Endothelial dysfunction in a patient with post-covid 19 syndrome and mutation of the MTHFR gene and prothrombin II

Description of Clinical Presentation: A 25-year-old Mexican woman with a history of two pregnancies complicated by threatened miscarriage, the first resulting in preterm delivery, presented for evaluation. Both parents had a history of venous thromboembolism (deep vein thrombosis, DVT). Six months prior, she experienced a viral infection associated with COVID-19 vaccination (ChAdOx1).

She reported a 4-month history of resting chest pain and dyspnea, which progressively worsened with emotional stress and during her menstrual cycle. Elevated anti-SARS-CoV-2 IgG levels (2893 AU/mL) supported the suspicion of persistent immuno-platelet activation, prompting platelet aggregometry. Light transmission aggregometry demonstrated massive hyperaggregation to epinephrine and ADP consistent with platelet hyperreactivity his finding prompted evaluation for primary thrombophilias, which revealed homozygous C677T mutation in the MTHFR gene and heterozygous C97G >A mutation in prothrombin gene (factor II).
Initial treatment of angina included isosorbide; however, it was discontinued due to severe headache. Therapy was switched to calcium channel blockade (diltiazem) under the suspicion of vasospastic angina, but this yielded no significant improvement. Due to persistent symptoms and suboptimal treatment response, endothelial function was assessed by brachial artery flow-mediated dilation

Final treatment consisted of folic acid and vitamin B complex supplementation (due to MTHFR mutation), low-dose aspirin (for sticky platelet syndrome), bisoprolol, and trimetazidine for angina control.

At one-year follow-up, repeat CMR (Figure 3) demonstrated improvement with near normalization of tissue characterization.

Diagnostic Techniques and Their Most Important Findings: Echocardiography (Figure 1) revealed abnormal regional longitudinal strain in the basal anteroseptal wall (-7%) and basal-mid anterolateral wall (-14%, -16%, respectively), with reduced myocardial work in basal and mid-segments (379-1715 mmHg%).

Coronary CT angiography excluded obstructive disease

Cardiac magnetic resonance imaging (Figure 2) revealed a left ventricle with normal morphology and no mobility alterations, with an ejection fraction (LVEF) of 66% and myocardial involvement, elevated global native T1 mapping 1048 ms (ref. < 1000 ms), global T2 mapping 60 ms (ref. ≤55 ms), and extracellular volume (ECV) fraction 32% (ref. < 30%). Late gadolinium enhancement (LGE) demonstrated subepicardial enhancement of the posterior and inferior walls, along with subendocardial perfusion defect with less than 50% transmurality in the septal and inferior walls on first-pass perfusion imaging.

Endothelial function was assessed by brachial artery flow-mediated dilation, which demonstrated a markedly reduced vasodilatory response of 2% (ref. < 7%).

Learning Points from this Case: This case suggests that patients with platelet hyperreactivity, MTHFR (C677T), and prothrombin factor II (G20210A) mutations may be predisposed to developing endothelial dysfunction impairment following SARS-CoV-2 infection in post-COVID-19 syndrome.

Figure 1: TTE with global longitudinal strain (GLS) and myocardial work analysis: Image A: Bull’s-eye plot of peak systolic strain showing segmental reduction in the basal anteroseptal wall (-7%) and basal-mid anterolateral wall -14%, -16%, respectively (Ref. ≤-16%). Image B: Bull’s-eye plot of the myocardial work index demonstrating reduced regional work in basal and mid segments (379-1715 mmHg %), with a global work index of 1457 mmHg%. (Ref. ≤1800 mmHg%). These findings suggest subclinical myocardial dysfunction.
Figure 2: Cardiac magnetic resonance imaging. Image A-C: LGE sequences in short-axis (A and B) and four-chamber (C) views showing subepicardial enhancement in the posterior and inferior walls (yellow arrows), a pattern consistent with non-ischemic myocardial injury of probable inflammatory origin. Image D: First-pass perfusion sequence demonstrating a subendocardial perfusion defect in the septal and inferior walls of the mid-apical segment (yellow arrows), suggestive of ischemia without a clear coronary territory.
Figure 3: CMR T1 native and T2 mapping. Baseline and Follow-up study one year later. Image A and C: Short-axis view of the left ventricle mid segment. Baseline study showing increased relaxation times with focal elevation of native T1 mapping in the anterior wall (1153 ms, yellow arrows) and T2 mapping of 60 ms. Image B and D: Follow-up study performed one year later demonstrates a reduction in anterior wall relaxation times (native T1 mapping 1021 ms, T2 mapping 54 ms).