Coronavirus disease (COVID-19) has recently been added to the medical literature and has affected millions of people.¹ Although COVID-19 was identified as a respiratory system disease in the early stages of the pandemic, it is now considered a multisystem disease.² Various clinical manifestations related to endothelial cell dysfunction, autonomic nervous system damage, and microvascular and lung tissue damage can be observed in the early or late stages of COVID-19.³ A recent study showed that endothelial cell damage may result in impaired arterial wall function and consequently reduced or impaired aortic elasticity within 3 to 6 months in COVID-19 survivors.⁴ Another recent study showed that impaired cardiac performance can be seen as a result of loss of endothelial and vascular function due to COVID-19.⁵

Lipoprotein(a) [Lp(a)] consists of low-density lipoprotein particles.⁶ Lp(a) is present in humans at low and stable levels and may increase during infections due to cytokine storm and various mechanisms.⁷ Lp(a) can cause oxidized phospholipids to accumulate in the arterial wall, causing inflammation and resulting in loss of function in endothelial cells.⁸ The pulmonary artery (PA) to ascending aorta (Ao) ratio (PA:Ao ratio) has been analyzed by various imaging modalities such as cardiac magnetic resonance and computed tomography (CT).^9,10 The PA:Ao ratio has been shown to be associated with various clinical conditions such as the presence and severity of pulmonary hypertension,¹¹ right ventricular outflow tract arrhythmias,¹² and prognosis of advanced heart failure.¹³ Additionally, the PA:Ao ratio has been shown to be correlated with clinical outcomes in patients with COVID-19.¹⁴

There are no studies in the literature examining the relationship between the Lp(a) levels measured at the time of diagnosis and the PA:Ao ratio in survivors of COVID-19 within 3 to 6 months. Therefore, the aim of this study was to investigate whether this relationship exists.

This study was conducted in a tertiary health center, and it included 100 patients who recovered from COVID-19 in the past 3 to 6 months. Patients with positive polymerase chain reaction (PCR) test for COVID-19 were included in the study. Combined throat/nose swabs were taken for PCR tests in accordance with the instructions of the Turkish Ministry of Health and the World Health Organization. Patients infected with SARS-CoV-2 confirmed by PCR were followed up in the intensive care unit (ICU) or general care (outside ICU).¹⁵

After receiving written informed consent, biochemical and hemogram parameters were acquired from peripheral blood samples taken at the time of hospitalization using standard laboratory techniques.

Patients with any of the following criteria were excluded: renal disease (estimated glomerular filtration rate < 30 mL/min/1.73 m²); heart failure with reduced left ventricular function (left ventricular ejection fraction ≤ 40%); contraindications for thromboprophylaxis; malignant disease; abnormal liver dysfunction (alanine aminotransferase and aspartate aminotransferase > 3 times the upper limit of normal); cerebrovascular disease; chronic atrial fibrillation or atrial flutter; history of heart attack; history of coronary artery bypass surgery; moderate or severe heart valve stenosis or insufficiency; connective tissue diseases; ascending Ao > 40 mm; prosthetic heart valves; bicuspid aortic valve; using cholesterol-lowering drugs; systemic lupus erythematosus; rheumatoid arthritis; using oral contraceptives, steroids, or monoclonal antibody drugs; endocrine diseases that may affect Lp(a) levels, such as familial hypercholesterolemia; pulmonary hypertension; chronic thromboembolic pulmonary hypertension; presence of congenital heart defect; younger than 18 years of age; and poor echocardiographic window.

The study received approval from the Ethics Committee (Decision no: 2022-YÖNP-0068). The study was performed in accordance with the Declaration of Helsinki.

The study consisted of 100 COVID-19 survivors (52 men and 48 women). The mean age of the patients was 56.01 ± 13.85 years (Table 1).

All patients needed nasal oxygen support. In 15 patients, oxygen support was provided by non-invasive mechanical ventilation or high-flow nasal cannula. Oxygen support was provided by orotracheal intubation in 2 patients, and 8 patients were admitted to the ICU (Table 2).

Table 3 shows the patients’ baseline and follow-up control echocardiographic parameters. When the baseline and follow-up echocardiographic parameters were analyzed, a significant difference was found in the values of PA (23.35 ± 2.51 mm and 25.55 ± 2.51 mm, p < 0.001), Ao (30.02 ± 2.53 mm and 31.92 ± 2.53 mm, p < 0.001), EAT (5.23 ± 0.82 and 6.10 ± 0.79, p < 0.001), and the PA:Ao ratio (0.77 ± 0.05 and 0.80 ± 00.4, p < 0.001).

While no relationship was found between ΔEAT, ΔPA, ΔAo, ΔPA:Ao ratio, and age and time elapsed since COVID-19 diagnosis, these variables were correlated with D-dimer, high-sensitivity cardiac troponin, and Lp(a). In particular, a strong correlation was observed between Lp(a), ΔPA:Ao ratio (r = 0.628, p < 0.001), and ΔEAT (r = 0.633, p < 0.001) (Table 4). The main findings are summarized in the Central Illustration.

The key findings of the present study were: (1) There was an increase in pulmonary and aortic diameters and EAT thickness in survivors of COVID-19; (2) A strong correlation was found between Lp(a) values measured at the time of COVID-19 diagnosis and ΔPA:Ao and ΔEAT obtained by echocardiographic imaging.

Although the respiratory system is the main target of SARS-CoV-2, deaths may be related to multiple organ damage including the heart, nervous system, and kidneys.¹⁷ The spike proteins found on the envelope of SARS-CoV-2 are the specific receptor of angiotensin converting enzyme-2 (ACE-2) in the host cell.¹⁸ High levels of ACE-2 expression have been detected in cardiac and vascular tissues, and the increase in ACE-2 expression plays a key role in facilitating virus entry into cells and subsequent cellular damage.¹⁹ Detection of diffuse thrombosis and intracellular virions in lung tissues in autopsy studies has been associated with severe endothelial damage.²⁰ Thromboembolic events such as myocardial infarction and deep vein thrombosis have been reported in patients with COVID-19 and are serious clinical endpoints of endothelial damage.²¹ Since the inner surfaces of blood vessels are covered with endothelial cells, these findings suggest that COVID-19 may directly or indirectly cause endothelial dysfunction. Endothelial damage can occur directly due to SARS-CoV-2 itself or secondary to the inflammatory process.²² Increased levels of interleukin-6 during the disease increase hepatic apo(a) synthesis, resulting in increased circulating Lp(a) levels.²³ It has been reported that Lp(a) may be an indicator of clinical outcomes in patients with COVID-19, as seen in previous studies.²⁴ This is the first such study in the literature, and it provides important information about the relationship between Lp(a) levels at the time of diagnosis and changes in PA and Ao diameters in patients with COVID-19.

PA dilatation is associated with poor prognosis in various lung diseases, such as interstitial lung fibrosis and chronic obstructive pulmonary diseases.^25,26 In a recent study, PA diameter measurements were made after hospitalization in patients with COVID-19 with CT, and it was reported that the increase in PA diameter could be a prognostic marker used to detect severe cases.²⁷ The present study showed that a specific cardiovascular risk marker such as Lp(a), especially during the disease, may be associated with PA diameter change in the long term in survivors of COVID-19. Previous studies have shown that approximately half of patients with COVID-19 have increased Ao diameter secondary to heart damage and severe inflammation. The studies have also stated that this may be due to the vascular endothelial damage triggered by COVID-19.²⁸ These findings suggest that increased PA and Ao diameters are associated with poor prognosis in patients with COVID-19. One of the key aspects of the present study is that it showed differences in PA and Ao diameters and the PA:Ao ratio in the long term among patients who survived COVID-19, and the relationship of these values with Lp(a) measured at the time of diagnosis was further investigated. It has been shown that PA diameter of 48 mm and above is a predictor of both unexpected death and all-cause mortality in patients with pulmonary hypertension.²⁹ Several studies have reported an association between PA:Ao ratio of 1.0 or greater with adverse events in patients with pulmonary hypertension.^30,31 However, the cut-off value obtained may not be accurate due to the fact that various factors such as ethnicity, age, and lifestyle, may differ between patient groups and studies. In fact, in a recent study, the PA: Ao ratio in COVID-19 patients was higher in those who lost their lives in the hospital compared to those who were discharged, but the ratio was found to be below 1.³² As seen in the present study, a higher PA:Ao ratio was obtained in a certain number of patients after discharge.

EAT is an important known risk factor associated with vascular structures, and it has been shown to be associated with aortic elasticity independent of blood sugar in diabetic patients.³³ In another study, increased EAT volume was shown to be associated with abdominal aortic aneurysm.³⁴ In a recent study, EAT was shown to be an independent risk factor for disease severity and mortality in patients with COVID-19, independent of obesity.³⁵ In the present study, in addition to the correlation between the PA: Ao ratio and Lp(a), there was also an increase in EAT thickness and this increase was found to be correlated with Lp(a). When these results are taken into consideration, baseline Lp(a) levels can be used as a predictor in the assessment of cardiopulmonary risk in COVID-19 survivors.

The pathogenesis of the effects of COVID-19 on the cardiopulmonary system is unclear, and there are serious adverse effects. COVID-19 can cause adverse changes in the aortic and pulmonary vascular walls. This is the first study in the literature to show a strong correlation between Lp(a) levels at diagnosis and ΔPA:Ao and ΔEAT in COVID-19 survivors.