[show abstract][hide abstract] ABSTRACT: BACKGROUND: LMNA 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. METHODS: Between 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. RESULTS: We 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. CONCLUSIONS: In 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.
BMC Medical Genetics 05/2013; 14(1):55. · 2.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background Danon disease is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2).Materials and Methods Our study describes a 19-year-old man with isolated hypertrophic cardiomyopathy, in whom we performed DNA analysis and compared results of microscopic analysis of skeletal and cardiac muscles.Results Sequencing of the LAMP-2 gene revealed a novel point mutation c.137G > A in exon 2, leading to premature stop codon. Ultrastructural analysis of cardiac and skeletal muscles revealed the presence of unusual autophagic vacuoles in both. Although some vacuoles in skeletal muscle reacted strongly with dystrophin, β-sarcoglycan, and laminin, those in cardiomyocytes showed no immunoreactivity.Conclusion Our immunohistochemical and ultrastructural findings reinforce the claim that in Danon disease the pathomechanism of chaperone-mediated autophagy in cardiomyocytes differs from that in skeletal muscle.
[show abstract][hide abstract] ABSTRACT: Lyme carditis can be a clinical manifestation of the early disseminated stage of Lyme disease caused by the tick-transmitted pathogen Borrelia burgdorferi. We present the case of a 41 year-old Caucasian woman referred to our hospital with symptoms of fatigue, progressive exertional dyspnoea, supraventricular cardiac arrhythmia, and an enlarged heart revealed on chest radiography. Following an untypical result of transthoracic echocardiography, cardiac magnetic resonance was performed. This showed structural cardiac changes and focus of late gadolinium enhancement in the midwall of the apex region. Further diagnostic processes, including endomyocardial biopsy and serology tests, made it possible to diagnose Lyme carditis. Clinical observation was followed-up for three years.
Kardiologia polska 01/2013; 71(3):283-5. · 0.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: We present a case of a 58-year-old female with neuropsychiatric symptoms, followed by recurrent episodes of atrial flagellation and symptoms of heart failure. Based on intraoperative myocardial biopsy, neuronal ceroid lipofuscinosis was diagnosed.
Kardiologia polska 01/2013; 71(8):855-7. · 0.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ultrastructural analysis was performed in cardiac ceroidlipofuscinosis to confirm the presence and the nature of storage material. Granular osmophilic deposits characteristic of GROD structures coincidented with particularly aberrant mitochondria. Remodeling of mitochondrial interior with the appearance of several form of abnormal inclusions was never observed in cardiac ceroidlipofuscinosis. The presence of dense osmophilic bodies, glycogen conglomerates, balloon-like and onion-like structures in mitochondrial interior seem to be early events of this storage process.
[show abstract][hide abstract] ABSTRACT: We performed ultrastructural testing of a cardiac biopsy taken from a heart with amyloidosis in which transthyretin mutation and light chain A amyloidosis were excluded. Cardiomyocytes of the affected heart showed accumulation of endosomal-like structures in which soluble amyloid oligomeric conformation was deposited. Intracellular accumulation of β -amyloid as well as phosphorylated tau protein seen in the immunohistochemical study suggest that the heart tissue may generate an amyloidogenic peptide leading to cardiomyocyte destruction and heart dysfunction.
Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. 01/2011; 49(1):64-70.
[show abstract][hide abstract] ABSTRACT: Many bacterial species can be a cause of various heart diseases, such as: Borrelia burgdorferi sensu lato, Coxiella burnetii and Bartonella spp. The aim of the present studies was to establish if any tick-borne infections can contribute to serious heart disorders resulting in the need for heart transplantation. Myocardium, aortic and mitral valve samples from hearts removed from patients undergoing heart transplantation were tested. The presence of Bartonella spp., Borrelia afzeli and C. burnetii bacteria in malfunctioning human hearts has been shown. DNA of Bartonella spp., B. burgdorferi and C. burnetii were detected in various parts of tested hearts. DNA of B. afzelii and Bartonella spp. were found in the aortic valves. DNA of C. burnetii was detected in the myocardium. Mixed infections with Bartonella spp. and C. burnetii were also observed. Obtained results indicate that diagnosis of Bartonella spp., B. burgdorferi C. burnetii and Rickettsia spp. infections should be considered in cases of infectious endocarditis with negative blood cultures.
Polish journal of microbiology / Polskie Towarzystwo Mikrobiologów = The Polish Society of Microbiologists 01/2011; 60(4):341-3. · 0.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: The etiology of peripartum cardiomyopathy (PPCM) is not well understood. Potential causal mechanisms include infection, autoimmune disease, and abnormal response to the hemodynamic stress of pregnancy. Recently it was shown that the development of PPCM in an experimental model is associated with the generation of a cleaved antiangiogenic and proapoptotic 16-kDa form of the nursing hormone prolactin, which impairs the cardiac capillary network and its function. The purpose of this study was to evaluate the ultrastructure of the myocardium in a patient with PPCM and in a comparative group of patients and to identify structural characteristics that may predispose to myocardium dysfunction.
A 28-year-old woman with PPCM had fulminant heart failure leading to the implantation of a biventricular assist device, but no myocarditis was found on histological examination of her myocardial tissue. An ultrastructural study of myocardial tissue taken from three patients (mean age: 22 years, 2 females) with fulminant heart failure not related to PPCM (2 myocarditis, 1 dilated cardiomyopathy) served as a comparison. The ultrastructural analysis revealed the presence of small capillary damage. Vascular lumen occlusion, endothelial cell remodeling, and apoptosis with the appearance of mast cells, plasma cells, and preadipocytes were the most characteristic features of the damaged myocardial tissue with secondary interstitial fibrosis. No vascular pathology of cardiac capillaries was observed in the comparative group.
A myocardial tissue study in PPCM revealed ultrastructural remodeling of small capillaries with the presence of endothelial cell apoptosis and impairment of the microcirculation.
Medical science monitor: international medical journal of experimental and clinical research 05/2010; 16(5):CS62-6. · 1.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Archiv für Kreislaufforschung 05/2010; 105(3):365-77. · 7.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the last few years endomyocardial biopsy becomes a useful diagnostic tool for the investigation of idiopathic dilated cardiomyopathy. The aim of our current study was to try to identify ultrastructural and immunohistochemical specificity of truncated cardiac proteins in affected heart. The focal loss of plasma membrane continuity together with the lack of dystrophin activity in affected myocytes facilitated to find mutation in dystrophin gene. The accumulation of granulofilamentous desmin-positive material in cytoplasm of myocytes was the main indicator of presented mutation in the desmin gene. Nuclear structure remodeling, concomitantly with loss of lamin A/C activity, contributed to identify mutation in lamin A/C gene. Analysis of hypertrophic heart with disarray of sarcomeres and lack of I-Z-I bands suggested embryonic faiulure in titin activity. All this findings indicate that endomyocardial biopsy reperesent a useful method for a correct diagnosis of heart dysfunction.
Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. 01/2010; 48(1):57-63.
[show abstract][hide abstract] ABSTRACT: Endomyocardial biopsy of a patient in transition stage from hypertrophic cardiomyopathy to heart failure was investigated. The tissue showed hypertrophy, atrophy of myocytes and an increased amount of fibrosis. In addition, numerous cardiomyocytes revealed ubiquitin positive inclusions. Ultrastructural analysis indicated that cardiomyocytes contained typical autophagic vacuoles including mitochondria, glycogen granules, degraded remnants and myelin structures. The most obvious ultrastructural finding was the presence of amorphous plaques and tubulofilamentous inclusions. Such ultrastructural abnormalities allow us to conclude that degeneration of myocardial cells by autophagy mechanisms leads to cardiomyocyte death, loss and heart failure.
Journal of electron microscopy 09/2009; 59(2):181-3. · 1.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: Desmin, one of the basic muscular-specific structural proteins, is believed to play an important role in the progression of heart failure (HF). The function of desmin in cardiomyocytes is still unclear. Mechanical, structural and regulatory functions are postulated. Regulatory function of desmin seems the most interesting. Desmin might be involved in the regulation of gene expression, myofibrillogenesis and intercellular signalling, and be responsible for shape and tension of the cell membrane and other organelles. Abnormal accumulation of desmin may disturb the function of myofibrils, lead to unusual tension of sarcolemma and atypical distribution of organelles (nucleus), and impair intra- and intercellular communication.
Evaluation of desmin expression in specimens derived from right ventricular myocardium during endomyocardial biopsy (EMB).
The study population consisted of 135 patients (86.7% males, mean age 49.4 +/- 14.1 years) presenting with clinical symptoms of HF and LVEF < 45%. During EMB 3-4 samples were taken from the right ventricular myocardium. The immunohistochemical studies of the endomyocardial specimens included immunostaining with desmin-specific antibodies. The study population was divided into three groups: I - 48 patients with normal expression of desmin, II - 54 patients with increased expression and accumulation of desmin and III - 33 patients with low expression of desmin in cardiomyocytes.
The LVEF was significantly higher in group I than in groups II and III. The LV diameter was significantly lower in group I than in groups II and III. Functional status according to NYHA class was the worst in group I compared to group II and III. These differences were statistically significant.
Evaluation of desmin distribution in specimens derived from the right ventricular myocardium may be useful as an objective tool in the assessment of left ventricle status.
Kardiologia polska 09/2009; 67(9):955-61. · 0.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Isolated ventricular noncompaction is considered to predominantly affect the left ventricle. It is characterized by increased left ventricular wall thickness and deep intertrabecular recesses with to-and-fro blood flow that remains in continuity with the ventricular flow. Aim of the study was to present a group of patients with isolated noncompaction of both ventricles mimicking arrhythmogenic right ventricular cardiomyopathy (ARVC).
Reported group consisted of 9 pts initially diagnosed with ARVC (mean age 37.9 y, 7 male), who underwent basic clinical evaluation. CMR was performed in 8 pts, cardiac catheterization in 2 pts and endomyocardial biopsy in 2 pts. Mean age at presentation of first symptoms was 23.5 y (5-44 y). Heart failure symptoms were observed in 4 pts, atrial fibrillation in 3 pts, ventricular tachycardia in 2 pts (polymorphic--in 2 pts) and syncope in 3 pts. Final diagnosis of noncompaction was established according to generally accepted criteria.
Morphologic and/or functional changes in the right ventricle were seen in 9 pts (100%): enlargement and hypertrabeculation of the right ventricle in all pts, global hypokinesis in 4 pts, focal wall motion abnormalities and/or bulges typical for ARVC in 5 pts. Two pts had significant tricuspid regurgitation. Endomyocardial biopsy (2 pts) showed abnormal thick endocardium, interstitial fibrosis, myocardial damage and lymphocyte infiltration.
1) Noncompaction of ventricular myocardium should be considered during the evaluation of right ventricular cardiomyopathies with excessive trabeculation. 2) In problematic cases Task Force criteria for ARVC should be used to improve the accuracy of assessment.
International journal of cardiology 08/2009; 145(1):107-11. · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The proteins of cardiomyocytes are interesting targets for investigations as they may directly reflect intracellular changes within the heart. Desmin is one of the fundamental cytoskeleton proteins of cardiomyocytes, and has a mechanical, structural and regulatory function. In comparison with healthy individuals, patients with heart failure (HF) present different expression of desmin content, that can be associated with its abnormal structure, different distribution, localisation and disturbed function. Abnormal expression of desmin in cardiomyocytes plays a key role in progression of HF.
To evaluate desmin expression in cardiomyocytes of patients with HF and to asses it's prognostic value during long-term follow-up.
Diagnostic endomyocardial biopsy (DMB) was performed in 135 patients (86.7% males, mean age 49.4 +/- 14.1 years) with clinical symptoms of HF (left ventricular ejection fraction %lt 45%). In each case four specimens were taken from the right ventricle. Desmin was detected with immunohistochemical staining of cardiomyocytes. The study population was divided into three groups: group I - 48 patients with normal expression of desmin; group II - 54 patients with abnormal accumulation of desmin; group III - 33 patients with low expression of desmin in cardiomyocytes. The ROC curves and Kaplan-Meier survival curves were constructed to analyse predictive value of examined parameters.
The mean duration of follow-up was 33.2 +/- 14.6 (6-72) months. Cardiac cause of death was confirmed in 2.08% of cases in group I, 7.4% in group II and 22.86% in group III. Group I vs. group II: Cox's F test - p = 0.07647; log-rank test - p = 0.15047, group I vs. group III: Cox's F test - p = 0.007, log-rank test - p = 0.005, group II vs. group III: Cox's F test - p = 0.033, log-rank test - p = 0.079.
Our results suggest that desmin content in cardiomyocytes directly affects the long-term prognosis in HF patients. The low expression of desmin in cardiomyocytes with immunohistochemical assay is associated with unfavourable clinical course.
Kardiologia polska 08/2009; 67(7):724-33. · 0.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Danon disease is a rare X-linked dominant lysosomal glycogen storage disease that can lead to severe ventricular hypertrophy and heart failure. We report a case of Danon disease with cardiac involvement evaluated with cardiovascular magnetic resonance, including late gadolinium enhancement and perfusion studies.
Journal of Cardiovascular Magnetic Resonance 05/2009; 11:12. · 4.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Borreliosis is a multisystemic disease transmitted by ticks. Its diagnosis still remains a challenge because of the varied clinical picture and of difficulties in detection of the etiological agent (Borrelia burgdorferi). We report a case of a 53-years-old woman admitted to the Clinic of Cardiology due to life-threatening arhythmias with simultaneous deficits in concentration and memory. A suspicion of borreliosis was driven from the presence of cardiac symptoms as well as of psychiatric and from the case histories of a tick bite. The diagnosis was confirmed both by specific serological test and endomyocardial biopsy which revealed spirochetes. The patient responded to treatment with doxycyclin and ceftriaxone. Cardiologic disorders retreated entirely, while cognitive deficits did only partly.
Polski merkuriusz lekarski: organ Polskiego Towarzystwa Lekarskiego 05/2008; 24(143):433-5.
[show abstract][hide abstract] ABSTRACT: Danon disease, an X-linked hypertrophic cardiomyopathy, is caused by primary deficiency of lysosome-associated membrane protein (LAMP-2). The pathological hallmark of the disease is the appearance of intracytoplasmic vacuoles containing autophagic material and the absence of LAMP-2 activity in the muscle.
To define the LAMP-2 protein deficiency we investigated cardiac and skeletal muscle of a 19-year-old man with hypertrophic cardiomyopathy without clinically apparent skeletal myopathy or mental impairment, whose mother died suddenly at 46 years of age.
Clinical, morphological, immunohistochemical and ultrastructural analysis was performed. Paraffin sections of cardiac muscle were stained using routine histochemical methods. Frozen sections of skeletal muscle were stained using histochemical methods as well as using monoclonal antisera against N-terminal of dystrophin and antisera against LAMP-2. Ultrastructural examination of both cardiac and skeletal muscle specimens were performed.
Cardiac and skeletal muscle revealed an excessive accumulation of early and late autophagic vacuoles containing various cytoplasmic debris. In immunohistochemical analysis the vacuolar membrane seen in skeletal muscle was decorated with antibody against dystrophin and such vacuoles were negative for LAMP-2.
Ultrastructural and immunohistochemical analysis of skeletal muscle (less invasive than myocardial biopsy) may be used in diagnosis of Danon disease. Early diagnosis of Danon disease is important for timely cardiac transplantation, the only effective therapeutic option.
Kardiologia polska 04/2008; 66(3):302-6. · 0.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: We analysed the architecture of cardiomyocyte nuclei lacking lamin A activity in three patients with dilated cardiomyopathy. The diagnosis was established on the basis of clinical and electrophysiological examinations, chest radiography and electrocardiography. An ultrastructural study of affected cardiomyocytes showed dramatic alterations in nuclear distribution and organization affecting nuclear shape, lamina structure, chromatin and nuclear interior organization. The most specific hallmark of nuclei with lamin A deficiency was the reorganization of the nuclear interior, the appearance of a various number of mitochondria within the nuclear matrix, and focal or total lack of nuclear membrane.
Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 02/2008; 46(3):196-203. · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: A vicious circle of interactions between dilated cardiomyopathy and longstanding persistent AF/AFL may cause symptoms of advanced congestive heart failure. In a 31-year-old patient with diagnosis of familial dilated cardiomyopathy and permanent AF lasting for five years, gradually decreased left ventricular ejection fraction (LVEF) and increased diameter of heart chambers - left ventricular diastolic dimension (LVdD) 7.7 cm, left atrium (LA) 5.4 cm, and LVEF 15% were noted. Pharmacological treatment was ineffective Successful RF ablation of AF/AFL substrate (CTI block, PVs isolation, CFAE ablation, roof and MIG line, CS applications) reversed symptoms of significant heart remodeling (LVdD 5.9 cm, LA 4.3 cm, LVEF 50%).
Kardiologia polska 02/2008; 66(1):109-13. · 0.54 Impact Factor