Abstract
Background
The 2019 novel coronavirus disease (COVID-19) has been reported as pandemy and the number of patients continues to rise. Based on recent data, cardiac injury is a prominent feature of the disease, leading to increased morbidity and mortality. In the present study we aimed to evaluate myocardial dysfunction using transthoracic echocardiography (TTE) and tissue Doppler imaging (TDI) in hospitalized COVID-19 patients.
Methods and Results
We recruited 30 patients (56.7% male, 55.80 ± 14.949 years) who were hospitalized with the diagnosis COVID-19 infection. We analyzed left ventricular (LV) and right ventricular (RV) conventional and TDI parameters at the time of hospitalization and during the course of the disease. Patients without any cardiac disease and with preserved LV ejection fraction (EF) were included. TTE examination was performed and all the variables were recorded and analyzed retrospectively.
We observed that both LV and RV conventional echocardiographic parameters were similar when the day of admission to the hospital was compared to the 5th day of the disease. Regarding TDI analysis, we demonstrated significant impairment in LV septal and lateral deformation (P < 0.001). In the correlation analysis no marked correlation was observed between impairment in LV deformation and inflammation biomarkers.
Conclusion
Cardiac involvement is an important feature of the COVID-19 infection but the exact mechanism is still undefined. Echocardiography is an essential technique to describe myocardial injury and provide new concepts for the possible definitions of cardiac dysfunction.
Introduction
Coronavirus disease 2019 (COVID-19) was first reported in December 2019 from Wuhan, China and became immediately a public health emergency worldwide [1]. SARS-CoV-2 infection is mostly characterized by respiratory tract symptoms, pneumoniae and acute respiratory distress syndrome [2].
Since the beginning of pandemic it was observed that COVID-19 virus affects mainly the respiratory system, but also various systems, and the cardiovascular system damage is life threatening [3]. Cardiovascular complications related to COVID-19 are mainly acute coronary syndrome, arrythmia, myocarditis, acute myocardial injury and heart failure. Myocardial injury is defined as electrocardiographic abnormalities, echocardiographic abnormalities and higher serum biomarkers. Among these manifestations the mortality rate of cardiac injury is the highest [4]. Current data reported that several echocardiographic abnormalities were confirmed in hospitalized patients with COVID-19, including left ventricular (LV) global dysfunction [3].
Tissue Doppler Imaging (TDI) is an important echocardiographic technique to evaluate global and regional myocardial systolic and diastolic function [5]. Recent studies have demonstrated its utility as a diagnostic tool in several cardiac and non cardiac disorders [6]. In the present study we aimed to evaluate myocardial function and possible myocardial damage of COVID-19, by using conventional echocardiography and TDI parameters.
Methods
Study design and patient population
Our study included 30 patients who were diagnosed as COVID-19 and hospitalized at our center between March 20th and April 10th, 2022. Patients with LV ejection fraction (EF) ≥ 55% and in sinus rhythm were included. Patients with LV EF <55%, coexistence of mitral and/or aortic valve disease more than mild degree, known coronary artery disease (CAD), low quality echocardiographic image for TDI analysis, having atrioventricular conduction abnormalities and atrial fibrillation were excluded from the study.
Study protocol was approved by local Ethics Committee of our institute, and a detailed written informed consent was obtained from each patient. The study was accomplished according to the Declaration of Helsinki.
Laboratory examination
Methods for laboratory confirmation of COVID-19 infection have been described elsewhere [2]. Our institution was responsible for COVID-19 detection by real time PCR method from throat and nose-swab specimens. PCR re-analysis for COVID-19 was performed for each patient in case of worsening of the symptoms or after clinical remission.
All the patients underwent routine blood examinations including complete blood count, serum biochemical tests defined as liver and renal function tests, high sensitive Troponin I (hs-TnI), ferritin, D-dimer and c-reactive protein (CRP).
Echocardiographic measurements
In this study, we included 30 patients who were hospitalized for COVID-19 infection in our center. During their follow-up, all of our COVID-19 patients underwent TTE, in order to evaluate possible myocardial damage. We analyzed all echocardiographic parameters retrospectively. TTE examinations were performed by only one cardiologist on the first day of the hospitalization and on the fifth day of the disease. We used bed-side echocardiography (laptop-sized portable machine) in the patient’ s room. In order to shorten the time of scanning, an experienced cardiologist performed the TTE examinations. We performed the procedure under personal protective equipment, as recommended by the American Society of Echocardiography [7]. We sterilized the machine after each exam first in the patient’ s room and again in the hallway and we used probe covers.
Patients underwent TTE (Vivid –I, GE Healthcare) by using a 2.3–3.5 MHz transducer. Left ventricular end-diastolic (LVEDD) and end-systolic diameters (LVESD), left atrial (LA) diameter, right ventricular end-diastolic (RVEDD) diameter, interventricular septum (IVS) and posterior wall (PW) thickness parameters were measured from parasternal long-axis view by using M-mode [8]. From apical four-chamber view, LV EF was calculated using modified Simpson’ s method (vi). Early (E) and late diastolic (A) transmitral flow velocities were also measured. Tricuspid annular plane systolic excursion (TAPSE) was measured by M-mode echocardiography, obtained by placing the cursor on the lateral tricuspid annulus at the level of the RV free wall in the apical 4-chamber view.
Tissue Doppler imaging
In the two-dimensional, four-chamber views, a 5-mm sample volume was placed just apical to the septal and lateral mitral annulus and lateral tricuspid annulus, identified using pulsed-wave tissue TDI. Settings were adjusted for a frame rate between 120 and 180 frame/s, and a cineloop of three to five consecutive heart beats were recorded. TDI-derived systolic index; peak velocity during systolic ejection (Sa) was measured from basal regions of LV septal and lateral walls and RV free wall. TDI-derived early diastolic velocity (e') was measured from mitral and tricuspid annuli. All the measurements were calculated from three consecutive cycles, and the average of three measurements was recorded.
Reproducibility
The degree of agreement among repeated measurements of TDI variables was expressed in terms of intraclass correlation coefficient (ICC) and corresponding 95% confidence intervals (CI). In order to evaluate intra-observer variability, the observer was repeated the measuring procedure for 10 randomly selected samples within the same day. ICCs were calculated based on a single rater, absolute-agreement, 2-way mixed-effects model [9].
Statistical analysis
Data were analyzed using SPSS, version 21.0 (IBM Corp, Chicago, IL, USA). Categorical variables are presented as frequencies and percentages, and continuous variables as mean and standard deviations (SD). The Wilcoxon signed-rank test was used to assess differences between the 1st day and 5th day measurements. The Spearman correlation coefficient was used for correlation analysis. For all statistical analyses, a two-sided P < 0.05 was considered significant.
Results
Clinical characteristics and conventional echocardiographic data
None of the patients had clinical signs of CAD and the electrocardiograms revealed no signs of ischemia during the study. Moreover, none of them had wall motion abnormality, based on transthoracic echocardiographic (TTE) examination.
All of the patients underwent TTE and laboratory parameters were examined on the first day of hospitalization and on the fifth day of the disease. During follow-up, 9 of 30 patients were admitted to the Intensive Care Unit (ICU) due to respiratory problems including shortness of breath and decrease in blood oxygen saturation, however none of them were intubated and they recovered in a few days. None of 30 patients died.
Demographic characteristics of patients are provided in Table 1. Serum level of hemoglobin decreased in the course of the disease (P = 0.003) while the number of thrombocytes increased (P = 0.004). There was no significant change in serum levels of biochemical parameters (Table 2).
Demographic and clinical characteristics of patients with COVID-19 (n = 30)
| Characteristic | No. (%) |
| Age, mean ± SD (range), y | 55.80 ± 14.949 (22–86) |
| Gender | |
| Male | 17 (56.7) |
| Female | 13 (43.3) |
| Blood pressure | |
| SBP, mmHg | 127.33 ± 4.866 |
| DBP, mmHg | 80.33 ± 4.536 |
SBP: Systolic blood pressure, DBP: Diastolic blood pressure
Clinical, biochemical and echocardiographic characteristics of patients with COVID-19 in the follow-up (n = 30)
| Characteristic | Measurement Date | P value | |
| 1st day | 5th day | ||
| Blood cell count | |||
| Hemoglobin, g | 13.18 ± 1.691 | 12.51 ± 1.596 | 0.003 |
| Hct, % | 39.47 ± 5.349 | 38.73 ± 4.182 | 0.41 |
| Leukocytes, 103 μL−1 | 6,233 ± 3520.914 | 7,079 ± 4409.732 | 0.10 |
| Thrombocytes, 103 μL−1 | 204.43 ± 81.131 | 252 ± 87.348 | 0.004 |
| Lymphocytes, 103 μL−1 | 1137 ± 475.571 | 1180.67 ± 478.031 | 0.43 |
| Neutrophils, 103 μL−1 | 4529.33 ± 3554.711 | 5108.63 ± 4648.774 | 0.64 |
| Biochemical parameters | |||
| High-sensitivity troponin I, ng mL−1 | 41.30 ± 131.556 | 97.62 ± 347.356 | 0.49 |
| Ferritin, ng mL−1 | 1513.44 ± 2810.766 | 1912.09 ± 4466.777 | 0.47 |
| D-dimer, μg L−1 | 3216.50 ± 10266.033 | 3587.93 ± 10177.555 | 0.76 |
| CRP, mg L−1 | 61.64 ± 65.621 | 50.86 ± 75.892 | 0.41 |
| Blood pressure | |||
| SBP, mmHg | 127.33 ± 4.866 | 127.33 ± 5.371 | 1.000 |
| DBP, mmHg | 80.33 ± 4.536 | 79.37 ± 3.846 | 0.14 |
| LVEDD,cm | 4.77 ± 0.109 | 4.76 ± 0.138 | 0.76 |
| LVESD, cm | 3.19 ± 0.210 | 3.18 ± 0.211 | 0.18 |
| IVS thickness, cm | 0.99 ± 0.064 | 0.99 ± 0.066 | 0.32 |
| PW thickness, cm | 0.92 ± 0.050 | 0.93 ± 0.052 | 0.32 |
| LV EF, % | 61.33 ± 3.772 | 61.23 ± 3.720 | 0.08 |
| LA diameter, cm | 3.78 ± 0.182 | 3.78 ± 0.185 | 0.16 |
| RA diameter, cm | 3.59 ± 0.241 | 3.59 ± 0.243 | 0.32 |
| RV EDD, cm | 3.40 ± 0.257 | 3.38 ± 0.258 | 0.16 |
| TAPSE, cm | 2.17 ± 0.130 | 2.15 ± 0.143 | 0.14 |
| Mitral early diastolic velocity (E), m s−1 | 0.81 ± 0.052 | 0.81 ± 0.058 | 0.11 |
| Mitral late diastolic velocity (A), m s−1 | 0.64 ± 0.079 | 0.64 ± 0.077 | 0.08 |
| E/A ratio | 1.28 ± 0.120 | 1.27 ± 0.123 | 0.64 |
| TDI early diastolic velocity (é), m s−1 | 7.00 ± 0.571 | 6.97 ± 0.564 | 0.20 |
| E/é | 0.12 ± 0.013 | 0.11 ± 0.013 | 0.20 |
| Tissue Doppler Imaging parameters | |||
| LV septal systolic velocity, m s−1 | 0.080 ± 0.0100 | 0.069 ± 0.0088 | <0.001 |
| LV lateral systolic velocity, m s−1 | 0.085 ± 0.0141 | 0.074 ± 0.0125 | <0.001 |
| RV lateral systolic velocity, m s−1 | 0.142 ± 0.0112 | 0.140 ± 0.0114 | 0.10 |
HCT: Hematocrit, CRP: C-reactive protein, LV EDD: Left ventricle end diastolic diameter, LV ESD: Left ventricle end systolic diameter, IVS: Interventricular septum, PW: Posterior wall, LV EF: Left ventricle ejection fraction, LA: Left atrium, RA: Right atrium, RV EDD: Right ventricle end diastolic diameter, TAPSE: Tricuspid annular plane systolic excursion, TDI: Tissue Doppler Imaging. P value is statistically significant.
Regarding echocardiographic analysis, we observed that LV and RV conventional parameters were similar when compared the day of hospitalization and 5th day of the disease (Table 2). When we evaluated TDI parameters, we established that LV septal (P < 0.001) and lateral peak systolic velocities (P < 0.001) markedly decreased in the follow-up of COVID-19 patients (Table 2).
In the correlation analysis we could not demonstrate any significant relationship between impairment in LV deformation and serum inflammation biomarkers (Table 3).
Correlations between some biochemical parameters and TDI measurements (n = 30)
| LV septal | LV lateral | |||
| rs | P | rs | P | |
| Leukocytes | 0.226 | 0.23 | 0.080 | 0.68 |
| Lymphocytes | −0.150 | 0.43 | −0.032 | 0.87 |
| Neutrophils | 0.240 | 0.20 | −0.009 | 0.96 |
| High-sensitivity troponin | −0.027 | 0.91 | −0.209 | 0.35 |
| D-dimer | −0.005 | 0.98 | −0.254 | 0.18 |
| CRP | −0.178 | 0.35 | −0.065 | 0.73 |
rs:Spearman's correlation coefficient
Discussion
In the present study, we evaluated the possible effects of COVID-19 infection on myocardial function, regarding patients without any cardiac disease or any symptoms and with preserved LV EF. We were able to reveal significant LV systolic dysfunction in patients affected by COVID-19 infection, based on tissue Doppler imaging which provides detailed assessment of myocardial wall motion and subtle changes in myocardial function despite normal LV EF.
COVID-19 is a global pandemic disease. Based on several reports it was confirmed that cardiovascular complications of COVID-19 are important and correlate with the disease severity and mortality [10].
COVID-19 infection provokes myocardial injury, leading to myocardial dysfunction. The possible mechanisms include cardiac stress due to hypoxemia, direct myocardial injury by COVID-19 through ACE receptors, systemic inflammation, cytokine storm, microthrombosis, endothelial damage [11, 12], Myocardial damage was firstly recognized by elevation of cardiac biomarkers. In a study with COVID-19 cases from China, elevated hs-cTnI and new electrocardiography (ECG) or echocardiography abnormalities was demonstrated in 7.2% of all the patients and 22% of which required intensive coronary unit care [13]. Recent studies also defined myocardial damage as elevation of serum troponin levels Zheng et al. [14] denote that COVID-19 infection causes acute myocardial injury as well as chronic damage to the cardiovascular system [15].
Patel G, et al. reported in their observational retrospective study that cardiac injury was an important feature of COVID-19 infection [16]. Since the beginning of pandemic period, it was declared several times that prevalence of cardiac injury is higher among patients with pre-existing cardiac conditions, such as hypertension, diabetes mellitus and congestive heart failure. However in a meta-analysis, it was reported that cardiac damage may occur even in patients without any cardiac diseases, similar to our study [17].
In the last two years valuable studies were performed to evaluate myocardial functions by echocardiography in COVID-19 patients. In the ECHO-COVID study, patients in the intensive coronary unit went under TTE and were assessed by conventional echocardiography parameters [18]. The researchers observed LV and right ventricular dysfunction in one third of critically ill patients. One remarkable finding in this study is detection of LV dysfunction without LV enlargement. This result can be explained as acute cardiac injury. Also only minority of patients had wall motion abnormality and LV dilatation. These observations show similarity with our results.
In this study, we aimed to assess myocardial injury of COVID-19 infection in patients without any cardiac disease and cardiac symptoms. We established significant impairment in LV myocardial function during the follow-up of hospitalized COVID-19 patients, based on TDI analysis. There is growing literature exploring cardiac injury in patients with COVID-19. Despite several proposed mechanisms the exact underlying causes of myocardial involvement are not clearly defined and understood, yet.
We could not demonstrate any mechanism of LV systolic dysfunction and no significant correlation was observed between LV deformation and biochemical parameters, which may be linked to the small number of our patient group. According to our results, we suggest that COVID-19 infection impairs myocardial motion, which we could demonstrate based on TDI analysis which provides detailed information and subtle changes of myocardial deformation. We would like to mention that follow-up of these patients is mandatory and re-evaluation of myocardial function after recovery from the disease may provide new insights into the mechanism of cardiac injury and therapies.
Limitations and strengths
The major limitation of our study is the small number of our patient group. However, we had one observer to perform all the TTE procedure, due to the difficulty of management of personal protection and strict isolation. We could not demonstrate any correlation between myocardial systolic dysfunction and serum biochemical parameters.
In our study, we clearly defined impairment of myocardial deformation, during the course of the disease when compared to the day of hospitalization. We included patients with no history of any cardiac disease, however we had no idea about TDI analysis or other TTE parameters of these patients, this determination may be suggested as another limitation.
Conclusion
COVID-19 has threatened global health since 2019. The disease mainly affects the respiratory system however its effect on cardiovascular system is of particular importance. Echocardiography is a valuable technique which evaluates myocardial functions with conventional and TDI parameters. Assessment of early myocardial damage in COVID-19 patients is useful and provides detailed information for the prediction of possible ventricular dysfunction, in order to prevent heart failure and to decide the optimal therapy.
Conflict of interests
None.
Funding sources
None.
Ethical statement
Ethical approval is obtained from local ethical committee.
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