12 research outputs found
Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy
Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized
by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac
death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its
role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM.
Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse
model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8–10). LV tissues were analysed
for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts
(hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy.
Results Lumican mRNA was increased threefold in HCM patients (P 2 = 0.60, P 2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM
(P 2 = 0.28, P = 0.05) and interstitial (R2 = 0.30, P < 0.05) fibrosis. In mice with HCM,
lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates.
Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased
co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM
super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In
these interstitial areas, collagen I deposits located closer to ( 15 nm, P < 0.05), overlapped more frequently with (+7.3%,
P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using
electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures,
resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer ( 8.9%, P < 0.001) collagen fibres.
Conclusions The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of
fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM
Outcome of Alcohol Septal Ablation in Mildly Symptomatic Patients With Hypertrophic Obstructive Cardiomyopathy: A Long-Term Follow-Up Study Based on the Euro-Alcohol Septal Ablation Registry
Background
The long‐term efficacy and safety of alcohol septal ablation (
ASA
) in patients with highly symptomatic hypertrophic obstructive cardiomyopathy has been demonstrated. The aim of this study was to evaluate the long‐term outcomes of mildly symptomatic patients with hypertrophic obstructive cardiomyopathy treated with
ASA
.
Methods and Results
We retrospectively evaluated consecutive patients enrolled in the Euro‐
ASA
registry (1427 patients) and identified 161 patients (53±13 years; 27% women) who were mildly symptomatic (New York Heart Association [
NYHA
] class
II
) pre‐
ASA
. The median (interquartile range) follow‐up was 4.8 (1.7–8.5) years. The clinical outcome was assessed and compared with the age‐ and sex‐matched general population. The 30‐day mortality after
ASA
was 0.6% and the annual all‐cause mortality rate was 1.7%, which was similar to the age‐ and sex‐matched general population (
P
=0.62). A total of 141 (88%) patients had resting left ventricular outflow tract gradient at the last clinical checkup ≤30 mm Hg. Obstruction was reduced from 63±32 to 15±19 mm Hg (
P
<0.01), and the mean
NYHA
class decreased from 2.0±0 to 1.3±0.1 (
P
<0.01); 69%, 29%, and 2% of patients were in
NYHA
class I,
II
, and
III
at the last clinical checkup, respectively.
Conclusions
Mildly symptomatic hypertrophic obstructive cardiomyopathy patients treated with
ASA
had sustained symptomatic and hemodynamic relief with a low risk of developing severe heart failure. Their survival is comparable to the general population.
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Left ventricular dysfunction in arrhythmogenic cardiomyopathy: Association with exercise exposure, genetic basis, and prognosis
Background
Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome.
Methods and Results
We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow‐up 7.6 [interquartile range (IQR), 5.4–10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was −18.8% [IQR, −19.2% to −18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%–0.17%] per 5 MET‐hours/week, P=0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%–0.12%] per year; (P<0.001), and progression was most evident in patients with desmoplakin genotype (P for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0–1.3] per 1% worsening by global longitudinal strain; P=0.02, adjusted for time and previous arrhythmic events).
Conclusions
Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow‐up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow‐up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification
Influence of Septal Thickness on the Clinical Outcome After Alcohol Septal Alation in Hypertrophic Cardiomyopathy
Long-term outcome of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: a Scandinavian multicenter study
Effect of Institutional Experience on Outcomes of Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy
Effect of impaired cardiac conduction after alcohol septal ablation on clinical outcomes:insights from the Euro-ASA registry
Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy:results from the Euro-ASA registry
Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD)
The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor