Wuhan, China, became the center of an epidemic of “unknown pneumonia” detected in December 2019.1,2 Blood samples, oral swabs, bronchoalveolar lavage fluid, and anal swabs collected from patients with severe pneumonia were analyzed. This novel pathogen, an enveloped RNA beta-coronavirus, was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease caused by this virus was called coronavirus disease 2019 (COVID-19). The COVID-19 pandemic has emerged as a public health crisis of global proportions.3 COVID-19 typically presents with respiratory tract symptoms including fever, dry cough, and dyspnea. The disease can progress to pneumonia and acute respiratory distress syndrome.4 The pathophysiology of COVID-19 infection is not clear. However, an extreme immune response and cytokine storm are thought to play pivotal roles in severe cases of the disease.4

Our knowledge of the cardiovascular effects of COVID-19 is limited. Studies have reported that left and right ventricular ejection fraction may be reduced by a cytokine-mediated systemic response to infection through increases in the end-diastolic and end-systolic volumes of both ventricles.5 However, it is not known whether left ventricular (LV) systolic and diastolic dysfunction develops in patients with COVID-19.

Two-dimensional and Doppler echocardiography provide important information about LV diastolic and systolic function. The myocardial performance index (MPI) is a reliable echocardiographic index that combines diastolic and systolic measurements.6 In this study, we aimed to assess left ventricular systolic and diastolic function in COVID-19 patients using MPI.

This study enrolled 40 consecutive patients (26 males (65%); mean age, 54±11 years) and 40 healthy control subjects (24 males (60%); mean age, 52±13 years). The patients were admitted to the hospital with fever >38°C, cough, sore throat, rhinorrhea, shortness of breath, headache, myalgia, and/or diarrhea. The PCR test was positive in all patients. The mean interval between the first echocardiogram and symptom onset was 9.3±5.5 days.

Clinical characteristics including age, gender, smoking status, hypertension, diabetes, systolic blood pressure, diastolic blood pressure, and heart rate were similar between patients and controls (p>0.05 for all). Compared with controls, COVID-19 patients had a significantly higher MPI (0.56±0.09 vs. 0.41±0.06, p<0.001), longer IRT (112.3±13.4 vs. 90.6±11.2 ms, p<0.001), longer deceleration time (182.1±30.6 vs. 160.8±42.7 ms, p=0.003), shorter ET (279.6±20.3 vs. 299.6±34.7 ms, p<0.001) and higher E/A ratio (1.53±0.7 vs. 1.21±0.3, p<0.001). LVEF was similar in COVID-19 patients and controls (60.3±3.2% vs. 61.9±4.8%, p>0.05), as was ICT (44.3±7.8 vs. 41.8±8.7 ms, p>0.05). Compared with controls, patients in the acute infection period had significantly higher cTnI (0.96±0.12 vs. 0.10±0.01 ng/ml, p<0.001), LDH (486.8±118.6 vs. 316.4±108.9 IU/l, p=0.002), WBC (12.3±4.7 vs. 7.0±2.6 103/μl, p<0.001) and neutrophil count (9.7±6.2 vs. 4.2±1.5 103/μl, p<0.001), and lower lymphocyte count (0.9±0.2 vs. 2.8±0.6 103/μl, p<0.001). Creatinine, CK and hemoglobin levels were similar in patients and controls (p>0.05 for all). Table 1 summarizes the clinical characteristics, laboratory and echocardiographic findings of patients in the acute period of COVID-19 infection and controls.

Systolic and diastolic blood pressure and heart rate were similar between the acute period of infection and after clinical recovery (p>0.05 for all). Compared with the acute infection period, after clinical recovery there was significantly lower MPI (0.44±0.07 vs. 0.56±0.09, p<0.001), shorter IRT (91.8±12.1 vs. 112.3±13.4 ms, p<0.001), shorter deceleration time (161.5±43.5 vs. 182.1±30.6 ms, p=0.003), longer ET (298.8±36.8 vs. 279.6±20.3 ms, p<0.001) and lower E/A ratio (1.22±0.6 vs. 1.53±0.7, p<0.001). LVEF was similar in the acute period of infection and after clinical recovery (60.3±3.2% vs. 60.7±3.8%, p>0.05), as was ICT (44.3±7.8 vs. 40.6±9.7ms, p>0.05). Compared with the acute period of COVID-19 infection, after clinical recovery there was significantly lower cTnI (0.11±0.08 vs. 0.96±0.12 ng/ml, p<0.001), LDH (334.5±110.9 vs. 486.8±118.6 IU/l, p=0.004), WBC (7.2±3.1 vs. 12.3±4.7 103/μl, p<0.001) and neutrophil count (4.5±1.8 vs. 9.7±6.2 103/μl, p<0.001) and higher lymphocyte count (2.1±0.4 vs. 0.9±0.2 103/μl, p<0.001). Creatinine, CK and hemoglobin levels were similar between the acute period of infection and after clinical recovery (p>0.05 for all). Table 2 presents the clinical characteristics, laboratory and echocardiographic findings of patients in the acute period of COVID-19 infection and after clinical recovery.

This is the first echocardiographic follow-up study to assess left ventricular systolic and diastolic function in COVID-19 patients. Our data showed that LV performance was impaired subclinically during the acute period of COVID-19 and that this impaired performance recovered with clinical improvement.

Since the first case was reported at the end of 2019, the COVID-19 outbreak has become a pandemic. The high transmission ratio of the virus has made it a threat to public health globally. Coronaviruses are non-segmented positive-sense RNA viruses that are broadly distributed in humans and other mammals, such as camels, bats, mice, dogs, and cats.10 Coronaviruses can cause respiratory, enteric, cardiovascular, and neurological disease.11–14 A 2020 report by the China Medical Treatment Expert Group for COVID-19 showed the spectrum of clinical and diagnostic features associated with SARS-CoV-2 infection among Chinese patients.15 According to this report, the most common symptoms in patients with COVID-19 were fever (in 88.7% of patients during hospitalization) and cough (in 67.8% of patients), as well as headache, fatigue, or shortness of breath. In our study, in agreement with previous data, fever was present in 84.2% of the patients on admission. The second most common symptom was cough (60.4% of patients). The overall mortality rate is 2.3% and those with pre-existing comorbid conditions have higher case mortality rates: diabetes 7.3%, chronic respiratory disease 6.3%, hypertension 6.0% cardiovascular disease 10.5%, and cancer 5.6%.16

We assessed left ventricular diastolic and systolic function using several echocardiographic parameters. Although systolic and diastolic dysfunction appear together, there are few Doppler echocardiographic variables that combine systolic and diastolic measurements. We used the MPI, which includes the LV systolic contraction and diastolic relaxation periods.17 This index was first used by Tei et al. to predict LV systolic and diastolic function noninvasively.9 MPI is not significantly affected by preload, afterload, sample volume location, age, or rhythm18,19 and is therefore a reliable index. The value of MPI in LV dysfunction has been confirmed in patients with symptomatic heart failure of non-ischemic or ischemic etiology and idiopathic dilated cardiomyopathy.17,18 We aimed to assess LV systolic and diastolic function in COVID-19 patients using MPI. In the present study, MPI was higher in the acute disease period in patients with COVID-19, but regressed significantly after clinical recovery. Previous reports showed that systolic function is affected in COVID-19 patients. However, there is limited information about LV diastolic function in these patients. Our study showed that not only systolic but also diastolic function may be impaired in COVID-19 patients. In other words, COVID-19 patients may develop subclinical diastolic impairment without systolic involvement.

The pathophysiological and cardiovascular effects of COVID-19 are not clear. However, the disease is thought to be associated with an excessive immune response triggered by the virus. Studies have found that COVID-19 patients have high levels of interleukin (IL)-1 beta, IL-6, interferon gamma, and monocyte chemoattractant protein-1, which probably leads to an activated type 1 helper T cell response.4 Studies of coronavirus and influenza outbreaks suggest that viral infections can trigger a systemic inflammatory response that causes acute coronary syndromes, arrhythmias, and heart failure.20–23 Similarly, underlying cardiovascular disease may be exacerbated or new cardiac disease may be induced during COVID-19. Acute coronary events may be due to increased myocardial demand triggered by infections that accelerate myocardial damage or infarction. Alternatively, circulating cytokines released during severe systemic inflammatory stress may cause instability and rupture of atherosclerotic plaque. Patients with heart failure are also prone to hemodynamic decompensation during the stress of severe infections. During most influenza outbreaks, more patients die of cardiovascular causes than from pneumonia.24 COVID-19 causes myocardial inflammation and myocarditis.25,26 The elevated cTnI in our patients might reflect myocardial damage. cTnI is part of the contractile apparatus in cardiomyocytes and is expressed only in the heart.27-29 As a result of its organ specificity, cTnI can be used to diagnose cardiomyocyte damage.28,29 The elevated LDH observed may reflect tissue damage and inflammation.

We assumed that the temporary impairment in echocardiographic parameters in the acute phase was caused by proinflammatory mediators, such as tumor necrosis factor (TNF) and the IL-1 and -6 families of cytokines, which have significant negative inotropic effects.30 Myocardial function may also be impaired through direct COVID-19 infection of myocytes, leading to active myocarditis. Reported data on the severity, extent, and short- and long-term cardiovascular effects of COVID-19 are limited.

Our study has some limitations, the main one of which is its small sample size. Another limitation is that circulating levels of cytokines such as IL-1, IL-6, and TNF could not be measured. In addition, the lack of clarity concerning the effects of hydroxychloroquine and favipiravir on cardiac function are also limitations of the study. Further studies that measure the circulating levels of these cytokines and echocardiographic variables are needed based on the current hypothesis of cytokine-mediated temporary impairment of left ventricular performance.

In conclusion, subclinical diastolic impairment without systolic involvement may be observed in patients with COVID-19. This could be due to isolated subclinical diastolic dysfunction. The underlying mechanism and its clinical significance can be established by further studies.

This study received no grant funding from any agency in the public, commercial or not-for-profit sectors.

The authors have no conflicts of interest to declare.