Chest pain and Raynaud’s phenomenon after COVID-19 vaccination in a patient previously diagnosed with systemic lupus erythematosus: a case report

Abstract

Background

Cardiovascular events, including pericarditis, myocarditis, and myocardial ischaemia, have been reported as complications following COVID-19 vaccination.

Case summary

A 28-year-old Japanese woman diagnosed 10 years earlier with systemic lupus erythematosus and antiphospholipid syndrome was admitted to our hospital because of chest pain and Raynaud’s phenomenon. She had received a second dose of the COVID-19 BNT162b2 mRNA vaccine 28 days earlier. ¹²³I-β-methyl iodophenyl pentadecanoic acid (BMIPP) and ²⁰¹thallium dual myocardial single-photon emission computed tomography demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle. Coronary angiography revealed normal coronary arteries; additionally, an endomyocardial biopsy was performed. Histopathological evaluation revealed a normal myocardium without cell infiltration. However, immunostaining for the severe acute respiratory coronavirus (SARS-CoV)/severe acute respiratory coronavirus 2 (SARS-CoV-2) spike protein was positive in the small intramural coronary arteries. The administration of azathioprine (50 mg/day) and amlodipine (5 mg/day) and increases in her prednisolone (10 mg/day) and aspirin doses led to improvements in the symptoms of the patient.

Discussion

Our data lead us to speculate that two events in the timeline of the patient, namely, receiving COVID-19 vaccination and the presence of SARS-CoV/SARS-CoV-2 spike protein in small intramural coronary arteries, may be related to the myocardial microangiopathy observed in this patient.

Learning points.

• Cardiovascular events have been reported as complications following vaccination with the COVID-19 vaccine.

• Although the precise mechanisms of microvascular angina following COVID-19 vaccination without COVID-19 infection has not been determined, the presence of SARS-Cov/SARS-Cov-2 spike protein in small intramural coronary arteries may be related to myocardial microangiopathy in this patient.

Introduction

Several severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccines have been proven safe and efficacious in preventing infection by this novel virus.^1–3 Although adverse events, including cardiovascular disease, have been reported after SARS-CoV-2 vaccination, these instances have been rare.^4–6 Reports have described a variety of flare-ups of immune-mediated disease or of new disease onset after SARS-CoV-2 vaccination.⁷ We present a case of chest pain and Raynaud’s phenomenon after COVID-19 vaccination in a patient previously diagnosed with systemic lupus erythematosus (SLE).

Timeline

Date	Event
10 years before	The patient had been diagnosed with SLE and antiphospholipid syndrome and had been in good condition with treatment.
28 days before	The patient had received the second dose of the COVID-19 BNT162b2 mRNA vaccine.
16 days before	The patient presented with Raynaud’s phenomenon and chest pain. Accordingly, then, the dose of prednisolone was increased from 4 to 10 mg/day, and azathioprine (25 mg/day) was added.
7th day	123I-β-methyl iodophenyl pentadecanoic acid (BMIPP) and 201thallium dual myocardial single-photon emission computed tomography demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle.
16th day	Coronary angiography was normal, and an endomyocardial biopsy was performed.
19 days	After the dose of azathioprine was increased from 25 to 50 mg/day, and amlodipine (5 mg/day) was added to the already increased prednisolone (10 mg/day) and aspirin, her symptoms improved.

Case presentation

A 28-year-old Japanese woman, who had been diagnosed 10 years earlier with SLE and the antiphospholipid syndrome, was admitted to our hospital because of chest discomfort and pain and Raynaud’s phenomenon (Figure 1). The condition of the patient stabilized after treatment with prednisolone (4 mg/day) and aspirin (100 mg/day). She had received a second dose of the COVID-19 BNT162b2 mRNA vaccine 28 days prior to hospital admission. She had general fatigue and chest discomfort 8 days after vaccination and visited our hospital 16 days before admission because of symptom progression, chest pain on exertion, and Raynaud’s phenomenon. Subsequently, the dose of prednisolone was increased from 4 to 10 mg/day, and azathioprine (25 mg/day) was added. However, the symptoms did not improve. The patient had no history of smoking or alcohol consumption. On admission, her body temperature was 36.9 °C, heart rate was 84 b.p.m., and blood pressure was 126/81 mm Hg. Further physical examination revealed Raynaud’s phenomenon but no heart murmur, rales, or oedema. Chest radiography revealed normal lung fields and no cardiomegaly (cardiothoracic ratio 0.42). Electrocardiography conducted on admission revealed mild ST depression and inverted T waves in leads II, III, aVF, and V2­–5 (Figure 2A) compared to the previous electrocardiogram (ECG; Figure 2B). Transthoracic echocardiography showed normal findings (left atrial dimension, 27 mm; left ventricular ejection fraction, 61%; thickness of the interventricular septum, 7 mm; thickness of the posterior wall of the left ventricle, 7 mm; left ventricular end-diastolic diameter, 41 mm). Laboratory analysis showed a mild-rise in serum high-sensitivity troponin T, 0.027 ng/mL (< 0.014 ng/mL), and negative RT–PCR for SARS-CoV-2, while other findings were normal. Laboratory data for SLE were normal except for IgG 2266 mg/dL (861–1747; Table 1). During admission, the patient had continuous chest discomfort, but no episodes of chest pain, and the ECG monitor showed no ST elevation, suggesting epicardial coronary vasospasm.

Figure 1.

Reynaud’s phenomenon is seen in the right fingertips of the patient.

Figure 2.

Electrocardiography (ECG) on admission revealing mild ST depression and inverted T wave in leads II, III, aVF, and V2–5 (A) compared to the previous ECG (B).

Table 1.

Laboratory data

WBC	5100/μL	BUN	9 mg/dL
RBC	489 × 104/μL	Cre	0.64 mg/dL
Hb	11.2 g/dL	TP	8.1 g/dL
Plt	246 × 103/μL	Alb	4.0 g/dL
RBC	489 × 104/μL	UA	3.4 mg/dL
Hb	11.2 g/dL	TG	0.69 mmol/L
D-dimer	<0.05 μg/mL	LDL-C	1.94 mmol/L
T-Bil	0.5 mg/dL	HDL-C	1.29 mmol/L
AST	23 IU/L	FPG	4.5 mmol/L
ALT	18 IU/L	HbA1c	5.4%
ALP	35 IU/L	NTproBNP	33.8 pg/mL
LDH	169 IU/L	CRP	0.01 mg/dL
γ-GTP	10 IU/L	IgG	2266 mg/dL (861–1747)
CK	140 IU/L	Anti-dsDNA antibody	<10 IU/mL (<12.0)
hs-TnT	0.027 ng/mL	CH50	34.4/mL (30–46)
Na	140 mEq/L	C3	79.6 mg/dL (73–138)
K	3.5 mEq/L	C4	13.2 mg/dL (11–31)
Cl	104 mEq/L	SARS-CoV-2 PCR (−)

WBC, white blood cell count; RBC, red blood cell count; Hb, haemoglobin; Plt, platelet count; T-Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; γ-GTP, γ-glutamyl transpeptidase; CK, creatine kinase; hs-TnT, high-sensitive troponin T; BUN, blood urea nitrogen; Cre, creatinine; TP, total protein; Alb, albumin; UA, uric acid; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; FPG, fasting plasma glucose; HbA1c, haemoglobin A1c; NT-pro BNP, N-terminal pro-brain natriuretic peptide; CRP, C-reactive protein; SARS-CoV-2 PCR, SARS-CoV-2 polymerase chain reaction;

Cardiac magnetic resonance imaging (CMR) revealed no late gadolinium enhancement (Figure 3A, B) normal T1 mapping (Figure 3C), and normal T2-weighted fat saturated image (Figure 3D). ¹²³I-β-methyl iodophenyl pentadecanoic acid (BMIPP) and ²⁰¹thallium (Tl) dual myocardial single-photon emission computed tomography (BMIPP/Tl SPECT) demonstrated a mild reduction in perfusion of BMIPP in the mid-anterior wall of the left ventricle and a slightly lowered perfusion of BMIPP in the interventricular septum (Figure 3E), suggesting a myocardial lesion. Coronary angiography showed normal coronary arteries, and an endomyocardial biopsy was performed in the right ventricle (taken from the interventricular septum) to exclude myocardial lesions, including myocarditis or other myocardial diseases. Histopathological evaluation revealed a normal myocardium without cell infiltration (Figure 4A). Therefore, we performed immunostaining for a biopsy of the myocardium using antibodies against SARS-CoV/SARS-CoV-2 spike protein to evaluate the relationship between chest symptoms and SARS-CoV-2 vaccination. The small intramural coronary arteries were positive for the antibody (Figure 4B) and negative for complement C4d (Figure 4C). We recommended that the patient should undergo a coronary physiology test for coronary microvascular dysfunction, i.e. a measurement of coronary flow reserve and/or microvascular resistance. However, the patient declined to undergo this test. After the dose of azathioprine was increased from 25 to 50 mg/day along with increased prednisolone dose (10 mg/day), we added aspirin and amlodipine (5 mg/day) for coronary microvascular dysfunction and Raynaud’s phenomenon. Her symptoms (Raynaud’s phenomenon and chest symptoms) gradually improved, and approximately 3 months later, the serum level of high-sensitivity troponin T had returned to normal (0.013 ng/mL).

Figure 3.

Cardiac magnetic resonance imaging (A and B, late gadolinium enhancement image; C, native T1 mapping image; D, T2-weighted fat saturated image). ¹²³I-β-methyl iodophenyl pentadecanoic acid (BMIPP) and ²⁰¹thallium (TL) dual myocardial single-photon emission computed tomography demonstrating mild low perfusion of BMIPP in the mid-anterior wall of the left ventricle (arrows) and slight low perfusion of BMIPP in the interventricular septum (blue circle and red arrow) (E).

Figure 4.

Haematoxylin and eosin staining of myocardial biopsy shows normal myocardium without cell infiltration (A, bars 50 μm). Immunostaining of SARS-CoV/SARS-CoV-2 spike protein is positive in the small intramural coronary arteries (arrow) (B, bars 20 μm) and negative for C4d (C, bars 20 μm).

Discussion

There have been some reports on the link between COVID-19 vaccination and SLE.^8,9 Felten et al.⁸ demonstrated that SLE flare-up was confirmed in 21 (3%) of 696 SLE patients where 343 (49%) patients had received a second dose of the COVID-19 vaccine. Izmirly et al.⁹ reported the occurrence of SLE flare-ups in 9 (11.4%) of 79 SLE patients receiving a second dose of the COVID-19 vaccine, but severe disease flare-ups were rare. In each of these studies, one patient was diagnose with pericarditis as a cardiovascular SLE flare-up.^8,9 However, there are no reports on Raynaud’s phenomenon as an SLE flare-up after COVID-19 vaccination. Moreover, microvascular angina (coronary microvascular dysfunction), previously demonstrated in SLE,^10,11 has not been reported as an SLE flare-up after COVID-19 vaccination. Myocarditis is an adverse event noted after COVID-19 vaccination. CMR, a useful technique for diagnosing myocarditis, revealed normal findings in our patient, and a myocardial biopsy did not show myocarditis. In this patient, BMIPP/Tl SPECT demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle and slightly lowered perfusion of BMIPP in the interventricular septum. An endomyocardial biopsy taken from interventricular septum was positive for SARS-CoV/SARS-CoV-2 spike protein in the small intramural arteries. We have previously reported that BMIPP/Tl SPECT may be useful for detecting coronary microvascular dysfunction.^12,13 Recently, we also reported that myocytes were positive for SARS-CoV/SARS-CoV-2 spike protein in a patient with fulminant myocarditis after the second dose of COVID-19 vaccination.¹⁴ Taken together, these findings imply that SARS-CoV/SARS-CoV-2 spike protein expression following COVID-19 vaccination may disturb small coronary artery function to induce or exacerbate coronary microvascular dysfunction, although the precise mechanism is unknown.

Raynaud’s phenomenon symptoms also improved in the patient after the treatment regimen described above. Using CMR, Mavrogeni et al.¹⁵ demonstrated that the myocardial perfusion reserve index was reduced in patients with Raynaud’s phenomenon. Thus, Raynaud’s phenomenon might also be related to COVID-19 vaccination, although a skin biopsy was not performed to evaluate the presence of the SARS-CoV/SARS-CoV-2 spike protein.

Conclusion

The presence of SARS-CoV/SARS-CoV-2 spike protein in the small coronary arteries of the patient a month after she had received a COVID-19 mRNA vaccine may be related to coronary microvascular dysfunction validated in this patient.

Lead author biography

September 2000, assistant professor, Department of Cardiology, Nagasaki University Hospital; March 2011, associate professor, Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports.