Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study

Abstract

Background: Alström syndrome is a rare inherited ciliopathy with progressive multisystem involvement. Dilated cardiomyopathy is common in infancy and recurs or presents de novo in adults with high rates of premature cardiovascular death. Although Alström syndrome is characterised by fibrosis in solid organs such as the liver, the pathogenesis of related cardiomyopathy are not clear. To date it is not known whether diffuse interstitial myocardial fibrosis is present before the onset of heart failure symptoms or changes in conventional parameters of left ventricular function.

Methods: In this observational study, 26 patients with Alström syndrome (mean age 27 ± 9 years, 65 % male, 24 h ABPM 130 ± 14 / 77 ± 9 mmHg) without symptomatic cardiovascular disease were recruited from a single centre and compared to matched healthy controls. All subjects underwent cardiac MRI (1.5 T) to assess ventricular function, diffuse interstitial myocardial fibrosis by measurement of extracellular volume on T1-mapping (MOLLI) and coarse replacement fibrosis using standard late gadolinium enhancement imaging.

Results: Global extracellular volume was increased in Alström syndrome with wider variation compared to controls (0.30 ± 0.05 vs. 0.25 ± 0.01, p < 0.05). Left ventricular long axis function and global longitudinal strain were impaired in Alström syndrome without change in ejection fraction, ventricular size or atrial stress (NT-proBNP) (p < 0.05). Global extracellular volume was associated with reduced peak systolic longitudinal strain (r = -0.73, p < 0.01) and strain rate (r = -0.57, p < 0.01), increased QTc interval (r = 0.49, p < 0.05) and serum triglycerides (r = 0.66, p < 0.01). Nine (35 %) patients had diffuse mid-wall late gadolinium enhancement in a non-coronary artery distribution.

Conclusion: Diffuse interstitial myocardial fibrosis is common in Alström syndrome and is associated with impaired left ventricular systolic function. Serial studies are required to determine whether global extracellular volume may be an independent imaging biomarker of vulnerability to dilated cardiomyopathy and heart failure.

Fig. 1

Box scatter plots of global extracellular volume (ECV) in patients with ALMS and controls. Error bars are standard error of the mean x2. Dashed horizontal line defines the upper value within the matched normal population (0.279). ECV was assessed in the left ventricle from the basal and mid ventricular levels and averaged to yield a “global ECV” measurement. * p <0.05

Fig. 2

Examples of late gadolinium enhancement and corresponding pre-contrast colour T1 maps in patients with ALMS. a Clear late enhancement (arrow) in the basal infero-lateral wall. b Corresponding high T1 (1057 ms) on the T1-map (arrow). c No late enhancement in the left ventricular myocardium. d Corresponding areas with high T1 (1043 ms) on the T1-map in the septum and infero-lateral wall (green)

Fig. 3

Association of diffuse myocardial fibrosis with markers of lipid metabolism, systolic function and cardiac electrical activity. Scatter plots demonstrating the association between global extracellular volume and a) global longitudinal strain, b) global systolic strain rate, c) 12 lead ECG QTc interval and d) serum triglycerides in patients with ALMS

Fig. 4

Myocardial fibrosis on CMR and post-mortem specimens from a patient with ALMS. a-c) 4 chamber CMR imaging; a cine, b late gadolinium enhancement and c T1 mapping. Note the extensive LGE in the RV (*) with corresponding low T1 on the post-contrast MOLLI. d Corresponding macroscopic image from autopsy of the RV with strands of sub-endocardial fibrosis seen as pallor within the RV (black arrow). e-f Corresponding low power views of part of the free wall of the right ventricle demonstrating patchy swathes of interstitial fibrosis replacing myocardiocytes with more subtle pericellular fibrous expansion. The fibrous tissue stains pink with H&E and red with EHVG (H&E & EHVG, original magnification X1.25). g-h Comparable intermediate magnification photomicrographs of the free wall of the right ventricle depicting more dispersed interstitial fibrosis enclaving groups of myocytes and focally insinuating between individual muscle cells. The fibrous tissue stains pink with H&E and red with EHVG (H&E stain, original magnification X1.25)