Persistent troponin elevation in the heart of Fabry disease due to coronary microvascular dysfunction

Abstract

Fabry disease is a rare X-linked lysosomal storage disorder caused by GLA variants leading to α-galactosidase A deficiency. The heterozygous phenotype predominantly affects the heart. We report a heterozygous woman in her 70s with known Fabry disease presenting with chest pain and palpitations despite well-controlled cardiovascular risk factors. High-sensitivity troponin remained persistently elevated. Coronary angiography showed non-obstructive arteries, and echocardiography revealed left ventricular hypertrophy without outflow tract obstruction. In the absence of epicardial disease, troponin elevation was attributed to coronary microvascular dysfunction, underscoring its role as a key mechanism of ischaemic symptoms and ongoing myocardial injury in Fabry disease.

Background

Fabry disease (FD) is an X-linked lysosomal storage disease seen in all racial and ethnic groups, caused by pathological variants of the galactosidase A (GLA) gene that results in the deficiency of α-galactosidase A or α-Gal A activity. ¹ This leads to the excessive deposition and accumulation of lysosomal glycosphingolipids with terminal alpha-galactosyl residues in various tissues including the heart, kidneys, vascular and peripheral nervous systems.^1,2 Classic, or early-onset FD, is characterised by undetectable enzyme levels. Young males typically present with multi-organ involvement and rapid disease progression in the heart, kidneys and nervous system. It is seen in approximately 1:22,000 to 1:40,000 males. Females can also exhibit heterozygous FD despite random X-chromosome inactivation (lyonisation). It FD is associated with low detectable enzyme levels, is often caused by missense mutations and usually limited to cardiac abnormalities. It occurs in around 1:6000 to 1:40,000 females.^1,3

Cardiac glycosphingolipid accumulation leads to gradual left ventricular hypertrophy, valvular pathology, cardiac conduction system defects, epicardial coronary artery disease (CAD) and coronary microvascular dysfunction (CMD).^4,5 FD patients are therefore prone to heart failure, arrhythmias, angina and myocardial infarction. Cardiac troponin I (cTNI) is a reliable biomarker that is proportional to the extent of myocardial muscular damage and is used commonly in clinical situations to investigate myocardial infarctions. cTNI levels have been postulated to be a useful biomarker in assessing myocardial damage from CMD.^6,7 The CARE guidelines have been used for the reporting of this case (Supplemental File 1). ⁸

Case presentation

A lady in her 70 s with heterozygous FD diagnosed on genetic studies in her fifth decade of life presented to the emergency department of a regional hospital with 2 hours of central chest pain with palpitations, diaphoresis and dyspnoea at rest, which was non-radiating and non-pleuritic. In addition to FD, medical history was significant for arterial hypertension, hyperlipidemia, chronic obstructive pulmonary disease and type 2 diabetes mellitus, all of which were well managed. She had recently undergone ablation for atrial fibrillation (AF) and had a primary prevention implanted cardiac defibrillator (ICD) for intermittent non-sustained ventricular tachycardia in the context of moderate left ventricular hypertrophy that was stable on serial transthoracic echocardiography. Medications included candesartan, felodipine, atenolol, metformin, frusemide, ezetimibe, perindopril, indapamide, seretide, salbutamol and migalastat for FD. She had not been on oral anticoagulation since shortly after her AF ablation. She was on long-standing diuretics and maintained on a 1.5 litre fluid restriction due to a previous pericardial effusion. There was no family history of premature CAD, but had 2 sons with classic FD, both on enzymatic replacement. On examination, temperature was 36.7°C, blood pressure 122/92 mmHg, heart rate of 74 bpm, oxyhaemoglobin saturation 97% on room air and respiratory rate of 24 per minute. Her chest was clear, her heart sounds were dual with no murmurs, and there was no peripheral oedema.

Her electrocardiogram (ECG) on presentation showed AF with left ventricular hypertrophy and intermittently paced beats (Figure 1). cTNI was 2060 ng/L (normal <45 ng/L), point-of-care troponin was 0.37 ng/mL (normal <0.05 ng/mL), brain natriuretic peptide 317 ng/L, international normalised ratio of 1.5, prothrombin time of 16s (normal 8–14 s), activated partial thromboplastin time of 30s (normal 23–38 s), fibrinogen of 2.73 g/L (normal 1.80–4.20 g/L) and baseline renal function with creatinine 89 umol/L and estimated glomerular filtration rate (GFR) of 57 (normal >90). Chest X-ray demonstrated no significant cardiomegaly, intact ICD leads, no pleural effusion or signs of pulmonary edema. ICD interrogation showed normal device function with no VT-related therapies being delivered.

Figure 1.

ECG on admission – Atrial fibrillation with intermittent ventricular pacing, LVH (voltage criteria), and deep T wave inversions.

ECG: electrocardiogram; LVH: left ventricular hypertrophy.

High-sensitivity troponins remained moderately elevated throughout admission. A review of serial troponins over the previous 20-month period showed a similar steady trend (Figure 2). Heterophile antibody screening was negative, and renal function had not declined. Transthoracic echocardiography (Figure 3) on admission showed a small left ventricle with an ejection fraction of 55%, severely increased left ventricular wall thickness from base to apex with no evidence of systolic anterior motion of the mitral valve, and no mid-cavitary or left ventricular outflow tract obstruction. Right ventricular size was normal, with a right ventricular systolic pressure of 21 mmHg. There was a small, circumferential pericardial effusion without haemodynamic signs of tamponade. There was no significant valvular pathology. Coronary angiography was performed due to recurrent episodes of cardiac-sounding chest pain while in hospital and showed angiographically normal epicardial coronary arteries, with no change in coronary artery appearances compared to previous angiogram done 9 years prior. (Figure 4). The patient was managed under the cardiology team and discharged with her usual medications with the addition of 2 anti-anginal medications, regular isosorbide mononitrate and a glyceral trinitrate spray, to be used for anginal attacks.

Figure 2.

cTNI levels of different timeframes – from 20 months prior up to latest admission and discharge.

cTNI: cardiac troponin I.

Figure 3.

TTE findings on admission.

TTE: Transthoracic echocardiogram.

Figure 4.

Coronary angiogram findings of LAD, LCX, and RCA – (Left column) Done this admission, (Right column) Done 9 years ago.

LAD: left anterior descending; LCX: left circumflex artery; RCA: right coronary artery.

Differential diagnosis

She was managed in the emergency department as an acute coronary syndrome with dual anti-platelet therapy and anticoagulation. Later, the establishment of the chronicity of cTNI levels in this patient made acute coronary syndrome less suspicious.

Chronic kidney disease and/or an acute kidney injury leading to poor troponin clearance was considered. The history was negative for any new nephrotoxins; furthermore, the investigations demonstrated a steady eGFR, with stable creatinine and urea throughout the course of the admission. Renal indices had been stable.

Macrotroponins and heterophile antibodies can give rise to falsely elevated cTNI through interfering with the assays used in assigned laboratories. However, when suspected, the point-of-care troponin test offered helps to combat these analytical interferences. In this instance, the point-of-care troponin was negative at 0.37 ng/mL, which ruled these out. Formal interference testing was also negative.

Discussion

We report an elderly lady with heterozygous FD, presenting to a regional hospital with chest pain and palpitations with persistently raised cTNI levels, later diagnosed with microvascular angina (MVA) from CMD. Diagnosis fulfilled all Coronary Vasomotion Disorders International Study (COVADIS) criteria: ischaemic symptoms, absence of obstructive CAD on angiography, objective ECG evidence of ischaemia and evidence of CMD demonstrated by coronary slow flow (Thrombolysis in Myocardial Infarction (TIMI) frame count 42 in the left circumflex and right coronary arteries; corrected TIMI frame count 27 in the left anterior descending artery). ⁹

Cardiac involvement included left ventricular hypertrophy without outflow tract obstruction. Although AF contributed to symptoms, it did not explain chronic troponin elevation. Rhythm control was limited by contraindication to amiodarone and avoidance of sotalol and flecainide due to hypertrophy; rate control followed by direct-current cardioversion was pursued. ¹⁰

Patients with FD are at higher risk of epicardial CAD and CMD.^11,12 Glycosphingolipid accumulation secondary to α-galactosidase A deficiency promotes vascular deposition, small-vessel occlusion, ischaemia and infarction.^2,12 The use of enzyme replacement therapy and oral chaperone therapy aims to attenuate this pathological process.^2,13

CMD in FD has previously been demonstrated using invasive measurement of myocardial blood flow and coronary flow reserve (CFR).^2,7 Investigation of CMD requires assessment of coronary vasomotor function beyond conventional evaluation for epicardial CAD. This involves administration of vasoactive agents, including adenosine and acetylcholine, to evaluate endothelial-independent, endothelial-dependent function and vasospasm.^7,14 While invasive physiology remains the reference standard, angiographic coronary slow flow – quantified by TIMI frame count – provides a pragmatic marker of increased microvascular resistance when formal testing (e.g. CFR or microvascular resistance indices) is unavailable, as in this case.^9,15 Non-invasive modalities such as positron emission tomography, stress cardiac magnetic resonance imaging and transthoracic Doppler echocardiography can provide supportive assessment of myocardial blood flow and flow reserve, ¹⁴ but were not accessible due to geographical and regional healthcare limitations.

Alternative causes of persistent troponin elevation, including renal impairment,^1,2,16 macrotroponins and heterophile antibody interference,^3,11 should be considered. Progressive CMD in FD contributes to myocardial fibrosis and adverse remodelling,^1,3 and chronic troponin elevation may reflect ongoing microvascular injury and cardiac involvement. ¹⁷

Conclusion

This case underscores MVA secondary to CMD as an important cause of chest pain and persistent troponin elevation in FD. Application of the COVADIS criteria, supported by angiographic coronary slow flow, enabled objective diagnosis despite the absence of obstructive coronary disease and limited access to advanced testing. Early recognition of MVA by CMD in FD is essential, as ongoing microvascular injury may contribute to progressive cardiac remodelling and adverse outcomes.