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

Abstract

BackgroundAlström 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.MethodsIn 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.ResultsGlobal 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.ConclusionDiffuse 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.

Prospective Cardiovascular Magnetic Resonance Imaging in Adults with Alström Syndrome: Silent Progression of Diffuse Interstitial Fibrosis.

“…Previous studies have demonstrated that T1 values and ECV are increased in ALMS compared to control subjects. 4,21 These data are consistent with post-mortem histology studies demonstrating both coarse and DIF in adults with ALMS. 1,22,23 Although the data correlating high T1, increased ECV, and histology in ALMS are limited 4 , T1 mapping and ECV on CMR as markers of DIF have been validated histologically in other conditions.…”

“…4,21 These data are consistent with post-mortem histology studies demonstrating both coarse and DIF in adults with ALMS. 1,22,23 Although the data correlating high T1, increased ECV, and histology in ALMS are limited 4 , T1 mapping and ECV on CMR as markers of DIF have been validated histologically in other conditions. [24][25][26] Longitudinal studies have shown T1 mapping to be a robust parameter, with little variability in healthy individuals over time, and in our study, the increase was measured in a single magnet using the same sequence with stable signal con rmed by phantom.…”

“…2 Autopsy data have demonstrated replacement myocardial brosis in non-coronary artery patterns, and diffuse interstitial brosis (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. In many cardiovascular diseases, it has been postulated that the development of DIF over time may be a driver of abnormal myocardial deformation and diastolic dysfunction, leading ultimately to systolic heart failure.…”

Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients

“…Edwards et al [12] found that one-third of 28 AS patients had LGE in a diffuse, non-coronary distribution. Moreover, they used newer T1 mapping techniques to quantify the size of the extracellular volume (ECV) as a more sensitive marker of diffuse fibrosis; half of the patients had an ECV level greater than matched controls.…”

“…Most of those with infantile onset of cardiomyopathy (before age 1) had apparent recovery of cardiac function within 3 years. Histopathology showed diffuse interstitial fibrosis affecting the myocardium, a finding later confirmed by cardiac MRI [11,12]. The mechanism and timing of intra-myocardial fibrosis is not known; in addition to loss of ALMS1 function, the complex metabolic disturbances (severe insulin resistance, activation of the renin angiotensin aldosterone system and increased triglycerides) may all be contributing factors [13,14].…”