COVID-19 and atherosclerosis: looking beyond the acute crisis : Emergency and Critical Care Medicine

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COVID-19 and atherosclerosis: looking beyond the acute crisis

Shi, Zhanga,b; Jiang, Yuanliangc; Weir-McCall, Jonathanb; Wang, Ximingd,∗; Teng, Zhongzhaob,e,∗

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Emergency and Critical Care Medicine: March 2022 - Volume 2 - Issue 1 - p 1-4
doi: 10.1097/EC9.0000000000000031
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The novel coronavirus disease 2019 (COVID-19) was firstly reported in Wuhan, China, and eventually identified on December 31, 2019 and remains as an ongoing worldwide pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades human alveolar epithelial cells in the nose and throat mainly through angiotensin-converting enzyme 2 (ACE2),[1] inducing innate inflammation in the lungs largely mediated by pro-inflammatory macrophages and granulocytes. In addition to the acute inflammatory changes in the lung, this inflammatory response has a systemic component which may have implications for atherosclerosis progression and development.

Viral infection and atherosclerosis

The role of viral infection in atherogenesis has been well documented, with viruses able to incite atherosclerosis through multiple pathways.[2] Direct infection of vascular cells has been proven, evidenced by the detection of DNA virus (such as cytomegalovirus, herpes simplex virus, and human papillomavirus) and RNA virus (such as influenza, and human immunodeficiency virus) in atherosclerotic plaques. They can also be atherogenic indirectly through the induction of systemic inflammation. Influenza infection is associated within an increased risk of myocardium infarction.[3] Risk of cardiovascular events is elevated not just in the acute period but for years afterwards. A potential source of this risk can be seen in the progression of coronary artery calcium burden following pneumonia.[4] Randomized control trials[5] have shown influenza vaccines to successfully reduce rates of cardiovascular events demonstrating the impact that these viruses can have on the cardiovascular system. SARS-CoV-2 is likely to have both direct and indirect pathways that promote atherosclerosis development and progression. The systemic response induced by SARS-CoV-2 holds significant potential to accelerate the progression of existing atheroma, destabilize high risk plaques and trigger the formation of new lesions.

The host response to SARS-CoV-2 infection involves several mechanisms. Immune responses are the initial steps elicited in an attempt to eliminate the virus or halt its growth. This response is typically dual phased, with the incubation and nonsevere stage, followed by a severe stage. During the first stage, a specific adaptive immune response is recruited to eliminate the virus and prevent disease progression. However, when the protective immune response is impaired, the virus will propagate with consequent damage of the affected tissues, especially in organs that have high ACE2 expression such as the lung, small intestine, heart, and artery.[6] These damaged cells in turn induce innate inflammation in the lungs largely mediated by pro-inflammatory macrophages and granulocytes. This inflammatory response in the lung may cause acute life-threatening respiratory disorder at the severe stage. At the onset stage, the length of which typically ranges from weeks to months,[7] inflammatory levels remain high. These inflammatory responses can potentially last for a much longer time period as some patients remain/return viral positive and others even relapse after discharge. In addition to causing respiratory compromise, such inflammatory responses might accelerate the development of existing atheroma through various pathways.

Evidence of coronary atherosclerosis development in patients with coronavirus disease 2019 infection

Lung computed tomography (CT) images from 42 patients with confirmed SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) in the General Hospital of Central Theater of the PLA, Wuhan, China, were retrospectively reviewed with approval by the local ethic committee. Multiple CT scans were performed using the Toshiba Aquilion CT system during the hospital stay with the following parameters: tube current, 250 mA; KeV, 120; data collection diameter, 40 cm; slice thickness, 1.2 mm; and acquisition matrix, 512 × 512. Patients with visible calcium nodulus in the coronary artery and with more than 3 CT scans were included. In total, 2 patients met the inclusion criteria with 6 scans in 50 days and 77 days, respectively.

The calcified area was identified using VascularView (Nanjing Jingsan Medical Science and Technology, Ltd.). Signal intensity of pixels enclosed was extracted and normalized to the mean signal intensity of an adjacent corpus vertebrae as,


in which I¯Colcium is the mean signal intensity of extracted pixels and I¯Corpus is the mean signal intensity of adjacent corpus vertebrae. Moreover, the area with Hounsfield unit (HU) ≥130 was calculated and the volume (CaV) was calculated subsequently with the consideration of slice thickness.

Patient 1# (age 54) and patient 2# (age 56) were males. Patient 1# did not have any previous history of cardiovascular disease, including hypertension and diabetes, nor other diseases, for example, hepatitis, and chronic obstructive pulmonary disease, nor smoking history. Similarly, patient 2# had a past history of pulmonary tuberculosis, but no history of cardiovascular disease or risk factors.

Patient 1# was admitted to the hospital with complaints of muscular soreness for 5 days and fever for 2 days. His body mass index was 29.7, blood pressure 120/78 mmHg. This patient was discharged following 22 days as an inpatient, with a follow-up 1 month later. Patient 2# was admitted to the hospital with complaints of fever and dry cough for 4 days, blood pressure 140/100 mmHg, heartbeat 110/min, and breath 22/min. He was discharged after 23 days of hospital care and followed up at 1 week and 2 months.

Both patients had slightly elevated inflammatory levels on admission (Table 1) with increased C-reactive protein and interleukin 6 (IL-6) and decreased T-lymphocyte. They also had a significantly increased level of ferritin. These remained deranged for at least 10 days for patient 1# and 25 days for patient 2#. Patient 2# also had elevated lactate dehydrogenase. Both patients had a minor increase in their blood glucose.

Table 1 - Results of Laboratory Tests
Patient 1# Patient 2#

Blood Reference Range (Adults) On Admission Day 4 Day 10 On Admission Day 7 Day 14 Day 25 Day 35
Hematocrit (%) 40.0–50.0 46.8 40.3 45.0 38.1 38.4 45.0 34.3 30.4
Hemoglobin (g/L) 130–175 154 139 148 135 140 148 116 104
Leucocytes (×109/L) 3.5–9.5 4.6 11.0 6.5 4.7 10.2 6.5 11.6 2.7
Neutrophils 1.8–6.3 3.3 9.5 4.4 3.37 9.42 4.44 10.37 1.68
Lymphocytes 1.1–3.2 0.9 0.72 1.3 0.84 0.34 1.3 0.66 0.78
Monocytes 0.1–0.6 0.4 0.8 0.7 0.42 0.39 0.69 0.58 0.18
Eosinophils 0.02–0.52 0.01 <0.01 0.02 0.03 <0.01 0.02 0.01 0.03
Basophils 0–0.06 0.01 0.01 0.01 <0.01 <0.01 0.01 0.01 0.01
Platelets 125–350 104 122 233 146 194 233 210 174
Prothrombin time (s) 11.5–14.5 11.5 12.1 11.5 12.0
Activated partial-thromboplastin time (s) 22–35 28 28 29 31.9
Glucose (mmol/L) 3.60–6.11 5.90 6.31 6.68 7.03 6.31 6.68 4.97 4.73
D-dimer (ng/mL) 0–500 68 75 71 724
C-reactive protein (mg/L) 0–8.0 13.4 14.2 14.6 47.3 22.9 17.6 46.4 12.1
Lactate dehydrogenase (U/L) 109–225 200 144 158 224 245 247 303 243
Creatine phosphokinase (U/L) 0–195 46 31 14 125 164 152 133 149
Alanine aminotransferase (U/L) 9–50 38 23 24 41 26 24 86 42
Aspertate aminotransferase (U/L) 15–40 40 23 22 34 32 25 59 37
Albumin (g/L) 40.0–50.0 47.6 36.6 33.4 35.0 25.6 25.4 30.7 36.5
Ferritin (ng/mL) 30–400 740 664 744 340 437 891 1812 1443
Total cholesterol (mmol/L) 3.10–5.69 4.10 4.50 4.81 4.14 3.98 3.85 3.62 3.81
Triglyceride (mmol/L) 0.41–1.92 1.91 1.93 1.95 1.21 1.32 1.25 1.17 1.28
High-density lipoprotein (mmol/L) 1.16–1.82 1.22 1.21 1.18 1.53 1.21 1.38 1.26 1.35
Low-density lipoprotein (mmol/L) 2.10–3.10 2.11 2.06 2.15 1.98 2.18 2.15 1.69 2.11
Interleukin-6 (pg/mL) 0.0–7.0 18.0 25.6 10.3 20.7 15.8 7.1 24.6 4.4
T-lymphocyte count (/μL) 955–2860 556 764 835 644 781 825 897 936
B-lymphocyte count (/μL) 90–560 107 137 162 154 161 165 163 159

Multiple peripheral ground-glass opacities (GGO) were present in the lungs bilaterally in both patients (Fig. 1). The extent of GGO initially increased following admission with the new development of solitary and peripheral lesions, and then decreased gradually after treatment, with the development of some interstitial thickening. The peripheral GGO and interstitial thickening were nearly completely resolved on post-discharge follow-up studies. Calcified plaques were present in the left anterior descending (LAD) artery in both patients (Fig. 1). Both the relative signal intensity and calcium volume increased continuously during the follow-up, which implied that the calcium became denser and the lesion became bigger.

Figure 1:
Series of CT images of the 2 patients and the change of coronary calcium score. CT, computed tomography.

It is time to look beyond the acute crisis

Over the follow-up scans, a consistently increased signal intensity and calcium score were observed, suggesting an association between SARS-CoV-2 and the progression of atherosclerosis. The current analysis was performed on nongated and noncontrast CT scans. In the early stages of the COVID-19 outbreak in Wuhan, China, noncontrast low dose CT was used as an alternative to RT-PCR due to limited testing capacity. This technique limits the detection of atherosclerotic lesions to those with calcium. However, the consistently increased signal intensity of calcified tissues during a short period in these 2 patients who did not have significant cardiovascular risk factors deserves serious consideration of the association between SARS-CoV-2 and atherosclerosis. Given the magnitude of the COVID-19 pandemic, the potential of such an effect warrants further evaluation due to the implications for primary and secondary prevention.

The inflammatory process plays a key role in atheroma formation and development.[8] The interaction between SARS-CoV-2 and ACE2 might have a direct impact on atherosclerosis. The level of ACE2 has been shown to be an independent factor associated with major adverse cardiac events in patients with obstructive coronary artery disease. It has been shown that the affinity of SARS-CoV-2 binding to ACE2 is nearly 20-fold higher than that of SARS-CoV,[9] which therefore reduces the level of ACE2 preventing the degradation of pro-atherosclerotic angiotensin II and generation of antiatherosclerotic angiotensin 1–7.[10] Elevated pro-inflammatory factors, for example, macrophages and granulocytes, can be transported physically to existing atheroma through intraplaque neovessels that originate from the vasa vasorum. These intraplaque neovessels are frequently immature and hence more susceptible to leakage. This in turn predisposes to the formation of intraplaque hemorrhage (IPH) accelerating lesion progression. Such IPH can enhance not only the inflammation itself but also the development of vasa vasorum neovascularization by releasing inflammatory cytokines, growth factors, and angiogenic stimuli, in a vicious cycle. Inflammatory cells are also an important source of matrix metalloproteinases (MMPs). MMPs degrade extracellular matrix to facilitate migration and recruitment of cells. Such degeneration weakens the lesion strength resulting in a rupture-prone atheroma. Furthermore, SARS-CoV-2 itself can also be transported into atherosclerosis via neovessels and the subsequent intraplaque reactions have not been investigated.

Scientists and clinicians have learned much about COVID-19 and its pathogenesis. Not all people exposed to SARS-CoV-2 are infected and not all infected patients develop respiratory illness,[11] which suggests that people with different genetic and comorbidity profiles may respond to the infection differently. Several studies have demonstrated that people who have underlying chronic conditions, including cardiovascular and cerebrovascular disease, are more susceptible to both infection and infection-related mortality.[11] Large-scale efforts are underway for the treatment of the acute infection and the design of a vaccine to better contain the virus. These efforts also include the treatment of the potential acute vascular complications of COVID-19 such as in the C-19-ACS trial ( However, we need to be cognizant of the effects that this population-wide infection might have on the acceleration of atherosclerosis, and the possible long-term implications. Studies on the long-term impact of the SARS-CoV-2 infection are required to help better understand the consequences of this on atherosclerosis and the role of preventative therapies.

Conflict of interest statement

Zhongzhao Teng is an Editorial Board member of Emergency and Critical Care Medicine. Zhongzhao Teng is the Chief Scientist of Tenoke, Ltd., Cambridge, UK and Nanjing Jingsan Medical Science and Technology, Ltd., China. The other authors have no conflict of interests to disclose.

Author contributions

Shi Z performed the analysis and drafted the manuscript; Jiang Y collected the data and performed the analysis; Weir-McCall J revised the manuscript significantly; Wang X designed the study and revised the manuscript; and Teng Z designed and supervised the study, and revised the manuscript.


This work is partially supported by British Heart Foundation (PG/18/14/33562), National Institute for Health Research Cambridge Biomedical Research Centre, National Natural Science Foundation of China (81871354, 81571672), the Taishan Scholar Projection, and Academic Promotion Programme of Shandong First Medical University (2019QL023).

Ethical approval of studies and informed consent

Written informed consent was obtained from each patient.




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