Effect of Coronavirus Disease-2019 Infection on Left Atrial Functions.

Objective: Left atrial (LA) dysfunction is a crucial risk factor for cardiovascular events, and various pathologies may affect LA function. Coronavirus disease-2019 (COVID-19) is an ongoing global pandemic causing morbidity and mortality. In the present study, we aimed to evaluate LA functions in patients who recovered from COVID-19.
Methods: Sixty consecutive patients recovered from COVID-19 and 60 healthy individuals as a control group were included in the study. Blood samples and echocardiography measurements were obtained from each subject. The two groups were compared in terms of demographic and echocardiographic characteristics.
Results: In the COVİD-19 group, LA maximum volume (LAVmax) (P = 0.040), LA pre-A volume (LAVpre-A) (P = 0.014), and LA active emptying fraction (P = 0.027) were higher, while LA passive emptying fraction (P = 0.035) was lower. In addition, left ventricular ejection fraction (P = 0.006) and isovolumetric relaxation time (P = 0.008) were decreased in this group. Although LA volume index was higher in the COVID-19 group, it does not reach statistical significance.
Conclusion: LA functions may be impaired in patients recovered from COVID-19 infection. Copyright:

INTRODUCTION

Left atrial (LA) function is essential for optimal cardiac performance and regulates left ventricular (LV) filling.[1] LA phasic volumes consist of passive discharge, conduit, and active discharge phases.[23] These phases are measured by electrocardiogram (ECG) with reference to the P, QRS, and T waves endpoints. Maximum volume is measured at the end of LV systole, minimum volume at the end of LV diastole, and LA volume (LAV) before atrial systole.[45] Total, passive and active ejection fractions can be calculated by using these volumes. LA dilatation is a crucial risk factor for cardiovascular events and mortality.[67] Increasing interest in atrial size and function in recent research has shed light on the effects of atrial contribution on cardiovascular performance.

Coronavirus disease-2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), resulting in morbidity and mortality.[8] The impact of COVID-19 infection ranges from self-limited respiratory disease to severe pneumonia, multi-organ failure, and even death.[910] COVID-19 infection is associated with various cardiovascular events, including myocarditis, myocardial damage, arrhythmia, heart failure (HF), and venous thromboembolism.[1112] Myocardial ischemia and necrosis are associated with ventricular dysfunction causing increased mortality.[13]

Despite many studies on COVID-19, its effect on LA functions has not been investigated; in the present study, we examined the effect of COVID-19 on LA functions.

METHODS

Study population

The present research is a prospective, single-center, observational cross-sectional cohort study conducted between November 2020 and January 2021. Sixty consecutive patients recovered from COVID-19 and 60 healthy controls as a control group were included in the study. Laboratory and echocardiography data of the patients were obtained 30 days after symptom onset. Patients were evaluated after recovery of symptoms. Healthy participants were confirmed free of COVID-19 disease by reverse transcriptase-polymerase chain reaction (RT-PCR) testing and computed tomography (CT) imaging. Pulmonary embolism, malignancy, congenital heart disease, moderate-to-severe heart valve disease, nonsinus rhythms, pericardial diseases, presence of a pacemaker, aortic-coronary bypass history, endocrinological diseases, collagen tissue disease, kidney or liver failure, and chronic inflammatory diseases were determined as exclusion criteria. The study was conducted according to the principles of the Helsinki Declaration and approved by the local Ethics Committee.

Demographic and laboratory data

Laboratory analysis was performed by the blood sample taken from the patients after 12 h of fasting. Hypertension (HT), diabetes mellitus (DM), and hyperlipidemia (HL) were defined according to current guidelines.[14] Participants were defined as regular smokers if they had smoked at least one cigarette per day for 5 years or more.[15] Body mass index (BMI) was calculated according to the weight/height (cm)2 formula.

Transthoracic two-dimensional echocardiography

Parasternal and apical images (two-dimensional [2D], M-mode, Doppler echocardiography) were analyzed by two cardiologists blinded to data using an X5 transducer (Philips Epiq7; Philips Healthcare, Inc., Andover, MA, USA) echocardiography device. Echocardiography images were obtained from the left decubitus position, and LV ejection fraction (LVEF) was calculated from apical four-chamber and two-chamber views using the modified Simpson's method.[16] A 3-mm tissue Doppler sample volume was placed on the lateral edge of the mitral annulus in the apical four-chamber view. Early diastolic peak (Em) and late diastolic peak (Am) velocities were measured at the level of the lateral wall annulus. E wave velocity was proportioned to the mean of Em septal and Em lateral, and the E/Em ratio was calculated. LV global longitudinal strain (LVGLS) was determined using 2D speckle tracking echocardiography. Three standard apical views (apical two-chamber (A2C), apical three-chamber (A3C), and apical four-chamber (A4C) views) were obtained. The mean GLS was measured by averaging the peak GLS values of these chamber images. Measurements of LVGLS were performed offline using commercially available software (QLAb) program.

LAVs were measured by the modified Simpson's method from apical four-and two-chamber views using the ECG-guided disc summation technique.[16] The LAV index (LAVI) (ml/m2) was calculated by dividing the LAV by body surface area.

Formulas used in the study:

LA total EF:(LAVmax–LAVmin)/LAVmax

LA passiveEF: (LAVmax– LAVPre-A)/LAVmax

LA active EF: (Vpre-A– Vmin)/Vpre-A.

The variables were defined as follows: LAVmax, the maximum volume of LA just before mitral valve opening; LAV Pre-A, LAV at the beginning of the P wave on ECG; LAVmin, the minimum volume at the time of closure of the mitral valve.

Coronavirus disease-2019 diagnosis

COVID-19 was diagnosed by the RT-PCR method or chest CT according to the guidelines of the World Health Organization and Turkey's Ministry of Health.[1718] According to the manufacturer's protocol, RT-PCR testing was performed using a SARS-CoV-2 (2019-nCoV) qPCR Detection Kit (Bioeksen R and D Technologies Co Ltd). The CO-RADS classification was evaluated in all patients with suspected COVID-19 disease. Nasopharyngeal swab samples were collected from all patients for SARS-CoV-2 RNA extraction, and PCR test positivity was accepted as infection. Patients with a negative test but with typical symptoms and a high probability according to the CO-RADS classification were considered COVID-19 positive.

Statistical analysis

SPSS software package (Version 23.0, SPSS, Inc., Chicago, IL, USA) was used to analyze the data. Since the true incidence of LA dysfunction in COVID-19 patients is unknown, the sample size calculation was obtained based on previous studies and the pilot form of the present study. The sample size was calculated by G Power 3.1 software (test power at 0.80; α error at 0.005; statistical significance level at 0.05, double-sided). The Kolmogorov–Smirnov/Shapiro–Wilk test and visual methods, including probability diagrams and histograms, were applied to assess the assumption of data normality. Homogeneity of variances was checked with Levene's test. Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as percentages. Chi-square or Fisher's exact test was performed to compare categorical groups. Two-tailed Student's t-test was used for normally distributed parameters, while continuous variables without normal distribution were evaluated with the Mann–Whitney U-test. Variables with unadjusted P < 0.05 in univariate analysis were accepted as confounding factors.

RESULTS

The mean age was 41.8 ± 13.4 in the COVID-19 (+) group, 41.6 ± 14.9 in the control group, and 26% of both the groups were male. BMI was higher in the COVID-19 (+) group (P = 0.024). There was no difference between the two groups regarding HT, DM, coronary artery disease, and HL. Smoking was higher in the control group, although it was not statistically significant (P = 0.065). Despite symptomatic improvement, CRP level was higher in the COVID-19 (+) group, (P = 0.017). There was no difference between the two groups in terms of other laboratory findings [Table 1].

Table 1

Comparison of demographic characteristics and laboratory data of COVİD-19 patients and control group

Variables	COVİD-19 (−) (n=60), n (%)	COVİD-19 (+) (n=60), n (%)	P
Age (years)	41.6±14.9	41.8±13.4	0.944
BMI (kg/m2)	27.1±4.81	29.2±4.8	0.024
Gander (male)	26 (43.3)	26 (43.3)	1
Hypertension	14 (23.3)	13 (21.7)	0.827
DM type	4 (6)	7 (11.6)	0.343
CAD	3 (5)	7 (11.6)	0.189
Current smoking	18 (30)	10 (16.7)	0.065
Dyslipidemia	9 (15)	6 (10)	0.291
ACE Inh.	4 (6.7)	5 (8.3)	0.500
ARB	10 (16.7)	6 (10)	0.211
Beta blocker	6 (10)	10 (16.7)	0.283
Statin	6 (10)	8 (13.3)	0.389
CCB	5 (8.3)	6 (10)	0.500
WBC (103/µL)	7.2±1.8	7.2±1.7	0.082
Hemoglobin	13.8±1.4	13.8±1.1	0.889
Gucose (fasting) (mg/dL)	102.2±21	109.6±31.2	0.139
Serum creatinine (mg/dL)	0.81±0.17	0.78±0.19	0.343
eGFR (mL/min/1.73 m²)	101.4±18.7	103.1±18.1	0.639
CRP (mg/dL)*	1.7 (0.68-3.1)	2.7 (1.15-5.19)	0.017

*Median value (25% percentile-75% percentile). Continuous variables were given as mean±SD. SD=Standard deviation, DM=Diabetes Mellitus, CAD=Coronary artery disease, ACE=Angiotensin converting enzyme ınhb., ARB=Angiotensin receptor blockers, CCB=Calcium channel blocker, BMI, Body mass index, Inh=Inhibitor, WBC=White blood cell, CR=C-reactive protein, eGFR=Estimated glomerular filtration rate

In echocardiography parameters, LVEF (P = 0.006), LVGLS (P = 0.006), and IVRT (P = 0.008) were lower in the group with COVID-19 (+). IVCT was decreased, although it does not reach statistical significance. There was no significant difference between the groups in terms of other diastolic parameters [Table 2].

Table 2

Comparison of echocardiographic data of COVİD-19 patients and control group

Variables	COVİD-19 (−) (n=60)	COVİD-19 (+) (n=60)	P
LV EF (%)	64.5±3	62.9±3.3	0.006
LVGLS (-%)	19.1±2.5	17.6±2.5	0.006
IVSD (mm)	9.8±1.9	9.6±1.8	0.767
PWD (mm)	9.3±1.5	9.1±1.4	0.569
IVRT (ms)	81.8±15.4	74.1±15.9	0.008
IVCT (ms)	73.5±16	68.2±14.8	0.066
ET (ms)	269±33.1	265±32.8	0.471
Mitral E (mm/s)	91.1±20.8	89.9±20.2	0.479
Mitral A (mm/s)	13.4±4.2	13.03±3.9	0.323
Mitral Em (mm/s)	13.4±4.2	13.03±3.9	0.560
Lateral Am (mm/s)	10.9±2.8	10.6±3.03	0.536
TAPSE (mm)	21.05±2.8	21.9±4.3	0.208
Mitral E/A	1.16±0.31	1.13±0.36	0.620
Mitral E/Em	7.38±2.9	7.5±28	0.799

LV=Left ventricle, EF=Ejection fraction, LVGLS=Left Ventricular global longitudinal strain, IVSD=Interventricular septum diameter, PWD=Posterior wall diameter, IVRT=Isovolumetric relaxation time, IVCT=Isovolumetric contraction time, ET=Ejection time, TAPSE=Tricuspid annular plane systolic excursion, Em=Early diastolic peak, Am=Late diastolic peak

LA maximum volume (P = 0.040), LA pre-A volume (P = 0.014), LA active emptying fraction (P = 0.027) were higher in COVID-19 group. Although LAVI was higher in the COVID-19 group (23.1 ± 9.6; 25.6 ± 8.8, P = 0.131), it does not reach statistical significance. Similar statistics exist for LA minimum volume (P = 0.055) and LA total emptying fraction (P = 0.088). In addition, LA passive emptying fraction was lower in the COVID-19 group (P = 0.035) [Table 3].

Table 3

Comparison of left atrial functions of COVİD-19 (+) patients and control group

Variables	COVİD-19 (−) (n=60)	COVİD-19 (+) (n=60)	P
LAVmax (ml)	42.2±18.2	49.2±18.5	0.040
LAVpre-A (ml)	26.1±14.7	32.8±14.8	0.014
LAVmin (ml)	16.1±10.6	19.7±9.6	0.055
LAVI (ml/m2)	23.1±9.6	25.6±8.8	0.131
LA total emptying volume (ml)	26.1±10.2	29.5±11.4	0.088
LA total emptying fraction (%)	63.3±12.5	60.3±10	0.152
LA passive emptying volume (ml)	16.1±7.6	16.4±9.5	0.855
LA passive emptying fraction (%)	39.6±14.2	33.9±14.6	0.035
LA active emptying volume (ml)	9.9±7.01	13.07±8.1	0.027
LA active emptying fraction (%)	38.9±17.1	38.8±14.7	0.995

LA=Left atrium, LAVmax=LA maximum volume, LAVpre-A=LA pre-A volume, LAVmin=LA minimum volume, LAVI=LA volume ındex

DISCUSSION

The present clinical study has shown that COVID-19 infection is related to an increase in LAV Max, LAV Pre-A, LA active EF, and decrease in LA passive EF. Although LAVI increased in the COVID-19 (+) group, it did not reach statistical significance.

LAV primarily increases in response to pressure and volume load and may reflect the duration and severity of increased LA pressure. Increased LAV is a risk factor for cardiac events such as AF, congestive HF, stroke, and acute myocardial infarction. Due to decreased arterial compliance, ventricular output decreases as vascular resistance increases.[19] LAV is also an indicator of new HF development independent of LV systolic function.[2021] Therefore, these indicators should be considered in the long-term follow-up of COVID-19 patients. Both LAVI and LA strain have been shown to predict AF and cardiovascular outcomes in outpatients.[22] Although LAVI is known to be associated with cardiovascular mortality and morbidity, decreased LA passive EF is also an independent predictor of cardiovascular morbidity and mortality.[723]

A study conducted on patients who were hospitalized due to COVID-19 showed that infection might affect LA functions. In a way that supports our data, the mentioned study showed that LA function diminished compared to the healthy control group, and it was more pronounced in COVID-19 patients who developed AF. LAVI was lower in COVID-19 patients compared to the control group and was similar in COVID-19 patients with or without AF.[24] Barman et al. found higher LV end-diastolic, LV end-systolic, and LA diameters in patients with severe COVID-19.[25] Unlike these researches, our study was conducted on patients who recovered from COVID-19 and revealed that LA functions continued to deteriorate after the disease process. The deterioration in LA functions in COVID-19 patients may be due to systolic and diastolic dysfunction that develops after systemic inflammation.

The reason for diminished LA functions in patients who recovered from COVID-19 infection is unclear. One possible reason may be increased LV end-diastolic pressure due to subclinical LV systolic dysfunction. LV systolic functions were evaluated with LV EF and LVGLS. In the present study, COVID-19 group had impaired LV systolic functions. This finding is consistent with previous research.[2627282930] According to Zhou et al., 23.0% of COVID-19 patients present with HF.[26] Driggin et al. observed that HF was more common in COVID-19 patients than acute kidney injury and was less common in survivors (51.9% vs. 11.7%) of hospitalized patients. Although the effect of COVID-19 on the cardiovascular system is uncertain, cytokine-mediated myocardial damage, oxygen supply–demand imbalance, microvascular and macrovascular thrombosis, endothelial damage, and direct viral invasion of the myocardium seem to play a role.[3132]

LA function is closely related to LV diastolic functions. At the end of diastole, LA contraction occurs, and blood flow to the left ventricle increases.[33] Thus, impaired LA compliance, conduit volume, or booster pump function theoretically play a substantial role in HF with preserved ejection fraction (HFpEF). LA size is an independent predictor of mortality and morbidity in HFpEF.[3435] LV diastolic function is correlated with the LA active emptying fraction.[36] Murata et al. reported that LA maximum and minimum volumes and LA total EF were associated with LV filling pressures in diastolic dysfunction.[37] LA active contraction augments to compensate for the LV diastolic dysfunction. However, they explained that this compensatory mechanism failed as the LA and diastolic function diminished, resulting in a lower total emptying volume.[38] Chronic LA remodeling is the final step in pressure overload that results in LA dilatation.[39] IVRT and IVCT were decreased in the present study, and there was no difference between other diastolic parameters. However, reduced IVRT and IVCT may impair LA functions by affecting LV diastolic filling. In the autopsy of COVID-19 patients, interstitial mononuclear inflammatory cells and epicardial edema were detected in the myocardium.[40] Whether the intense inflammatory response in COVID-19 causes myocardial edema and consequent diastolic dysfunction is unclear and deserves further investigation. LA dilatation may be a manifestation of prolonged LV diastolic dysfunction or direct endothelial injury of SARS-CoV-2. These findings indicate that care should be taken in terms of diastolic dysfunction in the long-term follow-up of COVID-19 patients.

Systemic inflammation in COVID-19 can cause atrial myopathy resulting in atrial arrhythmia. Atrial tissue stiffness is an independent risk factor and a possible mechanism of AF.[41] COVID-19, in the presence of microvascular edema, causes increased atrial and ventricular tissue stiffness due to valvular heart disease or pulmonary HT. Hemodynamic changes may trigger an immune response related to cardiac inflammation.[4243] Atrial or ventricular pressure overload had been shown to cause an immune activation in the myocardium of rats.[44]

Endothelial cells play a critical role in regulating vascular homeostasis; thus, endothelial dysfunction (ED) is associated with cardiovascular, renal, metabolic, and infectious diseases.[4546] ED is an early pathophysiological feature and independent predictor of cardiovascular diseases.[4748] ED is a common pathophysiological denominator of COVID-19 and cardiovascular diseases such as HT, DM, and obesity that contribute to COVID-19-related deaths. SARS-CoV-2 entry through ACE2 causes downregulation of membrane-bound ACE2 and simultaneous loss of catalytic activity of ACE2 in the RAS system.[49] Therefore, SARS-CoV-2 may reduce angiotensin levels, leading to impaired cardiovascular homeostasis in COVID-19 patients. SARS-CoV-2 can also induce vascular injury.[5051] This finding suggests that the coexistence of ED with direct invasion of SARS-CoV-2 to the vascular system may be responsible for the high mortality of COVID-19. Therefore, ED may play a crucial role in LA remodeling in patients recovered from COVID-19 and may cause LA dysfunction independent of ventricular function.

Limitations

The study was single-center and was conducted with a relatively limited number of patients. Therefore, the causal relationship between LA functions and COVID-19 disease could not be clarified. LA functions were assessed only with 2D echocardiography. The evaluation of LA function with invasive or advanced imaging methods may give better results. Furthermore, studies with large populations are needed to confirm these findings and clarify the underlying mechanisms.

CONCLUSIONS

LA functions are impaired in patients who have recovered from COVID-19.

Ethical clearance

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. This study was reviewed and approved by the Institutional Review Board of Recep Tayyip Erdogan University Ethical Board.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.