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Journal of Medical Genetics | 2005
Nicolas Sylvius; Zofia T. Bilinska; John P. Veinot; Anna Fidziańska; Pierrette M. Bolongo; S. Poon; P. Mckeown; Ross A. Davies; K.-I. Chan; Anthony Sl Tang; S. Dyack; Jacek Grzybowski; Witold Rużyłło; Heidi M. McBride; Frédérique Tesson
Context: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood. Methods and results: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern. Conclusion: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.
Basic Research in Cardiology | 2010
Pallavi Gupta; Zofia T. Bilinska; Nicolas Sylvius; Emilie Boudreau; John P. Veinot; Sarah Labib; Pierrette M. Bolongo; Akil Hamza; Tracy Jackson; Rafał Płoski; Michał Walski; Jacek Grzybowski; Ewa Walczak; Grzegorz Religa; Anna Fidziańska; Frédérique Tesson
Major nuclear envelope abnormalities, such as disruption and/or presence of intranuclear organelles, have rarely been described in cardiomyocytes from dilated cardiomyopathy (DCM) patients. In this study, we screened a series of 25 unrelated DCM patient samples for (a) cardiomyocyte nuclear abnormalities and (b) mutations in LMNA and TMPO as they are two DCM-causing genes that encode proteins involved in maintaining nuclear envelope architecture. Among the 25 heart samples investigated, we identified major cardiomyocyte nuclear abnormalities in 8 patients. Direct sequencing allowed the detection of three heterozygous LMNA mutations (p.D192G, p.Q353K and p.R541S) in three patients. By multiplex ligation-dependant probe amplification (MLPA)/quantitative real-time PCR, we found a heterozygous deletion encompassing exons 3–12 of the LMNA gene in one patient. Immunostaining demonstrated that this deletion led to a decrease in lamin A/C expression in cardiomyocytes from this patient. This LMNA deletion as well as the p.D192G mutation was found in patients displaying major cardiomyocyte nuclear envelope abnormalities, while the p.Q353K and p.R541S mutations were found in patients without specific nuclear envelope abnormalities. None of the DCM patients included in the study carried a mutation in the TMPO gene. Taken together, we found no evidence of a genotype–phenotype relationship between the onset and the severity of DCM, the presence of nuclear abnormalities and the presence or absence of LMNA mutations. We demonstrated that a large deletion in LMNA associated with reduced levels of the protein in the nuclear envelope suggesting a haploinsufficiency mechanism can lead to cardiomyocyte nuclear envelope disruption and thus underlie the pathogenesis of DCM.
Journal of Cardiac Failure | 1996
Jacek Grzybowski; Zofia T. Bilińska; Witold Rużyłło; Witold Kupść; Ewa Michalak; Danuta Szcześniewska; W. Poplawska; Rydlewska-Sadowska W
BACKGROUND Dilated cardiomyopathy, a heart muscle disease of unknown cause, is characterized by high mortality and is a major cause of cardiac transplantation. It has become, therefore, increasingly important to identify patients at higher risk. The aim of this study was to assess which of the data obtained at the time of diagnosis are the best predictors of survival. METHODS AND RESULTS One hundred forty-four patients with dilated cardiomyopathy (118 men; mean age, 39 years) were assessed clinically, noninvasively, and hemodynamically. The effect of variables derived from the evaluation on outcome (death or heart transplantation) was examined. During a mean follow-up time of 4.1 years, 68 patients (47%) died and 9 (6%) underwent heart transplantation. The 1-, 2-, and 5-year transplant-free survival rate was 79, 69, and 44%, respectively. Cox multivariate regression analysis identified three variables as independent predictors of outcome: (1) pulmonary artery systolic pressure, P = .0001; (2) left ventricular ejection fraction, P = .0013; and (3) left ventricular end-diastolic dimension, P = .007. The prognostic index was constructed from regression coefficients and parameters significant in the Cox model. The minimal prognostic index in the study group was 1.4 and the maximal was 6.0 with a corresponding 1-year survival of 98 and 18%, respectively. The validity of the prognostic index was tested in the consecutive group of 81 patients, who were followed for a mean 2.3 years. The prognostic index of the poor outcome group differed significantly from that in survivors (3.7 vs 2.9, respectively, P < .01). The sensitivity and specificity of model predictions were 68 and 52%, respectively. CONCLUSIONS The severity of pulmonary hypertension and left ventricular dysfunction provides an independent insight into the prognosis of patients with dilated cardiomyopathy. The prognostic index is useful when assessing prognosis and may be helpful in the timing of heart transplantation.
BMC Medical Genetics | 2015
Grażyna Truszkowska; Zofia T. Bilińska; Joanna Kosińska; Justyna Śleszycka; Małgorzata Rydzanicz; Małgorzata Sobieszczańska-Małek; Maria Franaszczyk; Maria Bilińska; Piotr Stawiński; Ewa Michalak; Łukasz A. Małek; Przemysław Chmielewski; Bogna Foss-Nieradko; Marcin M. Machnicki; Tomasz Stoklosa; Joanna Ponińska; Łukasz Szumowski; Jacek Grzybowski; Jerzy Piwoński; Wojciech Drygas; Tomasz Zieliński; Rafał Płoski
BackgroundIn humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients.MethodsWe studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction.ResultsWe detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied.ConclusionsIn Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9thPLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.
Journal of the Neurological Sciences | 2008
Anna Fidziańska; Zofia T. Bilinska; Frédérique Tesson; Teresa Wagner; Michał Walski; Jacek Grzybowski; Witold Rużyłło; Irena Hausmanowa-Petrusewicz
OBJECTIVE The aim of our study was to perform an immunohistochemical and ultrastructural analysis of the nuclear architecture of cardiomyocytes from an end-stage DCM patient with a missense point mutation in the exon 3 of the LMNA gene which is predicted to result in a D192G substitution. METHODS We studied endomyocardial biopsy samples taken from the right ventricle by immunostaining using antibodies against the lamins A and C and by electron microscopy. The cardiomyocyte ultrastructure was analysed, with particular attention to the nuclear architecture. RESULTS Thirty percent of cardiomyocyte nuclei from the D192G carrier showed chromatin disorganization and a changed nuclear shape. The most surprising finding was the appearance of sarcoplasmic organelles within the nuclear matrix of well enveloped nuclei. To our knowledge, this intriguing phenomenon was observed for the first time in cardiomyocytes. CONCLUSION The study documents that D192G mutation in LMNA gene may lead to the disruption of the nuclear wall in cardiomyocytes, thus supporting the mechanical hypothesis of dilated cardiomyopathy development in humans, which might be mutation-specific.
PLOS ONE | 2017
Maria Franaszczyk; Przemysław Chmielewski; Grażyna Truszkowska; Piotr Stawiński; Ewa Michalak; Małgorzata Rydzanicz; Małgorzata Sobieszczańska-Małek; Agnieszka Pollak; Justyna Szczygieł; Joanna Kosińska; Adam Parulski; Tomasz Stoklosa; Agnieszka Tarnowska; Marcin M. Machnicki; Bogna Foss-Nieradko; Małgorzata Szperl; Agnieszka Sioma; Mariusz Kusmierczyk; Jacek Grzybowski; Tomasz Zieliński; Rafał Płoski; Zofia T. Bilińska
TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.
BMC Medical Genetics | 2013
Michal Saj; Zofia T. Bilińska; Agnieszka Tarnowska; Agnieszka Sioma; Pierrette Bolongo; Małgorzata Sobieszczańska-Małek; Ewa Michalak; Dorota Goleń; Lukasz Mazurkiewicz; Lukasz A. Malek; Ewa Walczak; Anna Fidziańska; Jacek Grzybowski; Andrzej Przybylski; Tomasz Zieliński; Jerzy Korewicki; Frédérique Tesson; Rafał Płoski
BackgroundLMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro.MethodsBetween January, 2008 and June, 2012 two patient populations were screened for the presence of LMNA mutations by direct sequencing: 66 dilated cardiomyopathy patients including 27 heart transplant recipients and 39 dilated cardiomyopathy patients with heart failure referred for heart transplantation evaluation, and 44 consecutive dilated cardiomyopathy patients, referred for a family evaluation and mutation screening.ResultsWe detected nine non-synonymous mutations including three novel mutations: p.Ser431*, p.Val256Gly and p.Gly400Argfs*11 deletion. There were 25 carriers altogether in nine families. The carriers were mostly characterized by dilated cardiomyopathy and heart failure with conduction system disease and/or complex ventricular arrhythmia, although five were asymptomatic. Among the LMNA mutation carriers, six underwent heart transplantation, fourteen ICD implantation and eight had pacemaker. In addition, we obtained ultrastructural images of cardiomyocytes from the patient carrying p.Thr510Tyrfs*42. Furthermore, because the novel p.Val256Gly mutation was found in a sporadic case, we verified its pathogenicity by expressing the mutation in a cellular model.ConclusionsIn conclusion, in the two referral centre populations, the screening revealed five mutations among 66 heart transplant recipients or patients referred for heart transplantation (7.6%) and four mutations among 44 consecutive dilated cardiomyopathy patients referred for familial evaluation (9.1%). Dilated cardiomyopathy patients with LMNA mutations have poor prognosis, however considerable clinical variability is present among family members.
International Journal of Cardiology | 2002
Zofia T. Bilińska; Maria Bilinska; Jacek Grzybowski; Jakub Przyłuski; Ewa Michalak; Ewa Walczak; Teresa Wagner; Witold Rużyłło
We present the case of 23-year-old woman with good living conditions, one year history of ventricular arrhythmia and 6 months history of decreased exercise tolerance, who was found to have dilated cardiomyopathy after aborted sudden death. Endomyocardial biopsy did not show specific findings. Within 3 months she developed profound bradycardia requiring pacemaker implantation and refractory heart failure, treated with heart transplantation. Intense eosinophilic myocarditis was found in the explanted heart. Retrospective analysis of the patients blood count revealed mild eosinophilia (eosinophil count: 0.86 x 109/l) on one examination only. Following heart transplantation the patient had persistent eisinophilia (eosinophil count: 0.62 x 109/l). Although there was no proven parasitic infestation, based on positive family history of Enterobius vermicularis infestation she was treated with broad-spectrum antiparasitic agent: albendazole and her eosinophil count returned to normal values. This case shows that active eosinophilic myocarditis may present clinically as progressive dilated cardiomyopathy with severe involvement of conduction system. Massive myocardial tissue eosinophilia occurred in the setting of mild and transient blood eosinophilia. Favourable outcome following antiparasitic treatment suggests a potential parasitic infestation as a cause of the disease.
Journal of Cardiac Failure | 1995
Zofia T. Bilińska; Ewa Michalak; B. Kusmierczyk-Droszcz; Rydlewska-Sadowska W; Jacek Grzybowski; W. Kupsc; Witold Rużyłło
Idiopathic dilated cardiomyopathy is characterized by dilation and impaired contractility of one or both ventricles. Long-term prognosis is poor. Early diagnosis has the potential for substantial reduction of morbidity and mortality. Recent studies, based on echocardiographic assessment of relatives of the patients have shown that familial dilated cardiomyopathy is relatively common. The authors studied 215 relatives (mean age, 27 years; 111 male) of 38 index patients with idiopathic dilated cardiomyopathy by clinical examination, electrocardiography, and two-dimensional, M-mode and Doppler echocardiography. Seven relatives (3%) from six families were shown to have dilated cardiomyopathy. Thus, 6 of the 38 index patients (16%) had familial disease. Furthermore, left ventricular enlargement either during diastole or systole was found in 66 of 174 healthy relatives (38%). This is significantly more frequent than in our normal control population of 100 unrelated subjects studied in the same way (18%; P < .0001). These 66 relatives with left ventricular enlargement belonged to 27 of the 38 examined families (71%). Dilated cardiomyopathy was found to be familial in 16% of patients. Of the relatives examined, 41% had left ventricular abnormalities. These findings provide further evidence for a genetic background of dilated cardiomyopathy. Relatives with left ventricular enlargement may have an early stage and/or latent form of the disease.
Kardiologia Polska | 2017
Monika Gawor; Mateusz Śpiewak; Jadwiga Janas; Katarzyna Kożuch; Aleksandra Wróbel; Łukasz Mazurkiewicz; Rafał Baranowski; Magdalena Marczak; Jacek Grzybowski
BACKGROUND Estimation of sudden cardiac death (SCD) risk is an integral part of clinical management of patients with hypertrophic cardiomyopathy (HCM). Identification of novel biomarkers of this disease can provide additional criteria for SCD risk stratification. Soluble suppression of tumourigenicity (sST2) and galectin-3 (Gal-3) are useful biomarkers for prognosis of heart failure (HF). Both of them appear to mediate cardiac fibrosis - an important pathogenetic process in HCM. Data about sST2 and Gal-3 usefulness in patients with HCM are limited. AIM The aim of this study was to evaluate sST2 and Gal-3 as potential novel biomarkers for better risk stratification in hypertrophic cardiomyopathy. METHODS Serum sST2 and serum Gal-3 levels were measured in 57 patients with HCM and in 18 healthy controls. The patients with HCM underwent routine evaluation including medical history, physical examination, blood tests (including N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT] measurements), 12-lead electrocardiography (ECG), 48-h Holter monitoring and two-dimensional (2D) echocardiography with the assessment of the maximal left ventricular wall thickness, left atrial diameter, maximal left ventricular outflow tract gradient, and left ventricular ejection fraction. Risk of SCD at five years according to HCM SCD-risk calculator was evaluated. The control group underwent ECG, 2D echocardiography, and NT-proBNP measurements to exclude asymptomatic heart disease. RESULTS Concentrations of sST2 and Gal-3 were significantly higher in patients with HCM than in controls (14.9 ± 5.8 ng/mL vs. 11.7 ± 3.3 ng/mL, p = 0.03 and 8.4 ng/mL [6.8-10.0] vs. 6.2 ng/mL [5.8-7.7], p = 0.005, respectively). Levels of sST2 and Gal-3 were considerably different in the New York Heart Association (NYHA) groups (p = 0.008, p = 0.009, respectively). Patients who presented non-sustained ventricular tachycardia (nsVT) on 48-h Holter monitoring had higher levels of sST2 (19.1 ng/mL [12.2-24.2] vs. 13.2 ng/mL [10.0-17.1], p = 0.02). There were no significant relationships between sST2 and Gal-3 levels and HCM SCD-risk, history of syncope presence, family history of SCD, and echocardio-graphic parameters. CONCLUSIONS Gal-3 levels and sST2 levels were higher in patients with HCM than in the control group. There were significant differences in Gal-3 levels between NYHA classes, but no correlations between Gal-3 levels and other parameters were found. Apart from differences in sST2 levels between NYHA classes, we demonstrated higher levels of sST2 in patients with nsVT. These findings suggest that sST2 may be useful as an additional biomarker for better risk stratification in hypertrophic cardiomyopathy.