Assessment of Aortic Stiffness by Transthoracic Echocardiographic in Young COVID-19 Patients.

Background: Deteriorated aortic elasticity is part of the atherosclerotic process. Inflammation is an underlying factor in both COVID-19 and atherosclerosis. Aims and
Objectives: Using aortic elastic properties, we aimed to assess the subclinical indicators of susceptibility to inflammatory atherosclerosis in patients with COVID-19. Materials and
Methods: Out of 194 participants included in this study, 100 were diagnosed with COVID-19 in the last 6 months (60 women and 40 men with a mean age of 34.13 ± 6.45 years) and 94 were healthy controls (55 women and 39 men with a mean age of 30.39 ± 7.21 years). We analyzed transthoracic echocardiographic and aortic stiffness parameters in all participants.
Results: Values of systolic blood pressure (110 [85-140] vs. 110 [80-140], P = 0.037) and pulse pressure (PP) (37 [25-55] vs. 40 [25-55], P < 0.01) were significantly different between the groups. As for laboratory parameters, levels of glucose (97.89 ± 20.23 vs. 92.00 ± 9.95, P = 0.003) and creatinine (0.80 ± 0.13 vs. 0.75 ± 0.09, P = 0.003) were significantly higher in the COVID-19 group. Echocardiographic parameters showed that both groups differed significantly in diastolic aortic diameter (2.42 ± 0.28 vs. 2.31 ± 0.35, P = 0.017), aortic strain (9.66 [1.20-31.82] vs. 12.82 [2.41-40.11], P = 0.025), aortic distensibility (0.502 [0.049-2.545] vs. 0.780 [0.120-2.674], P < 0.01), and aortic stiffness (16.67 [4.19-139.43] vs. 11.71 [3.43-65.21], P = 0.006).
Conclusion: Measurement of aortic stiffness is a simple, practical yet inexpensive method in COVID-19 patients, and therefore, may be used as an early marker for COVID-19-induced subclinical atherosclerosis. Copyright:

INTRODUCTION

Declared as a pandemic by the World Health Organization on March 11, 2020, COVID-19 is an inflammatory disease caused by a novel type coronavirus named severe acute respiratory syndrome coronavirus (SARS-CoV-2) due to its close similarity to the SARS-CoV.[1] Although primarily assumed to affect mainly the respiratory system, it was later found that the virus is capable of adhering to angiotensin-converting enzyme-2 receptors and that arterial and venous endothelial cells of several human tissues may be involved, including oral and nasal mucous membranes, the lungs, small intestine, large intestine, skin, lymph nodes, thymus, bone marrow, spleen, kidneys, and the brain.[2] The levels of pro-inflammatory cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-αα), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII increase as a result of activation and endothelial dysfunction in endothelial cells to which the virus binds.[2]

Vascular damage secondary to diseases can be assessed both morphologically and functionally in daily practice. While imaging methods such as computed tomography, magnetic resonance imaging (MRI), and ultrasonography can be used in morphological assessment, indices that can be used to assess functional abnormalities include arterial stiffness, pressure wave reflection, and endothelial dysfunction.[3] Aortic strain (AS), stiffness index, and distensibility are parameters of local aortic stiffness.[4] In the literature, the relationship between arterial stiffness and inflammation has been shown in healthy individuals, hypertensive patients, and patients with severe chronic inflammatory disease.[5]

Pathological aortic stiffness is associated with hypertension, diabetes mellitus, smoking, obesity, subclinical inflammation, atherosclerosis, Marfan syndrome, dementia, kidney disease, and aging.[67] In addition, studies have shown that increased aortic stiffness may be a marker for cardiovascular morbidity and cardiovascular mortality.[8910] For example, elastic properties of the ascending aorta have been studied after three decades of follow-up in patients who underwent successful repair of the aortic coarctation and compared with patients having rheumatoid arthritis and controls. It was found that the aortic stiffness index was especially higher among a subgroup operated coarctation patients showing a high clinical risk profile for adverse cardiovascular events.[11]

Endothelial dysfunction and increased arterial stiffness occurring in COVID-19 patients are responsible for heart failure, arrhythmias, coronary ischemia, acute coronary syndrome, and stroke pathogenesis.[3]

Our aim in this study was to evaluate the aortic elastic properties measured echocardiographically, in young patients with COVID-19 and healthy young control groups.

METHODS

Study design

This single-centered study was conducted on a total of 194 participants between January 2021 and June 2021. The participants comprised 100 patients and 94 healthy controls, the former of whom were diagnosed with COVID-19 based on microbiological confirmation by reverse-transcription–polymerase chain reaction testing from nasopharyngeal and oropharyngeal samples, following the recommendations of the WHO within the last 6 months. Their age distribution was >18 and <45 years. All of the patients were followed up at home during their illness, with no indication for hospitalization.

Demographic data and laboratory parameters were recorded for all participants. Those with the following conditions were excluded from the study: age >45 years, withdrawal of informed consent, any presence of coronary artery disease, moderate-to-severe valvular disease, left ventricular systolic dysfunction (ejection fraction [EF] <50%), congenital heart disease, moderate-to-severe renal or liver disease, atrioventricular conduction abnormality, thyroid disease, systemic inflammatory disease, electrolytic imbalance, and poor echocardiographic acoustic window. All participants provided informed consent after the approval of the study protocol by the Local Ethics Committee of Abant Izzet Baysal University (approval number: 2021/82). The protocol complied with all ethical guidelines outlined by the 1975 Declaration of Helsinki.

Echocardiographic assessment

A 4-Mhz transducer of Vivid S6 (GE Vingmed, N-3191, Horten-Norway) was used to perform the required echocardiographic procedures. All echocardiograms were obtained using continuous electrocardiogram monitoring with the participants in the left lateral position. We also assessed the mean of three consecutive cardiac cycles and measured left ventricular end-diastolic and end-systolic diameters, left ventricular septum thickness, left ventricular posterior wall thickness, and left atrium diameters. We leveraged a modified Simpson's rule to measure the left ventricular EF. Two-dimensional and pulsed Doppler measurements were based on the American Society of Echocardiography criteria.[12] The ascending aorta was measured by M-Mod echocardiography using a parasternal long-axis view at 3 cm above the aortic valve level. We measured the aortic systolic diameter (AoSD) and aortic diastolic diameter (AoDD) diameters at the maximal anterior motion of the aorta and the onset of the QRS complex, respectively, and recorded them currently. The mean of systolic and diastolic values was obtained after three consecutive measurements.

The aortic stiffness parameters were calculated using the following equations:[13]

Aortic diameter change (ADC): AoSD-AoDD

AS %: ADC/AoDD

Aortic distensibility (cm2 dyn-1 10-3): 2 AS/pulse pressure (PP)

Aortic stiffness index (ASI): (systolic blood pressure [SBP]/diastolic blood pressure)/([ADC]/AoDD).

Statistical analysis

All statistical analyses were conducted using SPSS 20.0 Statistical Package Software for Windows (SPSS Inc., Chicago, IL, USA). The data were presented as the mean ± standard deviation for quantitative variables and as numbers or percentages for qualitative variables. To compare between independent groups, we used Student's t-test for normally distributed quantitative variables, Mann–Whitney's U-test for variables without normal distribution, and Chi-square test for qualitative variables. We conducted Spearman correlation analyses to evaluate correlations between the COVID-19 clinical findings and glucose level, PP, aortic strain, aortic distensibility, and ASI. Values of P < 0.05 were considered statistically significant.

RESULTS

There was no significant difference between the two groups in terms of demographic data. The values of systolic blood pressure (SBP) (110 [85-140] vs. 110 [80-140], P = 0.037) and PP (37 [25-55] vs. 40 [25-55], P < 0.01) were significantly different between the groups. We did not find any statistically significant difference in laboratory parameters except the levels of glucose (97.89 ± 20.23 vs. 92.00 ± 9.95, P = 0.003) and creatinine (0.80 ± 0.13 vs. 0.75 ± 0.09, P = 0.003) [Table 1].

Table 1

Demographic and laboratory variables of the study population

Variables	COVID-19 group (n=100)	Control group (n=94)	P
Demographics
Age (years)	32.94±6.55	31.56±7.17	0.164
Male/female, n (%)	40/60 (40/60)	39/55 (41/59)	0.884
SBP (mmHg)	110 (80-145)	105 (80-140)	0.037
DBP (mmHg)	70 (50-95)	70 (40-100)	0.620
PP	40 (20-55)	30 (20-55)	<0.01
BMI (kg/m2)	25.51±4.33	25.02±4.75	0.450
Hypertension, n (%)	2 (2)	3 (3.2)	0.601
Diabetes mellitus, n (%)	2 (2)	0	0.245
Hyperlipidemia, n (%)	1 (1)	1 (1.1)	0.997
Laboratory parameters
Fasting plasma glucose (mg/dL)	99.50±20.71	91.91±13.93	0.003
Creatinine (mg/dL)	0.80±0.12	0.75±0.12	0.003
Hemoglobin (g/dL)	13.97±1.47	13.92±1.63	0.843
WBC (k/uL)	7.29±2.87	6.90±1.71	0.248
Platelet counts (k/uL)	260±75	252±51	0.339
Total cholesterol (mg/dL)	174.61±34.11	170.40±36.56	0.408
LDL (mg/dL)	95.39±25.45	93.44±32.71	0.642
HDL (mg/dL)	53.55±10.00	54.68±12.61	0.489
TG (mg/dL)	135.41±100.21	130.20±88.53	0.702

SBP=Systolic blood pressure, DBP=Diastolic blood pressure, PP=Pulse pressure, BMI=Body mass index, WBC=White blood cell, LDL=Low-density lipoprotein, HDL=High-density lipoprotein, TG=Triglyceride

Echocardiographic parameters showed that both groups differed significantly in AoDD (2.42 ± 0.28 vs. 2.31 ± 0.35, P = 0.017), aortic strain (9.66 [1.20–31.82] vs. 12.82 [2.41–40.11], P = 0.025), aortic distensibility (0.502 [0.049–2.545] vs. 0.780 [0.120–2.674], P < 0.01), and aortic stiffness (16.67 [4.19–139.43] vs. 11.71 [3.43–65.21], P = 0.006) [Table 2].

Table 2

Echocardiographic measurements of the study population

Variables	COVID-19 group (n=100)	Control group (n=94)	P
Left atrium diameter (cm)	3.04±0.36	2.99±0.35	0.378
LVDD (cm)	4.46±0.47	4.39±0.41	0.250
LVSD (cm)	2.80±0.32	2.78±0.29	0.575
PW (cm)	0.95±0.14	0.95±0.12	0.924
IVS (cm)	0.92±0.16	0.92±0.13	0.784
EF (%)	66.64±5.20	66.50±4.60	0.351
Systolic aortic diameter (cm)	2.68±0.29	2.59±0.34	0.067
Diastolic aortic diameter (cm)	2.42±0.28	2.31±0.35	0.017
ADC	0.26±0.13	0.28±0.12	0.123
Aortic strain	9.66 (1.20-31.82)	12.82 (2.41-40.11)	0.025
Aortic distensibility	0.502 (0.049-2.545)	0.780 (0.120-2.674)	<0.01
Aortic stiffness	16.67 (4.19-139.43)	11.71 (3.43-65.21)	0.006

LVDD=Left ventricular diastolic diameter, LVSD=Left ventricular systolic diameter, PW=Posterior wall, IVS=Interventricular septum, EF=Ejection fraction, ADC=Aortic diameter change

Pearson correlation analysis revealed that the correlations of aortic stiffness and PP were positive with the COVID-19 clinical findings (r = 0.29, P = 0.006 vs. r = 0.40, P < 0.001, respectively) but negative with aortic distensibility (r = −0.36, P < 0.001) [Figure 1].

Figure 1

Comparing aortic stiffness index and distensibility between the COVID-19 group and the control group

DISCUSSION

This study has demonstrated that the aortic elastic properties were higher in COVID-19 patients than in the control group. This may be the first study to demonstrate that the echocardiographic aortic stiffness is significantly higher in this patient group.

Corresponding with the meta-analyses comparing mild and severe COVID-19 patients, where higher glucose levels were found to be correlated with the severity of disease, we have found statistically higher levels of glucose and creatinine in COVID-19 patients compared to healthy subjects.[1415] Such higher glucose levels in COVID-19 patients may result from insulin resistance secondary to an inflammatory storm, increased stress and sympathetic stimulation, and the direct impact of the virus on the pancreas.[16]

Although acute renal damage associated with COVID-19 may be caused by hypoxia, abnormal coagulation, medications, or hyperventilation-induced rhabdomyolysis, a postmortem histopathological examination of renal tissues has revealed direct SARSCoV-2 invasion in 29 patients with COVID-19.[17]

Methods that can determine aortic stiffness include applanation tonometry, brachial–ankle pulse wave velocity (baPWV), carotid–femoral pulse wave velocity (cfPWV), and transthoracic echocardiography (TTE). CfPWV as measured by applanation tonometry is the optimum method for measuring large artery stiffness.[18] However, this method is not recommended for routine practice because of its time-consuming, expensive, and impractical procedure to use in our daily practice. We, therefore, preferred the M-Mode echocardiography in our study to measure the AS, as it offers certain advantages such as being practical, noninvasive, and easily accessible.

According to Stefanadis et al., aortic measurements can be obtained with higher accuracy thanks to high-quality echocardiographic imaging.[19] Considered as an indicator of changes occurring in the aortic wall, aortic stiffness is assumed to reflect any underlying atherosclerosis at multiple levels.[20]

Rodilla et al. attributed the pathological AS to the PP ≥60 mmHg measured at the time of admission in hospitalized COVID-19 patients and considered the former as a predictor of all-cause in-hospital mortality in this patient group.[7]

Although this study was conducted on younger patients and therefore has a milder clinical picture of COVID-19, the PP value in COVID-19 patients was found to be statistically significantly higher than in the control group, which supports our findings. Since advanced age is one of the main risk factors for the AS, this study was designed to include individuals younger than 45 years of age to eliminate the factor of advanced age and therefore to determine only the effects of COVID-19 on aortic elastic parameters.

In another study, the AS determined using baPWV and cfPWV was compared in hospitalized COVID-19 and non-COVID-19 patients. The study showed that the AS was significantly different between the two patient groups. In addition, the PWV was found to be associated with clinical outcomes such as prolonged hospitalization and mortality in COVID-19 patients.[20]

The mechanisms underlying the pathological AS in COVID-19 patients can be explained by either directly an endothelial dysfunction resulting from the binding of this new coronavirus to ACE receptors or indirectly endothelial damage caused by both acute systemic inflammation, oxidative stress, and abnormal cytokine response.[21]

Ratchford et al. found, in their study, lower vascular functions in young patients with COVID-19 compared to young healthy controls, using flow-mediated dilatation (FMD) and cfPWV.[22] They concluded that a significantly lower brachial artery FMD value and higher cf PWV value could be used as a marker for increased risk of cardiovascular disease in patients who had COVID-19 three to 4 weeks before assessment.[22]

Cardiovascular MRI is the other method for the evaluation of regional PWV and cross-sectional area-derived measures of aortic stiffness.[23] However, the disadvantages of this method include that its methodology has not yet been standardized,[22] it is expensive, not easily accessible,[24] and the variability in MRI aortic stiffness measurements.[25]

Raisi-Estabragh et al. performed aortic measurements in their study from both the ascending and descending aorta using MRI to calculate the aortic strain. They investigated aortic distensibility and arterial stiffness index in patients with and without COVID-19, but they did not find a statistically significant relationship.[26]

Vascular functional damage is a more sensitive assessment compared to morphologic damage.[3] Identification of functional damage may allow the detection of vascular damage in the acute phase of exposure due to COVID-19 before morphological signs of damage become more visible. Echocardiographic assessment of local arterial stiffness in COVID-19 patients may be advantageous in the early stages of the atherosclerosis process, as it allows the identification of functional disorders before structural changes occur.

It is known that aortic elastic properties are primarily related to age and arterial hypertension. In the demographic data, study groups did not differ for age, but SBP was slightly but significantly higher in the COVID-19 patients than in the control group. However, it is not possible to match the standard values for SBP with all the categories of the population.[27]

The primary limitation is the single-centered design of this study. Another limitation lies in the fact that the follow-ups in short term cannot allow us to determine the long-term effects of our findings. Yet, another limitation is the failure of generalizing our results to all COVID-19 patients due to a number of reasons including the mild clinical course of our patients without any requirement for hospitalization and our rigid exclusion criteria such as age limit.

CONCLUSION

This study has demonstrated that the arterial stiffness as measured with M-Mod echocardiography may be higher in young COVID-19 patients compared to the control group. In conclusion, measurement of aortic stiffness is a simple, practical yet inexpensive method in COVID-19 patients, and therefore may be used as an early marker for COVID-19-induced subclinical atherosclerosis. We believe that periodic exams of AS may prevent future cardiovascular events in patients with a history of COVID-19. Further studies with larger sample size and longer follow-ups should be considered for better clarification of the possible cardiovascular effects in such patients.

Ethical clearance

The study was conducted according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects involved in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors report no conflict of interest.