Progressive myocardial injury in myotonic dystrophy type II and facioscapulohumeral muscular dystrophy 1: a cardiovascular magnetic resonance follow-up study

Aim Muscular dystrophy (MD) is a progressive disease with predominantly muscular symptoms. Myotonic dystrophy type II (MD2) and facioscapulohumeral muscular dystrophy type 1 (FSHD1) are gaining an increasing awareness, but data on cardiac involvement are conflicting. The aim of this study was to determine a progression of cardiac remodeling in both entities by applying cardiovascular magnetic resonance (CMR) and evaluate its potential relation to arrhythmias as well as to conduction abnormalities. Methods and results 83 MD2 and FSHD1 patients were followed. The participation was 87% in MD2 and 80% in FSHD1. 1.5 T CMR was performed to assess functional parameters as well as myocardial tissue characterization applying T1 and T2 mapping, fat/water-separated imaging and late gadolinium enhancement. Focal fibrosis was detected in 23% of MD2) and 33% of FSHD1 subjects and fat infiltration in 32% of MD2 and 28% of FSHD1 subjects, respectively. The incidence of all focal findings was higher at follow-up. T2 decreased, whereas native T1 remained stable. Global extracellular volume fraction (ECV) decreased similarly to the fibrosis volume while the total cell volume remained unchanged. All patients with focal fibrosis showed a significant increase in left ventricular (LV) and right ventricular (RV) volumes. An increase of arrhythmic events was observed. All patients with ventricular arrhythmias had focal myocardial changes and an increased volume of both ventricles (LV end-diastolic volume (EDV) p = 0.003, RVEDV p = 0.031). Patients with supraventricular tachycardias had a significantly higher left atrial volume (p = 0.047). Conclusion We observed a remarkably fast and progressive decline of cardiac morphology and function as well as a progression of rhythm disturbances, even in asymptomatic patients with a potential association between an increase in arrhythmias and progression of myocardial tissue damage, such as focal fibrosis and fat infiltration, exists. These results suggest that MD2 and FSHD1 patients should be carefully followed-up to identify early development of remodeling and potential risks for the development of further cardiac events even in the absence of symptoms. Trial registration ISRCTN, ID ISRCTN16491505. Registered 29 November 2017 – Retrospectively registered, http://www.isrctn.com/ISRCTN16491505

Modulation of Cardiac Fibrosis in and Beyond Cells

The extracellular matrix (ECM) plays important roles in maintaining physiological structure and functions of various tissues and organs. Cardiac fibrosis is the excess deposition of ECM, including both fibrillar (collagens I and III) and non-fibrillar proteins. Characteristics of fibrosis can vary depending on the pathology, with focal fibrosis occurring following myocardial infarction (MI), and diffuse interstitial and perivascular fibrosis mainly in non-ischemic heart diseases. Compliance of the fibrotic tissue is significantly lower than the normal myocardium, and this can compromise the diastolic, as well as systolic dysfunction. Therefore, strategies to combat cardiac fibrosis have been investigated. Upon injury or inflammation, activated cardiac fibroblasts (myofibroblasts) produce more ECM proteins and cause fibrosis. The activation could be inhibited or the myofibroblasts could be ablated by targeting their specific expressed proteins. Modulation of tissue inhibitors of metalloproteinases (TIMPs) and moderate exercise can also suppress cardiac fibrosis. More recently, sex differences in cardiac fibrosis have come to light with differential fibrotic response in heart diseases as well as in fibroblast functions in vitro. This mini-review discusses recent progress in cardiac fibroblasts, TIMPs, sex differences and exercise in modulation of cardiac fibrosis.

Model of hypereosinophilic syndrome in superinvasive opistorchosis. Report I. Liver pathology

Hypereosinophilic syndrome (HES) was modeled in mature Syrian hamsters of both sexes by the means of infecting them with O. felineus metacercariae (100 larvae); there were two superinvasions, of 100 larvae each. The animals were butchered on 10th day after invasion, the first superinvasion and, on 24th day after the second superinvasion. The material (liver) was stained by histological methods, the IHC method was used. The manifestations of HES were revealed: extensive fields of eosinophilic cell proliferates (index – 0.52), the absence of proliferation and differentiation of progenitor cells into elements of cholangio- and hepatocellular diferons (CCD and HCD). After the second superinvasion, a depletion of the liver’s replicative potential was noted: in the areas of infiltrates from eosinophils, the proliferation of connective tissue, diffuse and focal fibrosis were observed.

Overexpression of estrogen and progesterone receptors as indicator of endometrial receptivity disorder in women with early miscarriage

Background ― The endometrial factor is important in miscarriage (MC) pathogenesis. Objective. To perform a morphofunctional evaluation of endometrium in the patients with uncertain MC cause in anamnesis. Material and methods ― We examined 48 women 23-40 yo [30 (27, 35)]: the main group consisted of 33 patients with early MC in their medical history, while the control group included 15 healthy fertile women. All women had an ovulatory menstrual cycle, normal levels of gonadotropic and thyroid hormones, prolactin, and androgens. Ultrasound and hormonal examinations, along with morphological investigation of endometrial biopsies were performed. Data presented as median with lower and upper quartiles – Me (LQ, UQ). Results ― In 64% (n=21) of women in the main group, we detected inferior secretory phase of their endometrial cycle, focal fibrosis of endometrial stroma; synchronous overexpression of estrogen (ER) and progesterone (PR) receptors in endometrial glands and stroma. ER in the glands was 240 (160, 280) vs. 130 (80, 210) in the stroma, while PR values were 270 (210, 290) in the glands vs. 270 (240, 280) in the stroma: differences from the control group were significant (p<0.01). Remaining women in the main group (36%, n=12) and all women in the control group had full secretory transformation of the endometrium and normal expression of ER and PR. The levels of estradiol and PR in the blood of women with early MC in anamnesis, with different variants of ER and PR expression in the endometrium, did not differ significantly from the control group and corresponded to the reference values. Conclusion ― Nearly two-thirds of women with early miscarriage in anamnesis exhibited overexpression of ER and PR in the endometrium, which may be one of the indicators of its decreased receptivity status.

THU0342 DECLINE IN SUBCLINICAL SYSTEMIC SCLEROSIS PRIMARY HEART INVOLVEMENT ASSOCIATES WITH POOR PROGNOSTIC FACTORS AND ACTIVE INTERSTITIAL LUNG DISEASE

Background:Primary systemic sclerosis heart involvement (pSSc-HI) is described in the majority of SSc patients when sensitive methods such as cardiovascular magnetic resonance (CMR) are used1. The natural history of these subclinical findings are unknown.Objectives:To evaluate for interval change in subclinical pSSc-HI, the association between change in CMR abnormalities and disease phenotype and whether disease modifying antirheumatic (DMARD) and/or vasodilator treatment influence the CMR course.Methods:SSc patients, fulfilling the 2013 ACR/EULAR criteria, with no cardiovascular (CV) disease, diabetes and no more than 2 CV risk factors had two CMRs performed (V1 & V2; minimum 1 year apart). A 3T CMR with late gadolinium enhancement (LGE), T1 mapping for extracellular volume (ECV of diffuse fibrosis) quantification and stress perfusion was undertaken.Results:31 SSc patients were evaluated, with median (IQR) follow up (between the 2 CMR scans) of 33 (17, 37) months. Median (IQR) age was 52 (47,60), 32% had diffuse cutaneous SSc, 52% interstitial lung disease (ILD), 29% Scl70+.4/31 patients had a non-ischaemic LGE pattern suggesting focal fibrosis at V1, with no change in the pattern, distribution, or median (IQR) LGE scar mass between V1 and V2 [1.88 (1.01, 6.34) vs 1.70 (1.21, 4.18)]. At V2, 2 additional patients showed focal fibrosis, of which one had an episode of clinically diagnosed myocarditis. No significant change in ECV, T1 native, myocardial perfusion reserve (MPR) or left ventricle (LV) volumes and function were noted at V2 compared with V1 (p>0.01).SSc patients with either increase in pre-existing LGE scar mass (n=1) or new fibrosis were all dcSSc, with ILD, 2 Scl70+. A reduction in forced vital capacity and total lung capacity associated with a reduction in LV ejection fraction (LVEF) (rho=0.413, p=0.021; rho-0.335, p=0.07) and MPR (rho=0.543, p=0.007; rho=0.627, p=0.002).Patients receiving DMARD treatment had higher baseline LV end-diastolic volume compared to those with no DMARD treatment [mean (SD) 78 (19) vs 69 (10), p=0.167]. A decrease in LV stroke volume and an increase in T1 native at V1 vs V2 was noted for those on DMARD [mean (SD) 49 (8) vs 46 (8), p =0.023; 1208 (65) vs 1265 (56), p=0.008 respectively] (Figure 1). No significant change in CMR measures in those receiving vasodilator or angiotensin-converting-enzyme inhibitor treatment was noted (p>0.01).Figure 1.Mean (SD) of T1 native, LVSV/BSA, LVEF, and LVEDV/BSA at V1 compared to V2 in those with and without DMARD treatment. BSA, body surface area; DMARD, disease modifying antirheumatic drugs; EDV, end-diastolic volume; SV, stroke volume; LV left ventricular; EF, ejection fraction.Conclusion:This first, pilot longitudinal study of CMR-defined subclinical pSSc-HI suggests largely stable appearances with follow-up. Progression of new focal fibrosis and decline in LV function and MPR, where observed, associated with poor prognostic factors of SSc and ILD progression. Consistent with this, individuals on DMARD appeared to show interval decline. Larger longitudinal studies are warranted to confirm these findings and inform on utility of CMR monitoring of subclinical pSSc-HI in poor prognosis SSc.References:[1]Ntusi NA et al, J Cardiovasc Magn Reson. 2014Disclosure of Interests:Raluca-Bianca Dumitru: None declared, Lesley Anne Bissell: None declared, Bara Erhayiem: None declared, Graham Fent: None declared, Ananth Kidambi: None declared, Giuseppina Abignano: None declared, John Greenwood: None declared, John Biglands: None declared, Francesco Del Galdo: None declared, Sven Plein: None declared, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi