Abstract

BackgroundAlström syndrome (ALMS) is a rare ciliopathy characterised by early onset insulin resistance, obesity, and dyslipidaemia and is a model for diseases that have huge social, health and economic impact. Cardiomyopathy develops in the majority, with high rates of morbidity and mortality, the definitive features of which are coarse replacement fibrosis and diffuse myocardial fibrosis (DIF). The pathogenesis of heart failure is thought to involve fibroblast accumulation and expansion of the extracellular matrix with excess protein deposition, leading to distorted organ architecture and impaired contractile function. Consecutive adults with genetically proven ALMS attending the National Centre for Rare Disease in Birmingham, England were studied. All patients underwent serial CMR, echocardiography and venous blood sampling, with computed tomography coronary angiography (CTCA) performed to assess severity of CAD. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis.ResultsIn total, 30/32 adults (63% male; 67% White British) participated. The median age at first scan was 21.3 years (interquartile range: 19.0–32.6) and participants were followed for a maximum of 67 months. Only 4 patients had significant coronary artery stenosis on post-mortem, invasive coronary angiography or CTCA. Mid short axis myocardial T1 times, myocardial extracellular volume, and left ventricular mass increased significantly over time, by an average of 21.8 ms (95% CI 17.4–26.1; p < 0.001), 1.1 percentage points (0.6–1.6, p < 0.001), and 2.8 g/m2 (1.9–3.7; p < 0.001) per year, respectively. These changes were not associated with significant deterioration in myocardial structure or function.ConclusionsThis is the first comprehensive prospective study demonstrating progression of DIF in ALMS over time, although no structural or functional consequences were noted within a median three and a half years’ follow up. Further study is warranted to define whether DIF is a by-stander or the driver to impaired contractile function, heart failure and death.

Highlights

  • Alström syndrome (ALMS) is a rare autosomal recessive cardiomyopathy (OMIM 203800) characterised by multiorgan disease

  • Further study is warranted to define whether diffuse interstitial fibrosis (DIF) is a by-stander or the driver to impaired contractile function, heart failure and death

  • left ventricular (LV) volumes, ejection fraction (EF) and mass were within normal limits for age, sex and body surface area on cardiovascular magnetic resonance (CMR), global longitudinal strain (GLS) was low-normal and six patients (20%) had elevated NT-proBNP (≥144 ng/L)

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Summary

Introduction

Alström syndrome (ALMS) is a rare autosomal recessive cardiomyopathy (OMIM 203800) characterised by multiorgan disease. Autopsy data have demonstrated replacement myocardial fibrosis in non-coronary artery patterns, and diffuse interstitial fibrosis (DIF) has been detected on cardiovascular magnetic resonance (CMR) by elevation in T1 relaxation [3] and increased extracellular volume (ECV) in cross-sectional studies of ALMS [4]. These changes were associated with sub-clinical impairment of left ventricular (LV) function, assessed through change in myocardial strain. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis

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