European Heart Journal – Case Reports, Volume 7, Issue 9, September 2023

Published: 22 August 2023

Lead Author:

Dr. Gotabhaya Ranasinghe – Senior Consultant in General and Interventional Cardiology at the Institute of Cardiology, National Hospital of Sri Lanka

Contributors:

Dr. Rasika Sovis

Dr. Sajeev Shellvacumar

Dr. Vajira H W Dissanayake

Abstract

Background

Spontaneous coronary artery dissection (SCAD) is increasingly diagnosed as one of the infrequent causes of acute coronary syndrome. Almost no cause was identified in half of the cases. Here, we report a rare case of spontaneous coronary artery dissection with leucoencephalopathy (SCADLE) associated with a mutation of the thrombospondin Type 1 domain containing 1 (THSD1) gene.

Case summary

A 36-year-old lady who presented with ischaemic type chest pain for 4 h duration and found to have anterior ST elevation myocardial infarction. She was thrombolysed with tenecteplase and had good resolution. Her coronary angiogram revealed a spontaneous dissection in the left anterior descending artery (LAD) with TIMI 3 flow. Intra-vascular ultrasound study confirmed the LAD spiral dissection and intramural haematoma. She has had recurrent transient ischaemic attacks 5 years and 7 years ago, and there was a significant family history of young stroke. Her magnetic resonance imaging (MRI) brain showed peri-ventricular white matter hyper-intensities and lacunar infarcts suggestive of leucoencephalopathy. An association with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) and SCAD was suspected, and exome gene sequencing followed by genetic analysis was performed. It identified a variant c.67°C > G (p. Arg224Gly) in the THSD1 gene with normal NOTCH gene.

Discussion

Thrombospondin Type 1 domain containing 1 gene encodes proteins involving in the extra-cellular matrix (ECM). This THSD1 mutation is inherited as an autosomal dominant fashion and associated with arterial dissections (rare), fibromuscular dysplasia, intra-cranial aneurysm, and subarachnoid haemorrhages. Therefore, SCADLE could be a result of arteriopathy secondary to dysfunction of ECM proteins in cerebral and coronary vasculature resulting in neurological manifestations and MRI features like in CADASIL and SCAD.

Learning points

• Young females with myocardial infarction with the absence of risk factors always need to suspect spontaneous coronary artery dissection.
• Treating physicians should be alert on extra-cardiac manifestations or syndromes associated with some of the important cardiac diseases.

Introduction

Spontaneous coronary artery dissection (SCAD) is an infrequent cause of acute coronary syndrome (ACS), but it is becoming increasingly more common. The stressors causing a tear in the intima lead to separation of the intimal lining from the vessel wall, resulting in haematoma formation and extension of the dissection plane, eventually forming a thrombus-filled false lumen. Young women (<50 years) are commonly affected by SCAD, but no definite cause has been identified in roughly 45% of cases. Most identified predisposing factors are post-partum, fibromuscular dysplasia (FMD), connective tissue disease, and hormonal therapy. Extreme physical exertion, intense emotional stress, sympathomimetic drugs (i.e. cocaine and amphetamines), childbirth, and Valsalva-like activities (i.e. coughing, retching, and vomiting) have been identified as potential stressors.

Summary figure

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant cerebrovascular angiopathy that affects young people from 30 to 50 years of age. It commonly starts with migraine but can cause more severe manifestations like transient ischaemic attacks (TIAs) and recurrent strokes. It is characterized by periventricular white matter hyper-intensities on magnetic resonance imaging (MRI). This syndrome is the result of a single missense mutation in the NOTCH 3 gene, which modulates vascular smooth muscle activity. The mutation causes gradual destruction of vascular smooth muscle cells, arteriopathy, and cerebrovascular events due to decreased cerebral blood supply. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy has been associated with SCAD and coronary artery diseases in case reports.

Herein, we present a rare case of a young female patient with a history of recurrent TIAs and a strong family history of stroke, who presented with an anterior ST elevation myocardial infarction (STEMI). Magnetic resonance imaging revealed periventricular white matter changes, similar to the changes observed in CADASIL. Coronary angiogram revealed a spiral dissection of the left anterior descending artery (LAD) with TIMI 3 flow distally without atherosclerotic plaques.

Case presentation

A 36-year-old female presented at a peripheral hospital with ischaemic chest pain for 4 h, described as central tightening that occurred after dinner with autonomic symptoms. Her general examination and cardiovascular physical examination were normal, with stable heart rate and blood pressure. Anterior STEMI was seen on electrocardiogram (ECG). The primary percutaneous coronary intervention (PCI) centre could not be reached within the time limit; therefore, thrombolysis was initiated with intravenous tenecteplase. Post-thrombolysis ECG showed >70% resolution of ST elevations, and the patient was free of chest pain. The initial Troponin I level was 28 µg/L (<0.10), while 2D echocardiography revealed apex, anteroseptal, and anterolateral wall hypokinesis with an ejection fraction of 45%.

After thrombolysis, the patient was transferred to a centre with catheter lab facilities for an angiogram and PCI. Coronary angiogram revealed a spiral dissection of the LAD with TIMI 3 flow without significant plaque burden in the coronary vasculature (Figure 1). An angiographic diagnosis of Type 1 SCAD was made. The intra-vascular ultrasound (IVUS) examination confirmed a spiral dissection of the LAD and a small intramural haematoma (Figure 2).

Figure 1

Coronary angiography revealing long spiral dissection of the left anterior descending artery (Type 1 spontaneous coronary artery dissection).

Figure 2

Intra-vascular ultrasound revealing dissection with haematoma in the false lumen.

This patient has a history of multiple TIAs, specifically 5 and 7 years ago. Each episode lasted for a few minutes with complete recovery. Currently, she has been free of TIAs for the last 5 years and with no residual weakness. Previous MRI scans revealed multiple small infarctions involving the periventricular white matter. She also has a significant family history of stroke as her father and grandfather were affected by strokes. Her carotid Doppler did not reveal any carotid plaques, and her 2D echocardiography excluded cardioembolism. Risk factor screening, including blood sugar, and lipid profile including lipoprotein A levels, homocysteine levels, and autoimmune panel (anti-nuclear antibodies, anti-double stranded deoxyribonucleic acid [dsDNA], and anti neutrophil cytoplasmic antibodies [ANCAs]), were normal. She was then started on long-term single antiplatelet and statin therapy by the neurology team.

The SCAD was managed medically in accordance with the guidelines. The patient was started on dual antiplatelet therapy, statin therapy (due to lower density lipoproteins [LDL] levels of 107 mg/dL), and beta-blocker and angiotensin converting enzyme [ACE]-inhibitor therapies.

Further investigations were conducted to diagnose CADASIL associated with SCAD, considering the background history of recurrent TIAs, repeated MRI evidence of bilateral periventricular white matter hyper-intensities and lacunar infarctions (Figure 3), and strong family history of strokes. At present, her renal, liver, thyroid functions, glycated haemoglobin level, autoimmune panel (antinuclear antibody [ANA], dsDNA, ANCAs), lipoprotein A, and homocysteine levels were normal. A repeat brain MRI showed bilateral deep periventricular white matter ischaemic changes suggestive of leucoencephalopathy. A genetic study was arranged to confirm CADASIL by identifying the NOTCH3 mutation, but exon sequencing with gene mapping revealed a mutation of the thrombospondin Type 1 domain containing 1 (THSD1) gene.

Figure 3

Brain magnetic resonance imaging showing periventricular hyper-intensities (mainly on the left) correlating with small lacunar infarcts (leucoencephalopathy).

After 2 weeks, repeat 2D echocardiography revealed an ejection fraction of 55% with mild apical hypokinesia. The bubble contrast study was negative for shunts. Repeat coronary angiograms done 6 months after the index admission revealed a healing SCAD with small residual dissection in the mid LAD (Figure 4).

Figure 4

Coronary angiography demonstrating healing of the left anterior descending artery dissection after 6 months.

Discussion

Spontaneous coronary artery dissections account for 1−4% of all ACSs and can be categorized into three types. Our patient was diagnosed with Type 1 SCAD (spiral dissection of the artery), which accounts for 29% of all cases. On the other hand, Type 2 and Type 3 SCADs are characterized by focal and diffuse tubular narrowing, respectively, due to intramural haematoma. Majority of SCADs are managed conservatively and do not need intervention. The current guidelines recommend medical management for SCAD patients who are clinically stable and do not have high-risk vessel involvement.

Spontaneous coronary artery dissections can be associated with CADASIL, which results in non-atherosclerotic cerebral vascular angiopathy involving small arteries and capillaries. Similar angiopathies may occur in the coronary vessels, resulting in SCAD and intramural haematomas, eventually causing ACS. This is usually associated with pathogenic variants in the NOTCH3 gene. On the other hand, TSDH1 gene mutations have not been associated with CADASIL in the existing literature.

Despite having clinical and MRI features of CADASIL and SCAD, genetic analysis did not reveal NOTCH3 mutation, thus precluding the definite diagnosis of CADASIL in our patient. Instead, a new mutation was identified in the THSD1 gene variant c.670C > G (p.Arg224Gly), which is an inherited autosomal dominant mutation that can cause neurological symptoms and MRI features similar to CADASIL and SCAD.

The proteins encoded by the THSD1 gene are found in the complement pathway and the extra-cellular matrix (ECM). The THSD1 gene is associated with various diseases such as coronary artery dissections (rare), arterial dissections (rare), FMD, intra-cranial aneurysm (saccular and fusiform), and subarachnoid haemorrhages. Therefore, this clinical syndrome could be a phenotypic presentation of this particular THSD1 mutation.

Conclusion

We present the case of a young female diagnosed with Type 1 SCAD following anterior STEMI and a history of recurrent TIAs, notably with a strong family history of stroke and brain MRI of bilateral periventricular changes. The periventricular leucoencephalopathy and SCAD could be attributed to the THSD1 gene mutation, as it can cause arteriopathy of cerebral and coronary arteries secondary to ECM protein dysfunction. Cerebral arteriopathy could result in periventricular leucoencephalopathy manifesting as strokes or TIAs, and coronary arteriopathy may result in coronary dissections. No such syndrome associated with THSD1 mutation has been described in the literature to date.

Journal Article: Spontaneous coronary artery dissection with leucoencephalopathy associated with thrombospondin Type 1 domain containing 1 gene mutation: a case report