Abstract
Background:
Coronavirus disease 2019 (COVID-19) might be associated with cardiac injury as a part of multisystem affection in response to cytokine storms. However, left ventricular (LV) function appears preserved in most of the cases, whereas subtle LV dysfunction might happen in others. Hence, we tried to detect subtle LV dysfunction in patients with COVID-19 using global longitudinal strain (GLS).
Patients and Methods:
We performed a single-center observational study on 90 stable patients who were recently recovered from mild to moderate COVID-19 infections. A transthoracic echocardiographic examination was done for all patients, and GLS assessment was used as an indicator of LV function.
Results:
The population age ranged from 27 to 66 years, and the majority of patients were males (54, 73.3%). Besides, 46.7% of the included patients were smokers, 33.3% had hypertension, and 23.3% were diabetics. All the patients had normal LV internal dimensions and ejection fractions. However, 33.3% of them had subclinical LV dysfunction as expressed by reduced GLS. There was no statistically significant correlation between GLS and age, gender, or other risk factors, whereas troponin and C-reactive protein significantly correlated with GLS.
Conclusions:
Recovered patients from recent mild to moderate COVID-19 infections might show subtle LV dysfunction as manifested by reduced GLS.
Keywords: Coronavirus disease 2019, C-reactive protein, global longitudinal strain, left ventricular dysfunction, troponin
INTRODUCTION
Coronavirus disease 2019 (COVID-19) was first identified as an outbreak of respiratory illness in Wuhan City in December 2019, and later, it was declared a global pandemic.[1]
The impact of COVID-19 on the heart is quite variable. Increased right ventricular afterload resulting from pulmonary embolism, negative inotropic effects of cytokines, and direct angiotensin-converting enzyme 2-mediated cardiac injury from COVID-19 are the potential mechanisms that can affect the heart.[2]
Evaluation of the ventricular size and function in such patients implies essential diagnostic and prognostic implications.
Many reports pointed to a potential subclinical left ventricular (LV) dysfunction with preserved LV ejection fraction (LVEF) that might be evident in some recovered post-COVID-19 patients. Subsequently, delineating the crucial role of nonconventional echocardiographic modalities, especially LV myocardial strain, putting in mind their widespread availability, suitable cost, and noninvasive nature in comparison to cardiac magnetic resonance (CMR),[3] the aim of this work was to evaluate the impact of COVID-19 infection on LV function using myocardial deformation imaging, mainly LV global longitudinal strain (GLS).
PATIENTS AND METHODS
This study was conducted during the period from August 2020 to March 2021 on recently recovered COVID-19 patients.
Inclusion criteria
All patients with an age range of 18–75 years were included. All of them were stable and recovered from the COVID-19 infection within 4–8 weeks (symptom-free and had negative Polymerase chain reaction (PCR)) after being stratified as mild-to-moderate COVID-19 cases (did not require intermediate or intensive care unit [ICU] admission).
Exclusion criteria
Patients with rheumatic heart disease, congenital heart disease, documented pulmonary embolism before COVID-19 infection, significant (more than grade II) valvular lesions, known ischemic heart disease, and LV dysfunction were excluded.
Ethical considerations
Informed consent was obtained from all patients.
Methods
All subjects were subjected to:
Full history taking, including age, gender, comorbidities, different risk factors, and medications
Full clinical and physical examination, including measurements of blood pressure, heart rate, respiratory rate, body weight, and height
Detailed cardiac and chest examination
Twelve-lead surface electrocardiogram
Laboratory investigations were done for all patients on admission including complete blood count, serum creatinine, creatine kinase MB fraction (CK-MB), highly sensitive troponin, D-dimer, C-reactive protein (CRP), and serum ferritin
Echocardiographic assessment: All patients underwent a complete transthoracic study 4–8 weeks after recovery from COVID-19 infection.
Standard transthoracic conventional echocardiographic examination
A GE Vivid E95 machine was used to acquire the standard images in the parasternal (long- and short-axis views) and apical (two-, three-, four-, and five-chamber images) views. M-mode, two-dimensional (2D), and tissue Doppler imaging (TDI), as well as pulsed and continuous Doppler flow across the different heart valves in all the standard views, were performed according to the recommendations of the American Society of Echocardiography.[4]
The following measurements were recorded: LV end-diastolic diameter, LV end-systolic diameter, LVEF using modified Simpson’s method, left atrial dimensions, and volume assessment of LV diastolic function: using pulsed-wave Doppler and TDI, the E/E’ ratio was calculated.
Speckle-tracking echocardiography
Cine loops from apical four, two, and three chambers views were recorded and then offline analysis was carried out using the Echo PAC application software, PC version 110.1.13. A topographic representation of the regional and GLS of the 17 analyzed segments (the bull’s eye configuration) was then automatically generated. All LV segments’ strain values were recorded and averaged to obtain the GLS.[3] GLS was used as an indicator of LV function.[5]
Statistical analysis
The Statistical Package for the Social Sciences (SPSS Inc by IBM, Chicago, USA) version 23 was used for data analysis. As regards descriptive statistics, quantitative parametric continuous variables were described as mean ± standard deviation, whereas nonparametric quantitative data were presented as medians with an interquartile range. Meanwhile, categorical variables were described as numbers and frequencies. The comparison between groups regarding categorical data was completed by a Chi-square test. The comparison between two independent groups with quantitative data was performed by either an unpaired t-test or a Mann–Whitney test. The confidence interval was adjusted to 95% with a margin of error of 5%. The results were considered statistically significant if P < 0.05.
RESULTS
Our study was conducted on 90 patients. Their ages ranged from 27 to 66 years, with a mean value of 41 ± 11 years. The majority were males: 54 (73.3%), 46.7% of the included patients were smokers, 33.3% had hypertension, and 23.3% were diabetics.
Regarding laboratory findings during active COVID-19 infection, 23.4% of the patients had high CK-MB, and 20% of the studied population had high troponin levels. All of them had high CRP, as appreciated in Table 1.
Table 1.
Laboratory finding (n=90)
| Variables | Results |
|---|---|
| HGB (g/dL), mean±SD (range) | 13.67±1.90 (10–17) |
| Platelets (×103/µL), mean±SD (range) | 264.27±53.98 (155–378) |
| TLC (×103/µL), mean±SD (range) | 9.16±2.52 (4–16) |
| Troponin (ng/L), median (IQR) (range) | 14.5 (7–22) (2–60) |
| Normal, n (%) | 72 (80) |
| High, n (%) | 18 (20) |
| CK-MB (IU/L), mean±SD (range) | 18.10±6.42 (5–35) |
| Normal, n (%) | 69 (76.6) |
| High, n (%) | 21 (23.4) |
| D-dimer (mg/L FEU), median (IQR) (range) | 1 (0.6–1.5) (0.6–2.5) |
| CRP (mg/L), median (IQR) (range) | 56 (44–95) (15–156) |
| Ferritin (µg/L), median (IQR) (range) | 572.5 (423–890) (300–1420) |
SD=Standard deviation, IQR=Interquartile range, CRP=C-reactive protein, TLC=Total leukocyte count, CK-MB=Creatine kinase MB fraction, HGB=Hemoglobin
Moreover, it was appreciated that 33.3% of the included patients had abnormal LV function as declared by GLS, whereas all of them had normal LVEFs and dimensions, as demonstrated in Tables 2 and 3.
Table 2.
Two-dimensional echocardiography findings (n=90)
| Mean±SD (range) | |
|---|---|
| ECHO 2D | |
| LVEDD (mm) | 47.90±3.37 (43–55) |
| LVEDD index (mm/m2) | 24.67±2.12 (20–30) |
| LVESD (mm) | 30.27±2.52 (25–37) |
| LVESD index (mm/m2) | 15.63±1.77 (12–21) |
| IVS thickness (mm) | 10.07±0.74 (9–12) |
| PW thickness (mm) | 9.83±0.87 (8–11) |
| EF (%) | 61.77±5.57 (51–73) |
| Simpson | |
| LVEDV (mL) | 89.73±17.67 (51–132) |
| LVEDV index (mL/m2) | 47.30±10.77 (25–75) |
| LVESV | 36.83±10.24 (18–63) |
| LVESV index (mL/m2) | 18.80±5.63 (10–35) |
SD=Standard deviation, IVS=Interventricular septum, PW=Pulsed-wave, EF=Ejection fraction, LVEDV=Left ventricular end-diastolic volume, LVESV=Left ventricular end-systolic volume, LVEDD=Left ventricular end-diastolic diameter, LVESD=Left ventricular end-systolic diameter, ECHO=Echocardiography, 2D=Two-dimensional
Table 3.
Left ventricular function assessed by left ventricular global longitudinal strain (n=90)
| Variables | Results |
|---|---|
| GLS (%), mean±SD (range) | −18±−2.92 (−15–−22) |
| Normal ≥–17, n (%) | 60 (66.7) |
| Abnormal <–17, n (%) | 30 (33.3) |
SD=Standard deviation, GLS=Global longitudinal strain
Figure 1 shows normal LVEF as calculated by 2D Simpson’s method, and Figure 2 shows normal GLS as demonstrated by bull’s eye for the same patient.
Figure 1.
Patient A with normal LV function as shown by Simpson’s Method.
Figure 2.
Patient A with normal LV GLS as shown by Bull’s eye plot
Figure 3 shows normal LVEF as calculated by 2D Simpson’s method, whereas Figure 4 shows abnormal GLS as demonstrated by bull’s eye for the same patient.
Figure 3.
Patient B with normal LV function as shown by Simpson’s Method
Figure 4.
Patient B with abnormal LV GLS as shown by Bull’s eye plot (Inspite of having normal LV function by Simpson’s Method)
Interestingly, there was no statistically significant correlation between GLS, age, gender, and different risk factors, whereas troponin and CRP were significantly correlated with GLS, as appreciated in Tables 4 and 5.
Table 4.
The relation between those who had normal global longitudinal strain versus who had abnormal global longitudinal strain regarding demographic data
| Normal GLS (≥−17%) (n=60), n (%) | Abnormal GLS (<−17%) (n=30), n (%) | Test value | P | Significant | |
|---|---|---|---|---|---|
| Age, mean±SD (range) | 41.50±11.46 (27–66) | 40.30±10.34 (28–60) | 0.279• | 0.782 | NS |
| Gender | |||||
| Female | 18 (30.0) | 6 (20.0) | 0.341* | 0.559 | NS |
| Male | 42 (70.0) | 24 (80.0) | |||
| Smoking | |||||
| No | 30 (50.0) | 18 (60.0) | 0.268* | 0.605 | NS |
| Yes | 30 (50.0) | 12 (40.0) | |||
| HTN | |||||
| No | 36 (60.0) | 24 (80.0) | 1.200* | 0.273 | NS |
| Yes | 24 (40.0) | 6 (20.0) | |||
| DM | |||||
| No | 42 (70.0) | 27 (90.0) | 1.491* | 0.222 | NS |
| Yes | 18 (30.0) | 3 (10.0) |
*Chi-square test, •Independent t-test. P>0.05 NS, P<0.05 significant, P<0.01 HS. HS=Highly significant, NS=Nonsignificant, HTN=Hypertension, DM=Diabetes mellitus, GLS=Global longitudinal strain
Table 5.
The relation between those who had normal global longitudinal strain versus who had abnormal global longitudinal strain regarding laboratory findings
| Normal GLS (n=60) | Abnormal GLS (n=30) | Test value | P | Significant | |
|---|---|---|---|---|---|
| HGB, mean±SD (range) | 13.35±1.68 (10–16) | 14.30±2.24 (10.8–17) | −1.303• | 0.203 | NS |
| PLT, mean±SD (range) | 261.80±44.70 (185–378) | 269.20±71.63 (155–345) | −0.349• | 0.730 | NS |
| TLC, mean±SD (range) | 9.32±2.49 (6–16) | 8.85±2.68 (4–14.5) | 0.475• | 0.638 | NS |
| Creatine, mean±SD (range) | 0.93±0.21 (0.6–1.3) | 1.03±0.27 (0.7–1.6) | −1.137• | 0.265 | NS |
| hsTrop, median (IQR) (range) | 14 (8–20) (2–45) | 21.5 (11–29) (2–60) | −2.176ǂ | 0.021 | Significant |
| CK-MB, mean±SD (range) | 18.55±5.82 (11–35) | 17.20±7.74 (5–28) | 0.536• | 0.596 | NS |
| D-dimer, median (IQR) (range) | 1.1 (0.7–1.5) (0.2–2.5) | 0.95 (0.5–1.5) (0.4–2) | −0.332ǂ | 0.740 | NS |
| CRP, median (IQR) (range) | 56 (44–93.5) (15–140) | 68.0 (53–95) (22–156) | −2.309ǂ | 0.013 | Significant |
| Ferritin, median (IQR) (range) | 624 (359.5–900) (122–1420) | 553 (444–700) (220–1100) | −0.352ǂ | 0.44 | NS |
•Independent t-test, ǂMann–Whitney test. P>0.05 NS, P<0.05 significant, P<0.01 HS. HS=Highly significant, NS=Nonsignificant, IQR=Interquartile range, CRP=C-reactive protein, SD=Standard deviation, PLT=Platelets, TLC=Total leukocyte count, GLS=Global longitudinal strain, CK-MB=Creatine kinase MB fraction, HGB=Hemoglobin, hsTrop=Highly sensitive troponin
DISCUSSION
A COVID-19 infection might initiate a cytokine storm, resulting in multi-organ damage. The possible high burden of systemic inflammation accompanying COVID-19 infection has been proposed as the initiating trigger for cardiovascular injury.[6] COVID-19 has an exceptional route for cell entry, which is prompted by binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2) on the host cell surface to enter inside. The ACE2 reveals a widespread configuration in the human body, especially in the heart, lungs, gastrointestinal system, and kidneys. Besides, ACE2 plays a crucial role in the neurohormonal regulation of the cardiovascular system.[7] ACE2 guards the heart against stimulation of the renin–angiotensin–aldosterone system as it converts angiotensin II to angiotensin.[1,2,3,4,5,6,7] Angiotensin II has a vasoconstrictor, pro-inflammatory role that damages capillary endothelium, whereas angiotensin[1,2,3,4,5,6,7] is a vasodilator.[8,9] Accordingly, augmented ACE2 receptor density might increase the viral load, resulting in a potential cardiac injury.[10] Nevertheless, the virus entry results in the downregulation of ACE2 and upsurges angiotensin II levels, which might trigger many cardiovascular disorders, such as myocardial injury, arrhythmias, acute coronary syndrome, and venous thromboembolism.[11] Additionally, as hypoxia is one of the clinical symptoms of the COVID-19 infection, this might result in myocardial injury. Besides, the metabolic demand of various organs, especially the heart, rises significantly during fever and inflammation.[12]
Multiple studies have conveyed that the cytokine storm is a complex network of various molecular events, including multi-organ failure and hyperferritinemia.[13] It is generated by the activation of an innumerable amount of white blood cells, including B-cells, T-cells, macrophages, dendritic cells, neutrophils, monocytes, and resident tissue cells, such as epithelial and endothelial cells, which release high amounts of pro-inflammatory cytokines.[14] This cytokine storm leads to cardiac tissue ischemia, which increases intracellular calcium, leading to the apoptosis of cardiac myocytes and a troponin leak.[15]
Moreover, endothelial cell injury plays a vital role in the pathogenesis of multi-organ failure in COVID-19, in view of the fact that the endothelium is one of the largest organs in the human body.[16] Endothelial damage leads to excessive cardiovascular impairment and might cause extreme heart attacks in COVID-19.[17]
Histologic proof of inflammatory cell infiltrates by endomyocardial biopsy (EMB) is the gold standard for diagnosing myocarditis. Similarly, CMR is an alternate noninvasive imaging modality.[18] However, EMB and CMR have not been routinely offered during the COVID-19 pandemic, resulting in a chief obstacle to the appropriate diagnosis of the cardiac abnormalities occurring in patients with COVID-19.
Myocardial distortion analysis by 2D strain predominantly offers a unique method for perceiving cardiac dysfunction in COVID-19 patients. Parameters of longitudinal strains are associated with the levels of lymphocytic infiltrates in EMB samples and with the amount of edema detected by CMR.[19] The decline in longitudinal strains in the subepicardium was more severe than that in the subendocardium, signifying that cardiac dysfunction was located predominantly in the subepicardial layer of the myocardium, which is considered a vital feature consistent with the subclinical myocarditis common in patients after COVID-19 infection.[20] That is why using echo machines to assess the subtle LV damage in recovered COVID-19 patients was a much easier and more accessible tool than other modalities.
Subsequently, based on that rationale, our study was enrolled on a cohort of 90 post-COVID-19 patients and assessed the left ventricle using conventional echo parameters and GLS, which has been proven to be a sensitive marker for early ventricular dysfunction, and compared all those indices with different patients’ demographics, risk factors, and other laboratory parameters. Interestingly, all of the patients had normal LVEF and dimensions as demonstrated by 2D echo and M-mode, whereas 33.3% of them had abnormal LV function as shown by GLS. There was no statistically significant correlation between GLS and age, gender, or other different risk factors. However, troponin and CRP significantly correlated with GLS, which was reduced in about one-third of the patients with preserved LV systolic ejection fraction, confirming the data about inflammation and myocardial injury associated with the COVID-19 virus and, moreover, delineating the hypothesis of asymptomatic subtle LV dysfunction in those patients.
Concordantly, a retrospective study that was done by Bhatti et al. on 90 COVID-19 hospitalized patients showed a significant decline in LV GLS in nonsurvivors as compared with survivors, whereas no significant alteration in LVEF was found, indicating that COVID-19 patients might have subclinical LV dysfunction, especially in those who were exposed to a more powerful cytokine storm and hence myocardial injury, which could result in more decline in cardiac function.[21]
Likewise, another study aimed to evaluate cardiac involvement in patients after their recovery from COVID-19 using 2D speckle-tracking echocardiography. It declared that LV systolic function as expressed by ejection fraction was normal. However, LV GLS was significantly lower in COVID-19-recovered patients as compared to controls.[19]
Besides, another study assessed the severity of myocardial dysfunction in 218 COVID-19 patients using 2D speckle-tracking echocardiography. It showed that GLS was reduced in about 83% of patients. GLS reduction was more common in critically ill patients (98% vs. 78.3%, P = 0.001), and GLS was linked to high-sensitive CRP (r = 0.20, P = 0.006) and inflammatory cytokines, particularly interleukin-6 (r = 0.21, P = 0.003). Alterations in myocardial strain values were linked to indices of inflammatory markers and hypoxia, signifying the potential mechanisms involved in the pathophysiology of myocardial dysfunction.[20]
According to our work, a study evaluating 32 COVID-19-hospitalized patients revealed impairment of LV GLS in patients with myocardial injury as manifested by elevated highly sensitive troponin (hsTnT) (−13.9% vs. −17.7% for hsTnT + vs. hsTnT−, P = 0.005) with preserved LVEF (52% vs. 59%, P = 0.074).[22]
In contrast to our results, a retrospective cohort study on 96 critically ill patients diagnosed with SARS-CoV-2 showed that GLS decreased in more than 90% of patients, whereas LVEF and LV volumes were normal. Moreover, there was no significant correlation between GLS and hsTnT levels, whether on initial evaluation, peak value, or at the time of echocardiogram (r = 0.008, P = 0.96, n = 35; r = 0.11, P = 0.46, n = 47; r = 0.21, P = 0.45, n = 15, respectively). These outcomes proposed that patients with SARS-CoV-2 infection might have subclinical LV systolic dysfunction that was not precisely detected by traditional echocardiographic parameters. This study might advocate that LV systolic dysfunction might be related to COVID-19 infection and not only a nonspecific reaction to systemic inflammation, sepsis, or a critical illness.[23] The different results may be related to the different presentation as compared to our work, as most of the patients in that study were critically ill, and most of them required ICU admission (84%), with intubation and/or ventilator support (75%).
Limitations
A single-center study with a relatively small population did not include a follow-up for a longer duration.
Our study was prone to selection bias as it included only mild-to-moderate cases; consequently, our results might not spread over all COVID-19 patients
It is an observational single-group study lacking a cross-matched control group, giving a potential for having confounding variables
Finally, strain analysis was completed using software from a single vendor, so it might not be generalizable to all means of strain calculation.
CONCLUSIONS
Patients with mild-to-moderate COVID-19 infection might have abnormal LV systolic function as measured by GLS in spite of normal LVEF, suggesting that GLS might be a sensitive indicator for cardiac injury in COVID-19 patients. Furthermore, the short- and long-term implications of this outcome for treatment and prognosis are still indeterminate.
Recommendations
Myocardial strain analysis might be a valuable method to identify subtle LV dysfunction and might be validated as a fundamental modality during the echocardiography assessment of patients with COVID-19.
Ethical statement
Ain shams university , Faculty of Medicine, Research ethics Committee (REC) has approved the study (The number is FWA 0000157585).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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