Cardiovascular Manifestations and Outcomes in Patients Admitted with Severe COVID-19: Middle Eastern Country Multicenter Data.

OBJECTIVES: Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) -that can affect the cardiovascular system. The aim of our study was to assess the cardiovascular manifestations and its effect on the overall mortality among patients with severe COVID-19 who were admitted in the intensive care units (ICU).
METHODS: This is a retrospective, multicenter cohort study that included all adult patients admitted to the ICU with laboratory-confirmed COVID-19 in three major hospitals in Oman between March 1, 2020, and August 10, 2020.
RESULTS: A total of 541 patients (mean age of 50.57 ± 15.57 years; 401 [74.1%] male) were included in the study of which 452 (83.5%) were discharged and 89 (16.5%) died during hospitalization.Evidence of cardiac involvement was found in 185 (34.2%) patients, which included raised troponin (31.6%), arrhythmias (4.3%), myocardial infarctions (2.6%), or drop in ejection fraction (0.9%). High troponin of >100 ng/l was associated with higher mortality (odds ratio [OR] = 7.98; 95% confidence interval [CI]: 4.20-15.15); P < 0.001). Patients with any cardiovascular involvement also had a high risk of dying (OR = 8.8; 95% CI: 4.6-16.5; P < 0.001).
CONCLUSION: Almost a third of patients in our study had evidence of cardiovascular involvement which was mainly myocardial injury. This was associated with increased mortality. Copyright:

INTRODUCTION

The first local outbreak of Coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) was reported in Wuhan, China, on December 2019.[1] Since then, it has spread rapidly to almost all countries of the world and was declared a global pandemic on March 2020.[2] It has overwhelmed the health-care systems and significantly impacted the economies of many countries around the world. The first reported case of COVID-19 from the middle east region was from the United Arab Emirates.[3]

In the following weeks, a major outbreak was reported in neighboring Iran, which has since then, reported the highest number of confirmed cases with the highest mortality in the region.[4] Oman reported its first COVID-19 cases on February 24, 2020 in two citizens who returned from Iran. As in other countries in the region, after a slow increase, Oman saw the numbers dramatically increase towards the beginning of summer. At the time of writing, Oman had reported around 115,000 COVID-19 cases with more than 1200 deaths.[5]

The SARS-CoV-2 is a member of the βcoronavirus family and is related to the other two coronaviruses that have caused pandemics in the recent past namely the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). As with SARS-CoV and MERS-CoV, SARS-CoV-2 also predominantly causes a respiratory infection, which leads to viral pneumonia and acute respiratory distress syndrome (ARDS).[1] However, in addition to respiratory symptoms, uncontrolled SARS-CoV-2 infection can trigger a cytokine storm with overproduction of pro-inflammatory cytokines and chemokines, leading to multiorgan damage.[6] In addition, a substantial proportion of patients develop coagulation abnormalities resulting in thromboembolic events.[7]

Distinct from the other coronaviruses, SARS-CoV-2 has a propensity for the cardiovascular system.[8] This is due to the fact that the virus uses the spike protein on its envelope to attach to the angiotensin converting enzyme (ACE) receptor, which is found in large numbers in many organs including the lung, bronchi, endothelium, and the heart.[9] As the virus directly affects the heart and the endothelium, it can lead to myocarditis, plaque rupture, and even thrombotic occlusion of the coronaries due to its procoagulant action.[10] In addition, preexisting cardiovascular disease and risk factors such as hypertension are associated with increased mortality.[11]

Our study aimed to assess the impact of COVID-19 on the cardiovascular system and to assess the outcomes and mortality based on the involvement of the cardiovascular system among the patients admitted to the intensive care unit (ICU) in Oman.

METHODS

Study population

This is a retrospective, multi-center cohort study of all adult COVID-19 patients admitted to the ICU at three centers (Sultan Qaboos University Hospital, Royal Hospital, and Al Nahdha Hospital) in Muscat, Oman, between March 1, 2020, and August 10, 2020.

All patients aged 18 and older with laboratory confirmed SARS-CoV-2 infection using real-time reverse transcription–polymerase chain reaction (PCR) assay of nasopharyngeal swab who required inpatient admission in the ICU were included in the study. We did not include hospitalized patients who did not require ICU care during their in-hospital stay. Similarly, patients who were diagnosed to have COVID-19 and did not require hospitalization were also not included in the study.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained by the medial ethics committees at each participating center, which are the Sultan Qaboos University Hospital medical ethics committee and the Ministry of Health medical ethics committee Oman, prior to commencement of the study.

Patient and public involvement

This was a retrospective study and hence consent was not required. There was no direct involvement of the public or patients either in the planning or execution of the study. However, the ethics committees of the institutions from where approval was sought, has members of the lay public as members. The plan is to disseminate the results of this study to the members of the public to be aware of potential cardiac involvement in those who develop COVID-19.

Data collection

The data were extracted retrospectively from electronic health record systems at the participating centers. This included demographics, comorbidities, clinical characteristics, laboratory findings, complications, therapeutic measures, and outcome data.

Cardiac manifestations of COVID-19 including elevated cardiac biomarkers, acute myocardial injury, myocardial infarction, myocarditis, arrhythmias, congestive heart failure, and cardiogenic shock were recorded. All data were transferred to a prespecified electronic data sheet by two dedicated data collectors and cross-checked.

For the study, the following definitions were used. All confirmed cases were diagnosed using the SARS-CoV-2 PCR assay. “Severe COVID-19 pneumonia” was defined as per the National protocol from the Ministry of Health, Oman for management of hospitalized adult COVID-19 patients.[12] It was defined as patients fulfilling the following criteria: (i) oxygen saturation <93% on room air, (ii) respiratory rate >30 per minute, (iii) ratio of the partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mmHg or lung infiltrates involving >50% of lung parenchyma, and (iv) all patients who require supplemental oxygen (requiring more than 5l oxygen to maintain an oxygen saturation of more than 93%), mechanical ventilation or extracorporeal mechanical ventilation.

Acute respiratory distress syndrome (ARDS) was defined as per Berlin Definition,[13] which includes all the following criteria: (i) respiratory symptoms for 1 week, or worsening of these symptoms during the past week, (ii) bilateral opacities must be present on a chest radiograph or computed tomographic scan, (iii) the patient's respiratory failure must not be fully explained by either heart failure or fluid overload, and (iv) a moderate to severe impairment of oxygenation must be present as defined by the PaO2/FiO2 ratio of <300 mmHg.

Acute myocardial injury and myocardial infarction were defined according to the Fourth Universal Definition of Myocardial Infarction.[14] Congestive heart failure was defined according to the European Society of Cardiology criteria.[15] The presence of hypertension, diabetes, or hyperlipemia was identified through either documentation in the medical records or if they were already on treatment for the same. Cardiac involvement was defined as either a raised troponin value above the 99th percentile or evidence of myocardial infarction, evidence of decreased left ventricular ejection fraction by 20% and new cardiac arrhythmias.

Statistical analysis

All the data were analyzed using Statistical Package for the Social Sciences version 25 software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Baseline demographic data and clinical characteristics were described as numbers (n) and percentages (%) for categorical variables, or means and standard deviations for continuous variables with normal distribution, and as medians and interquartile range for skewed data. The t-test was used to compare continuous variables and Chi-squared test was used to compare categorical variables.

Univariable and multivariable logistic regression analysis methods were applied to evaluate the relationship between in-hospital mortality and both history of coronary artery disease and/or current troponin rise. A P < 0.05 was considered statistically significant.

RESULTS

A total of 541 patients (mean age of 50.57 ± 15.57 years; 401 [74.1%] male) were included in the study. A little over half (293 or 54.2%) of the patients were Omani citizens and the rest were non-Omani nationals, including non-Omani Arabs (112 or 20.7%) and non-Arabs (133 or 24.6%).

The main symptoms on admission to hospital were fever (77.1%), breathlessness (72.8%), cough (68%), and gastro-intestinal symptoms (diarrhoea or vomiting) (58%). The other complaints on presentation included, chest pain (15.9%), and loss of smell/taste (5.2%). Diabetes (43.0%) and hypertension (38.3%) were the most common co-existing illness. Around a fifth of patients (22.2%) had a history of coronary artery disease including stable angina, unstable angina, previous myocardial infarction or a history of coronary intervention (either percutaneous coronary intervention), or coronary artery bypass grafting [Table 1].

Table 1

Clinical characteristics of the study patients

Characteristics	All patients (n=541), n (%)	Cardiovascular involvement		P
		No (n=356), n (%)	Yes (n=185), n (%)
Age (years)	50.57±15.57	46.1±14	59.4±13.9	<0.001
Sex, n (%)
Female	140 (25.9)	91 (25.5)	49 (26.4)	0.85
Male	401 (74.1)	265 (74.5)	136 (73.6)
Nationality
Omani	294 (54.3)	186 (52.2)	108 (58.3)	<0.001
Non-Omani Arabs	113 (20.8)	61 (17.1)	52 (28.1)
Non-Arabs	134 (24.9)	109 (30.7)	25 (13.6)
Diabetes	233 (43.0)	114 (32)	119 (64.3)	<0.001
Dyslipidemia	83 (15.3)	39 (10.9)	44 (23.7)	<0.001
Hypertension	207 (38.3)	98 (27.5)	108 (58.3)	<0.001
Renal disorder	59 (10.9)	16 (4.4)	42 (22.7)	<0.001
Cerebrovascular disease	17 (3.1)	7 (1.9)	10 (5.4)	0.03
Respiratory disease	30 (5.5)	18 (5)	12 (6.4)	0.5
Cardiovascular history*	95 (17.5)	43 (12)	52 (28.1)	0.01
Presenting symptoms
Fever	417 (77.1)	288 (80)	127 (68.6)	0.004
Cough	373 (68.9)	261 (73.3)	111 (60)	0.001
Breathlessness	394 (72.8)	254 (71.3)	138 (74.5)	0.68
Chest pain	86 (15.0)	60 (16.8)	26 (7.3)	0.19
Loss of smell/taste	28 (5.0)	22 (6.1)	6 (3.2)	0.06
Others	314 (58.0)	224 (62.9)	89 (48.1)	<0.001

Values are mean±SD or n (%). Analysis by student’s t-test or Chi-square test as appropriate. *History of previous myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, or valve disease or valve surgery. SD: Standard deviation

One hundred and eighty-five (34.2%) patients had evidence of cardiac involvement [Tables 1 and 2]. This was mainly a rise in the level of serum troponin above the 99th percentile (31.6%), myocardial infarction (2.6%), drop in ejection fraction on echocardiogram (0.9%), arrhythmias such as new onset ventricular fibrillation or tachycardia (4.3%) and atrial fibrillation (0.6%) and myocarditis (0.6%). Patients with co-existing illnesses such as diabetes (64% vs. 32%, P < 0.001), hypertension (58.3% vs. 27.5%, P < 0.001), past history of ischemic heart disease (28.1% vs. 12%, P = 0.01), and renal failure (22.7% vs. 4.4%, P < 0.001) were more likely to have evidence of cardiovascular involvement. Patients with any cardiac involvement were at a higher risk of death, with cardiac involvement present in 77 of the 89 patients who died (86%).

Table 2

Cardiac involvement in the study patients

Variables	All patients (n=541), n (%)	In hospital death		P
		Yes (n=89), n (%)	No (n=452), n (%)
No cardiac involvement	356 (65.8)	12 (13.5)	344 (76.1)	<0.001
Cardiac involvement	185 (34.2)	77 (86.5)	108 (23.9)
Cardiogenic shock	9 (1.7)	7 (7.9)	2 (0.4)	<0.001
Myocardial infarction	14 (2.6)	6 (6.7)	8 (1.7)	0.016
Arrhythmia (VT/VF)	23 (4.3)	17 (19.1)	6 (1.3)	<0.001
Myocarditis	3 (0.6)	1 (1.1)	2 (0.4)	0.417
Drop in EF by >20%	5 (0.9)	3 (3.3)	2 (0.4)	0.328
Raised troponin (>14 ng/l)	171 (31.6)	68 (76.4)	103 (22.8)	<0.001
New atrial fibrillation	3 (0.6)	3 (3.4)	0	0.01
Normal troponin	370 (68.4)	21 (23.6)	348 (77.0)	<0.001*

*Compared to those with raised troponin. Values are n (%). Analysis by Chi-square test. EF: Ejection fraction, VF: Ventricular fibrillation, VT: Ventricular tachycardia

Table 3 shows the laboratory findings of these patients. Those with cardiac involvement were more likely to have raised white cell count (69.7% vs. 32%, P < 0.001), higher d-dimer (78.3% vs. 54.2%, P < 0.001), and LDH (85.9% vs. 70.7% P = 0.01) values as compared to those without cardiac involvement. Patients with cardiac involvement also were more likely to have septic shock (20% vs. 0.8%, P < 0.001), ARDS (63.7% vs. 14.2%, P < 0.001), evidence of multiorgan failure (22.1% vs. 1.1%), and coagulopathy (17.8% vs. 1.9%, P < 0.001) [Table 4].

Table 3

Laboratory findings of the patients

Variables	All patients (n=541), n (%)	Cardiovascular involvement		P
		No (n=356), n (%)	Yes (n=185), n (%)
WBC >10×109 g/l	243 (44.9)	114 (32)	129 (69.7)	<0.001
CRP >10 mg/l	499 (92.2)	321 (90.1)	178 (96.2)	0.5
ALT >49 IU/L	279 (51.6)	173 (48.5)	106 (57.2)	0.1
AST >35 IU/L	176 (32.5)	95 (26.6)	91 (49.1)	0.3
LDH >246 IU/L	411 (76.0)	252 (70.7)	159 (85.9)	0.01
Creatine kinase >171 IU/L	59 (10.9)	35/69 (50.7)	24/51 (47)	0.44
Cross linked D-dimer >0.5 mg/l	339 (62.7)	193 (54.2)	145 (78.3)	<0.001
Interleukin 6 >7 pg/ml	121 (22.6)	79/84 (94)	42/45 (93.3)	0.8
Ferritin >708 ug/l	279 (51.5)	205/243 (84.3)	74/87 (85)	0.8
Lactic acid	188 (34.7)	92/232 (39.6)	96/165 (58.1)	0.01

Values are n (%). Analysis by Chi-square test. ALT: Alanine transaminase, AST: Aspartate transaminase, CRP: C-reactive protein, LDH: Lactate dehydrogenase, WBC: White blood cell count

Table 4

Clinical course of the patients

Variables	All patients (n=541), n (%)	Cardiovascular involvement		P
		No (n=356), n (%)	Yes (n=185), n (%)
Noncardiac complications
Septic shock	40 (7.4)	3 (0.8)	37 (20)	<0.001
ARDS	193 (35.7)	77 (14.2)	114 (63.7)	<0.001
Pneumonia	512 (94.6)	332 (61.3)	178 (96.2)	0.3
PE/DVT	12 (2.2)	5 (1.4)	7 (3.7)	0.07
Acute kidney injury	123 (22.7)	34 (9.5)	88 (47.5)	<0.001
Ventilation*	158 (29.2)	40 (11.2)	118 (63.7)	<0.001
Dialysis	46 (8.5)	7 (1.9)	39 (21)	<0.001
Coagulopathy	40 (7.3)	7 (1.9)	33 (17.8)	<0.001
Multi-organ failure	45 (8.3)	4 (1.1)	41 (22.1)	<0.001
Death	89 (16.4)	12 (3.3)	77 (41.6)	<0.001

Values are n (%), analysis by Chi-square test. *Both invasive or noninvasive ventilation. ARDS: Acute respiratory distress syndrome, DVT: Deep vein thrombosis, PE: Pulmonary embolism

These patients also were more likely to undergo dialysis (21% vs. 1.9%, P < 0.001) and be subject to ventilation (either invasive or noninvasive) (63.7% vs. 11.2%, P < 0.001). The mortality of those with cardiovascular involvement was 41.6% as compared to 3.3% for those with no evidence of cardiovascular involvement (P < 0.001).

By multivariate analysis, the predictors of increased mortality included a history of coronary artery disease (odds ratio [OR] = 1.83, 95% confidence interval [CI]: 1.04–3.22; P = 0.046), raised troponin of >100 ng/L (OR = 7.98; 95% CI: 4.20–15.15; P < 0.001), any cardiac involvement (OR = 8.8; 95% CI: 4.6–16.5; P < 0.001), or cardiogenic shock or cardiac arrhythmia (VT or VF) (OR = 35.33; 95% CI: 18.75–66.58).

DISCUSSION

Cardiac involvement has previously been demonstrated to be present in around 7% to 40% of patients diagnosed with COVID-19 and has been shown to be associated with a poorer prognosis.[8101617].

The involvement can range from limited myocardial necrosis, myocardial injury, myocarditis to cardiomyopathy, and myocardial infarction. Myocardial injury as reflected by raised levels of serum cardiac troponin is usually the most common manifestation and occurs in patients with or without pre-existing cardiac conditions.[18] Raised troponin levels on their own (myocardial injury) has been shown to be associated with raised levels of markers of inflammation and increased cardiovascular risk.[19]

With widespread myocardial inflammation, global myocarditis can occur and is also associated with a worse prognosis than limited myocardial injury. Here, the widespread inflammation can lead to pump failure resulting in cardiogenic shock and its associated complications and conduction abnormalities and arrhythmias.

Our data confirms what has been reported before, with around 34.2% of patients demonstrating cardiac involvement and this was associated with a seven-fold increased risk of mortality [Table 5]. As in other studies[1117182021] in our cohort as well, raised troponin (myocardial injury) on its own was the predominant manifestation of cardiovascular involvement. These patients with raised troponin had no significant electrocardiogram (ECG) or echocardiogram findings suggesting injury without infarction.

Table 5

Factors predicting death

Variable	OR	95% CI	P
History of CAD	1.83	1.04-3.22	0.046
Troponin >100 ng/l	7.98	4.20-15.15	<0.001
Cardiac involvement	8.8	4.6-16.5	<0.001
Cardiogenic shock or arrhythmias	35.33	18.75-66.58	<0.001

Many mechanisms have been proposed to explain the pathogenesis of myocardial injury in patients affected by COVID-19. The various mechanisms that have been put forward include cytokine/inflammation mediated damage, oxygen supply-demand mismatch, ischemic injury from microvascular, thrombi formation, and direct viral invasion of the myocardium. Additionally, there is a high risk of rupture of atherosclerotic plaque due to the stress of the infection leading to an acute coronary syndrome.[22]

In our study, we also found that patients with cardiovascular involvement had a higher incidence of septic shock, ARDS, pneumonia, coagulopathy, and multiorgan failure. These patients were also more likely to require dialysis and ventilation. This also suggests that the myocardial injury is most likely part of a generalized systemic process rather than direct cardiac involvement with the virus. The mortality rate was also exceedingly high in these patients reflecting the overall severity of the disease.

Indeed, in a histopathological study from 39 consecutive autopsy cases of patients who died from COVID-19, high viral load was seen in the myocardium in 16 (41%) of these patients suggesting that perhaps most of the myocardial damage might be due to the inflammatory response rather than direct viral invasion.[23]

However, it has been suggested that subclinical myocardial involvement can also occur in patients who are not critically ill. A recent study of magnetic resonance imaging scans of unselected patients with COVID-19 revealed that a high proportion of them (78%) had evidence of myocardial involvement even without any clinical signs.[24] Their findings were evidence of ongoing perimyocarditis, peri-epicardial, patchy late gadolinium enhancement (LGE), evidence of myocardial fibrosis, and oedema. Their findings suggest that myocardial involvement is independent of the severity of the original infection (the study included patients with mild disease who were not hospitalized) and persists beyond the period of initial infection (some of the scans were done as late as 2 or 3 months after initial infection). Although there was no follow up of these patients, many of the findings described have previously been associated with poor outcomes in inflammatory cardiomyopathy.

There were a few limitations to this study. This was a retrospective analysis of the patients admitted to three institutions across Oman. The data was collected between three sites and hence there would have been inherent differences in the quality of data collected. However, all the data collected was cross checked by a second person in each institution to assure quality control.

As this is a retrospective study, the quality of the data collected was a reflection of the quality of the data entered into the clinical case notes. Due to the limited access to these patients in highly controlled environments, tests such as ECG and echocardiography were not performed routinely and hence not all patients had these done. As these three centers were tertiary care centers, there were patients who were transferred from regional hospitals to these centers after they were intubated, and these patients have only limited information available.

CONCLUSIONS

Cardiac involvement is common in patients admitted with COVID-19. In our cohort, around a third of the patients had evidence of cardiac involvement which was associated with a worse outcome. Patients with COVID-19 should be investigated to rule out cardiac involvement even in the absence of symptoms.

Financial support and sponsorship

This study was supported by Medical Research Centre, Sultan Qaboos University.

Conflicts of interest

There are no conflicts of interest.

Contributory statement

Fahad Alkindi, - Planning, conduct, OVERALL responsible khamis AlHashmi, Planning, conduct Sunil Nadar, conduct, reporting, writing Salma Alharthi, conduct, reporting, data collection khalid alsaidi, conduct, reporting data collection Tasneem Alrashdi, conduct, reporting data collection shabib alasmi, conduct, reporting Feryal Khamis, conduct, reporting Adil Algafri, conduct, reporting Sultan Allawati, conduct, reporting Muzna Alfarsi, conduct, reporting Sathiya Murthi, conduct, reporting Mujahid Albusaidi, conduct, reporting Abdullah balkhair, conduct, reporting Hafidh Alhadi, conduct, reporting khalid Alrasadi, conduct, reporting Maather Alabri, conduct, reporting Maryam AlIssai, conduct, reporting Shihab Alkindi, conduct, reporting Hilal Alsabti, conduct, reporting, planning, writing

Author disclosures

This study was funded by the Sultan Qaboos University (SQU). Dr. Alkindi has received grants from the research medical centre in SQU, Muscat, Oman.. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.