Results of a recent prospective cohort observational study have revealed that diffuse interstitial myocardial fibrosis is common in Alström syndrome (ALMS), though not universal. The results were recently published in Orphanet Journal of Rare Diseases. The study’s first author is Nicola C Edwards, PhD, of the University of Birmingham, UK.
ALMS is a rare autosomal recessive disorder caused by a mutation in the ALMS1 gene. The gene codes for a ciliary protein, causing a syndrome with great variability in onset and severity of symptoms. Characteristics of the condition include cone-rod dystrophy, hearing loss, and metabolic disturbances such as severe insulin resistance and type 2 diabetes, hypertriglyceridemia, and activation of the renin angiotensin aldosterone system.
The condition also causes fibrosis in multiple organs, leading to dilated cardiomyopathy and progressive lung, liver, and kidney dysfunction. The mechanism of the development of fibrosis in ALMS is unknown; it may result from a primary genetic defect or as a byproduct of its metabolic disturbances, all of which can contribute to fibrosis.
Two main presentations of heart dysfunction occur in individuals with ALMS. About half of people with ALMS have an acute dilated cardiomyopathy as infants. In survivors, this process appears to be fully reversible, with no persisting signs of heart dysfunction via clinical signs or imaging. Later in adolescence or adulthood, dilated cardiomyopathy and congestive heart failure occur in roughly two thirds of individuals with ALMS, equally including both those who did and did not previously have infantile disease. Before this research, it was not known whether interstitial cardiac fibrosis was present in adult ALMS patients without cardiac symptoms.
In this present study, the authors chose to obtain more detailed information about cardiac fibrosis and other heart function markers in ALMS. Twenty-six adults with ALMS participated in the study out of the National Center for Rare Disease at Queen Elizabeth Hospital in Birmingham, UK. None of the subjects had symptomatic heart disease.
The subjects underwent contrast enhanced cardiac MRI with late enhancement imaging, an imaging technique that detects pattern of disease in the heart, including reparative fibrosis. The researchers also utilized T1 mapping, an imaging technique that is better able to detect diffuse fibrosis. They also collected a number of biochemistry markers and electrocardiogram readings.
Interstitial diffuse fibrosis was evident in over 50% of the ALMS subjects. Ventricular size and ejection fraction were not significantly different from the healthy controls. The ALMS subjects with fibrosis did, however, show reduced left ventricular deformation and diastolic function as well as increased QT intervals on electrocardiogram.
Table – Cardiac MRI Functional and Fibrosis Data
EDV end-diastolic volume, ESV end-systolic volume, EF ejection fraction, LA left atrium, LGE late gadolinium enhancement, long; longitudinal, LV left ventricle, MAPSE mitral annular plane systolic excursion, RV right ventricle, TAPSE tricuspid annular plane systolic excursion, SS systolic strain, SR systolic strain rate, ESR early diastolic strain rate, ULN ECV above the upper limit (0.279) observed in matched control. aP < .05, Bonferroni post-hoc tests for differences ECV above upper limit of normal controls vs. increased ECV no LGE bP <.05, Bonferroni post-hoc tests for differences. ECV above upper limit of normal controls vs. increased ECV with LGE. ANOVA * P <.05, ** <.01, ALMS vs. controls
All of the patients showed metabolic derangements, which included insulin resistance, elevated triglycerides, and low HDL levels. Notably, NT-proBNP levels were above normal in only two patients, raising the possibility that surveillance for cardiomyopathy using this marker may not be effective. The level of triglycerides positively correlated with the degree of fibrosis, and the authors suggest it may be one of the mediating factors. The researchers found no correlation with infantile cardiomyopathy disease and later fibrosis, consistent with previous studies.
Figure – Examples of Late Gadolinium Enhancement and Corresponding Pre-Contrast Color 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)
The authors note that not all the patients showed evidence of myocardial fibrosis. The authors also suggest that the fibrosis and other cardiac abnormalities often seen in ALMS do not appear to be an inevitable consequence of the genetic defect, and that environmental conditions seem to play a critical role. Better management of metabolic derangements in ALMS might lead to improved patient outcomes.
Understanding ALMS may have further implications for other more common conditions as well. The authors explain that there has already been a great deal of research interest in understanding ALMS as a single-gene model for end-organ fibrosis. The authors also note, “
[ALMS] offers a model of disease processes, including metabolic syndrome, which are of increasing importance to a much wider population.”
Edwards NC, Moody WE, Yuan M, et al. Diffuse left ventricular interstitial fibrosis is associated with subclinical myocardial dysfunction in Alström Syndrome: an observational study. Orphanet J Rare Dis. 2015;10:83. http://www.ojrd.com/content/10/1/83.