|Year : 2021 | Volume
| Issue : 1 | Page : 20-26
Cardiovascular manifestations and outcomes in patients admitted with severe COVID-19: Middle Eastern Country multicenter data
Fahad Alkindi1, Khamis Alhashmi2, Sunil Nadar1, Salma Alharthi3, Khalid Alsaidi4, Tasneem Alrashdi4, Shabib Alasmi4, Feryal Khamis4, Adil Algafri5, Sultan Allawati5, Muzna Alfarsi5, Sathiya Murthi3, Mujahid Albusaidi1, Abdullah Balkhair1, Hafidh Alhadi1, Khalid Alrasadi2, Maather Alabri2, Maryam Alissai2, Shihab Alkindi2, Hilal Alsabti2
1 Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
2 College of Medicine, Sultan Qaboos University, Muscat, Oman
3 Oman Medical Specialization Board, Muscat, Oman
4 Department of Cardiology, Royal Hospital, Muscat, Oman
5 Department of Medicine, Alnahda Hospital, Muscat, Oman
|Date of Submission||29-Dec-2020|
|Date of Acceptance||12-Jan-2021|
|Date of Web Publication||22-Apr-2021|
Cardiology Unit, Department of Medicine, Sultan Qaboos University Hospital, P. O. Box: 38/PC 123, Muscat
Cardiothoracic Surgery, Department of Surgery, Sultan Qaboos University Hospital, P. O. Box: 38/PC 123, Muscat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
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.
Keywords: Cardiovascular manifestations, COVID-19, mortality, SARS-CoV-2, troponin
|How to cite this article:|
Alkindi F, Alhashmi K, Nadar S, Alharthi S, Alsaidi K, Alrashdi T, Alasmi S, Khamis F, Algafri A, Allawati S, Alfarsi M, Murthi S, Albusaidi M, Balkhair A, Alhadi H, Alrasadi K, Alabri M, Alissai M, Alkindi S, Alsabti H. Cardiovascular manifestations and outcomes in patients admitted with severe COVID-19: Middle Eastern Country multicenter data. Heart Views 2021;22:20-6
|How to cite this URL:|
Alkindi F, Alhashmi K, Nadar S, Alharthi S, Alsaidi K, Alrashdi T, Alasmi S, Khamis F, Algafri A, Allawati S, Alfarsi M, Murthi S, Albusaidi M, Balkhair A, Alhadi H, Alrasadi K, Alabri M, Alissai M, Alkindi S, Alsabti H. Cardiovascular manifestations and outcomes in patients admitted with severe COVID-19: Middle Eastern Country multicenter data. Heart Views [serial online] 2021 [cited 2021 Jun 13];22:20-6. Available from: https://www.heartviews.org/text.asp?2021/22/1/20/314398
| 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. Since then, it has spread rapidly to almost all countries of the world and was declared a global pandemic on March 2020. 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.
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. 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.
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). 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. In addition, a substantial proportion of patients develop coagulation abnormalities resulting in thromboembolic events.
Distinct from the other coronaviruses, SARS-CoV-2 has a propensity for the cardiovascular system. 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. 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. In addition, preexisting cardiovascular disease and risk factors such as hypertension are associated with increased mortality.
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|| |
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.
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.
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. 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, 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. Congestive heart failure was defined according to the European Society of Cardiology criteria. 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.
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].
One hundred and eighty-five (34.2%) patients had evidence of cardiac involvement [Table 1] and [Table 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 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].
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.,,,.
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. 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.
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,,,, 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.
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.
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.
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. 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.
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
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.
| References|| |
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al
. A new coronavirus associated with human respiratory disease in China. Nature 2020;579:265-9.
Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: Immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74.
Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al
. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:2950-73.
Gupta AK, Jneid H, Addison D, Ardehali H, Boehme AK, Borgaonkar S, et al
. Current perspectives on coronavirus disease 2019 and cardiovascular disease: A white paper by the JAHA editors. J Am Heart Assoc 2020;9:e017013. doi: 10.1161/JAHA.120.017013.
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al
. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.
Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al
. COVID-19 and cardiovascular disease. Circulation 2020;141:1648-55.
Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng J, et al
. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. J Infect 2020;81:e16-25.
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al
. Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012;307:2526-33.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al
. Fourth universal definition of myocardial infarction (2018). Circulation 2018;138:e618-51.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al
. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975.
Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al
. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-8.
Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Prog Cardiovasc Dis 2020;63:390-1.
Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M, et al
. Characterization of myocardial injury in patients with COVID-19. J Am Coll Cardiol 2020;76:2043-55.
Topol E, Inserro A. What accounts for the high cost of care? It's the people: A Q& A with Eric Topol, MD. Am J Manag Care 2020;26:17-8.
Fried JA, Ramasubbu K, Bhatt R, Topkara VK, Clerkin KJ, Horn E, et al
. The variety of cardiovascular presentations of COVID-19. Circulation 2020;141:1930-6.
Garg S, Kim L, Whitaker M, O'Halloran A, Cummings C, Holstein R, et al
. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2. MMWR Morb Mortal Wkly Rep 2020;69:458-64.
Schiavone M, Gobbi C, Biondi-Zoccai G, D'Ascenzo F, Palazzuoli A, Gasperetti A, et al
. Acute coronary syndromes and Covid-19: Exploring the uncertainties. J Clin Med 2020;9:1683.
Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C, Meissner K, et al
. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol 2020;5:1281-5.
Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, et al
. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:1265-73.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]