind the change of practice of managing STEMI patients and the fall in PPCI procedures according to some reports [12–15].

In this study, we aimed to assess the impact of COVID-19 on in-hospital clinical outcome of STEMI patients managed with PPCI.

#### **2. Experimental Section**

#### *2.1. Study Design*

This is a retrospective observational study conducted on consecutive STEMI patients who presented to the International Cardiac Center (ICC) hospital, Alexandria, Egypt between 1 February and 31 October 2020. The inclusion criteria were established diagnosis STEMI (ST segment elevation more than 1 mm in two consecutive leads or new left bundle branch block associated with typical chest pain with or without elevated cardiac markers) fulfilling guidelines recommendation for PPCI treatment [1,16]. The exclusion criteria were previous CABG, cardiogenic shock, previous PCI of the same culprit vessel and severe left main (LM) coronary artery disease. Data from a group of STEMI patients who presented to ICC during the same period of 2019 was used for comparison, as control. Twenty patients in group A and 5 patients in group B were excluded. The study population included 634 patients who were classified into two groups:

Group A: Included 364 STEMI patients treated with PPCI before COVID-19 (year 2019). Group B: Included 270STEMI patients treated with PPCI during COVID-19 (year 2020).

#### *2.2. Data Collection*

All patients' demographic data were collected including age, gender, comorbidities (hypertension, diabetes, dyslipidemia), obtained PPCI procedure details including time from symptom onset to first medical contact (FMC), and time from first medical contact to needle (FMC-to-N). From coronary angiograms the following information were collected; the culprit artery, number of diseased vessels, the use of antithrombotic treatment (acetyl salicylic acid, clopidogrel, ticagrelor, heparin, enoxaparin, and glycoprotein IIb/IIIa inhibitors), balloon pre-dilatation, stent details (number, length, and diameter), Thrombolysis In Myocardial Infarction (TIMI) score, flow at the end of the procedure, and duration of hospital stays. Also, any subsequent procedure related complications—e.g., heart failure, stroke, or bleeding—were documented.

#### *2.3. Endpoint Measurements*

The primary clinical outcomes were the percentage of PPCI procedures performed before and during the COVID-19 and the median time of first medical contact to needle (FMC-to-N), while the secondary outcomes were in-hospital mortality, major adverse cardiac and cerebrovascular events (MACCE) during hospital stay and the duration of hospitalization. MACCE was defined as death, re-infarction, need for revascularization, heart failure, stroke, and bleeding.

#### *2.4. Statistical Analysis*

Statistical Package for Social Sciences (SPSS version 20.0. IBM Corp, Armonk, NY, USA) was used for data analysis [17]. We described qualitative data using numbers and percentage. For quantitative data we used range (minimum and maximum), mean, standard deviation, and median. Chi-square test was used to compare categorical variables between different groups. Fisher's exact probability or Monte Carlo correction for Chisquare were used when more than 20% of the cells have expected count less than 5. Mann-Whitney test was used to compare groups for abnormally distributed quantitative variables. A *p*-value of <0.05 was considered significant for all tests.

An informed consent was obtained from every patient or the legal guardians. The study was approved by the local ethics committee (approval number 0304893).

#### **3. Results**

#### *3.1. Patients Characteristics and Number of Procedures*

During the COVID-19 period, the number of PPCI procedures was reduced by 25.7% compared with previous year (30.0 ± 4.01 vs. 40.4 ± 5.3 case/month). Both patient groups (A and B) were well matched with respect to demographic data and clinical characteristics with no significant difference between them. Only eight patients in group A and five patients in group B were more than 65–70 years of age. The baseline characteristics of both groups are presented in Table 1.

**Table 1.** Baseline characteristics, laboratory findings, procedural characteristics of the studied populations.


*p* value for comparing between the two studied groups. \*: Statistically significant at *p* ≤ 0.05.

#### *3.2. Laboratory Findings*

The incidence of lymphopenia was significantly higher in group B than in group A (14.78 ± 5.85 vs. 18.6 ± 6.21, *p* = 0.012), serum ferritin and D-dimer levels were also higher in group B than in group A. Cardiac enzymes, haemoglobin and serum creatinine did not differ between groups. The laboratory findings of both groups are shown in Table 1.

#### *3.3. Time FMC-To-N*

Patients in group B had significantly longer FMC-to-N compared to patients in group A (125.0 ± 53.6 vs. 52.6 ± 22.8, *p* = 0.001). The FMC-to-N of both groups is presented in Table 1.

#### *3.4. Procedural Characteristics of the Two Groups*

With regard to the angiographic data, the incidence of multivessel disease was not different between the two groups, as was the culprit artery. Also, the antiplatelet treatment with clopidogrel or ticagrelor did not differ. None of the patients in the two groups received fibrinolytic therapy. All patients in the two groups received drug eluting stents (DES) and no patient had procedure related dissection or perforation. The final TIMI flow at the end of the procedure was similar among patients of both groups. All patients received in-hospital medical treatment and follow up according to the latest STEMI guidelines [1,16]. Data of the procedural characteristics of the studied population are summarized in Table 1.

#### *3.5. In-Hospital Outcomes*

In hospital mortality was higher in group B (7.4 vs. 4.6%, *p* = 0.036) as was the incidence of re-infarction (12.2 vs. 7.7%) compared to group A, the difference between the two was significant (*p* = 0.041). Twenty patients in group B died, mostly because of arrhythmia (ventricular fibrillation) and the rest developed intractable cardiogenic shock and pulmonary edema. The need for revascularization was also higher in Group B (15.9 vs. 10.7%, *p* = 0.046) but the incidence of heart failure or bleeding was not different between groups. Although there was statistically high stroke prevalence in group A, we are unable to ascertain an exact explanation for it. One possible practice-based explanation for this finding is that in 2019 we used more thrombus aspiration catheters during PPCI than in 2020.The data of procedural outcomes are summarized in Table 2.

**Table 2.** In hospital outcomes of the studied population.


*p* value for comparing between the two studied groups. \*: Statistically significant at *p* ≤ 0.05.

#### *3.6. Duration of Hospitalization*

The duration of hospital stay was significantly longer in group B compared with group A (6.85 ± 4.22 vs. 3.5 ± 2.3 day, *p* = 0.0025).

#### **4. Discussion**

Findings: COVID-19 pandemic has adversely affected various aspects of health care services including patients with heart disease and acute coronary syndrome [4]. The objective of this study was to evaluate the impact of COVID-19 on STEMI patients requiring conventional PPCI treatment and their clinical outcomes. Our results show that all studied STEMI patients were treated with PPCI without need for fibrinolytic therapy, even for highly suspected COVID-19 patients. However, the frequency of PPCI treatment was significantly reduced and the intervention was delayed when compared with 2019 controls. Also, the hospital stay was prolonged and associated with some complications including re-infarction, need for coronary artery bypass surgery, CVS and increased in-hospital mortality. Despite that, the prevalence of developed heart failure and bleeding was not different from controls, treated by similar strategy a year before COVID-19.

Comparative results: Our findings can be summarized in showing significant change in STEMI practice during COVID-19 with delayed acute presentation and its management. The delay in presentation was mainly due to patients' fear of catching the viral infection at the hospital. This finding in ICC is compatible with other countries. HunShing Kwok et al. reported a dramatic reduction in PPCI procedures in the UK during the lockdown period [18], Dingcheng Xiang et al. reported 62% less PPCI in China [19], and 73 centers reported 40% reduction in PPCI in Spain [20].The delayed PPCI was merely due to the screening tests performed before procedure, particularly in highly suspected patients who occasionally required other necessary investigations first, e.g., chest computed tomography (CT) scans. The increased in-hospital mortality with COVID-19 is similar to that reported by Dingcheng Xiang et al. [19] but contradicted Hun Shing Kwok et al. reports [18]. Other important findings in our study were the increased rate of re-infarction, the need for revascularization and the doubled hospital stay period, during the pandemic despite similar incidence of heart failure, stroke and bleeding. These findings were similar to that reported by Dingcheng Xiang et al. [19] but contradicted Hun Shing Kwok et al. results [18] which reported significant reduction ofin-hospital stay period.

It seems therefore that the internationally agreed impact of COVID-19 on conventional interventional management of STEMI is mainly during the acute phase of the disease with delayed presentation, reduced number of cases, and delayed procedure. While the former is mainly patient related, the latter is hospital controlled which is based on the nature of presentation of individual patients. In this scenario, it cannot be ignored that the rest of the clinical outcome is determined by the extent of co-morbidities, and severity of COVID-19 infection which vary between individual patients.

Limitations: This study has some obvious limitations. The recruited patients were those referred to the ICC hospital with STEMI diagnosis, mostly by individual cardiologists or other local hospitals, thus do not reflect a population. The follow-up duration was short and concerned only in-hospital stay, based on the study nature and design. Although patients were referred from different sources, they were all managed in one center from which the results were generated.

#### **5. Conclusions**

Our study shows that COVID-19 was associated with a significant decrease in the number of STEMI patients treated by PPCI at the ICC- Egypt, delayed procedure, higher in-hospital mortality, higher rates of re-infarction, need for repeat revascularization, and longer duration of hospital stay but with similar rates of heart failure, stroke, and bleeding.

**Author Contributions:** Conceptualization, S.A., R.S., and M.H.; Methodology, S.A., M.H., and R.S.; Software, R.S.; Validation, S.A.; Formal analysis, S.A., R.S., and M.H.; Investigation, S.A., M.H., and R.S.; Writing—original draft preparation, S.A.; Writing—review and editing, S.A., M.H., and R.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Faculty of Medicine, Alexandria University Ethics Committee. (Approval number 0304893-Approval date 19/11/20).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** Data available in a publicly accessible repository.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

CABG: coronary artery bypass grafting; LCX: left circumflex artery; STEMI: ST segment elevation myocardial infarction; PPCI: primary percutaneous coronary intervention; TIMI: Thrombolysis In Myocardial Infarction; MACCE: Major Adverse Cardiac and Cerebrovascular Events; CVS: cerebrovascular stroke; RCA: right coronary artery; LAD: left anterior descending artery; LM: left main; MVD: multi-vessel disease; SVD: single vessel disease; TVR: target vessel revascularization; FMC-to-N: first medical contact to needle time;COVID-19: corona virus disease-2019; WHO: world health organization; DES: drug eluting stents; ICC: International Cardiac Center; CK-MB: creatinine kinase— MB isoenzyme.

#### **References**

