Clinical features, etiology, and survival in patients with restrictive cardiomyopathy: A single-center experience.

BACKGROUND: Numerous prognostic factors have been proposed for cardiac amyloidosis (CA). The knowledge about other subtypes of restrictive cardiomyopathy (RCM) is scant. AIMS: This study aimed to elucidate the etiology and prognostic factors of RCM as well as assess cardiac biomarkers: high-sensitive troponin T (hs-TnT), growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2, as mortality predictors in RCM. METHODS: We enrolled 36 RCM patients in our tertiary cardiac department. All patients were screened for CA. Genetic testing was performed in 17 patients without CA. RESULTS: Pathogenic or likely pathogenic gene variants were found in 86% of patients, including 5 novel variants. Twenty patients died, and 4 had a heart transplantation during the study. Median overall survival was 29 months (8-55). The univariate Cox models analysis indicated that systolic and diastolic blood pressure, GDF-15, hs-TnT, NT-proBNP, left ventricular stroke volume, the ratio of the transmitral early peak velocity (E) estimated by pulsed wave Doppler over the early mitral annulus velocity (e'), tricuspid annulus plane systolic excursion, early tricuspid valve annular systolic velocity, the presence of pulmonary hypertension, and pericardial effusion influenced survival (P <0.05). A worse prognosis was observed in patients with GDF-15 >1316 pg/ml, hs-TnT >42 ng/l, NT-proBNP >3383 pg/ml, and pericardial effusion >3.5 mm (Kaplan-Meier analysis, log-rank test, P <0.001). CONCLUSIONS: Genetic testing should be considered in every RCM patient where light-chain amyloidosis has been excluded. Survival remains poor regardless of etiology. Increased concentrations of GDF-15, hs-TNT, NT-proBNP, and pericardial effusion are associated with worse prognosis. Further studies are warranted.

Impaired right ventricular function as a predictor of early mortality in patients with light­ chain cardiac amyloidosis assessed in a cardiology department.

INTRODUCTION    Light­chain (AL) amyloidosis is the most common cardiac amyloidosis. Despite progress in treatment, early mortality remains a substantial problem in these patients. OBJECTIVES    The aim of this study was to determine a clinical profile of patients diagnosed with AL amyloidosis in a cardiology department, as well as to define the cut­off point for early mortality and identify predictors of early mortality in this population. PATIENTS AND METHODS    The study included 30 patients (14 women; median age, 61.5 years) with AL amyloidosis confirmed by echocardiography and biopsy of 2 organs. RESULTS    Six patients were diagnosed with stage II amyloidosis according to the Mayo 2004 classification, and 24 patients-with stage III. Early mortality was defined as death during 102 days after diagnosis and was observed in 14 patients. Patients who died earlier were younger and more frequently reported a weight loss of more than 10 kg and orthostatic hypotension than patients who died later. Moreover, they had higher concentrations of high­sensitivity troponin T and N­terminal pro­B­type natriuretic peptide (NT­proBNP) and worse left and right ventricular (RV) contractility. In the Cox models, the age of less than 64 years, NT­proBNP levels exceeding 4968 pg/ml, RV end­diastolic diameter of less than 34 mm, and tricuspid annular plane systolic excursion lower than 13 mm were significant predictors of mortality within 102 days after diagnosis. CONCLUSIONS    We presented the results of the first Polish prospective noninterventional study on AL amyloidosis diagnosed in the cardiology department. We found that patients have advanced disease at the time of diagnosis. Younger age, impaired RV function, and higher concentrations of cardiac markers are predictors of worse prognosis.

Heterotopic pancreatic tissue in the gastric cardia: a case report and literature review.

The heterotopic pancreas, which is usually described as an untypical presence of pancreatic tissue without any anatomic or vascular continuity with the pancreas, is relatively rare. Clinical manifestations may include bleeding, inflammation, pain and obstruction; however, in most cases it remains silent and is diagnosed during autopsy. Here, we report a case of ectopic pancreatic lesion located in the gastric cardia. The patient was a 73-year-old woman who had a history (over four months) of chronic epigastric pain accompanied by heartburn. Esophagogastroduodenoscopy revealed inflammatory changes throughout the stomach and lower esophagus, as well as a flat polypoid mass with benign features located in the gastric cardia, approx. 10 mm below the "Z" line, measuring approx. 7 mm in diameter. Endoscopic biopsy forceps were used to remove the lesion. Histological examination of the lesion revealed the presence of heterotopic pancreatic tissue in the gastric mucosa. On the basis of the presented case, we suggest that pancreatic ectopia should be a part of differential diagnosis, not only when dealing with submucosal gastric lesions, but also with those that are small, flat and/or untypically located.

[Cardiac involvement in neuronal ceroid lipofuscinosis]. / Zajecie serca w przebiegu neuronalnej lipofuscynozy ceroidowej.

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.

[Unclassified cardiomyopathy or Lyme carditis? A three year follow-up].

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.

Remodeling of mitochondrial interior in cardiac lipofuscinosis.

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.

Are cardiomyocytes able to generate pre-amyloid peptides?

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 ß -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.

Usefulness of the ultrastructural and immunohistochemical analysis of cardiac biopsy in affected heart.

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.

Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption.

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.

Isolated ventricular noncompaction mimicking arrhythmogenic right ventricular cardiomyopathy--a study of nine patients.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Autophagy in transition from hypertrophic cardiomyopathy to heart failure.

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.

Desmin expression in human cardiomyocytes and selected clinical and echocardiographic parameters in patients with chronic heart failure.

BACKGROUND: 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. AIM: Evaluation of desmin expression in specimens derived from right ventricular myocardium during endomyocardial biopsy (EMB). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cardiomyocyte desmin abnormalities - an accurate predictor of long-term survival in patients with chronic heart failure.

BACKGROUND: 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. AIM: To evaluate desmin expression in cardiomyocytes of patients with HF and to asses it's prognostic value during long-term follow-up. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cardiovascular magnetic resonance findings in a case of Danon disease.

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.

[Borreliosis--simultaneous Lyme carditis and psychiatric disorders--case report]. / Borelioza--jednoczesne zajecie serca oraz zaburzenia psychiczne--opis przypadku.

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.

[Morphological and clinical aspects of Danon disease]. / Morfologiczne i kliniczne aspekty choroby Danona.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Lyme carditis--a bitter lesson or a delayed diagnostic success--a case report]. / Borelioza serca - gorzka lekcja czy spózniony sukces diagnostyczny? Opis przypadku.

Lyme carditis is a well known disorder; however, its diagnosis still remains a challenge because of varied clinical picture, low incidence rate and difficulties in detection of the aetiological agent (Borrelia burgdorferi). We report a case of a 60-year-old man with a 2.5-year history of dilated cardiomyopathy, recurring episodes of acute heart failure and arrhythmias which finally were diagnosed as Lyme carditis. The diagnosis was confirmed by endomyocardial biopsy that revealed spirochetes as well as by serological tests which showed complexed Borrelia antibodies. The patient responded to treatment with ceftriaxone and doxycycline.

Abnormal chaperone-mediated autophagy (CMA) in cardiomyocytes of a boy with Danon disease.

Ultrastructural analysis of the cardiomyocyte structure in Danon disease reveals dramatic accumulation of abnormal late autophagic vacuoles (AVd) suggestive of primary lysosomal defect. Moreover, the accumulation of AVd in cardiomyocytes is consistent with a decreased rate of autophagic to lysosomal trafficking. These results suggest that the loss of the LAMP-2 protein strongly inhibits uptake of proteins into lysosomes for degeneration. The significant reduction of chaperone-mediated autophagy (CMA) activity in the affected cardiomyocytes induces a dramatic increase in the number and size of AVd and a severe reduction of myocardial contractility.

Evaluation of desmin activity using immunohistochemical and immunofluorescent staining of myocardial biopsies in patients with chronic heart failure. Comparison of the two methods.

BACKGROUND: Desmin plays one of the key roles in cardiomyocytes. The protein protects the integration of the cell and has the following actions: mechanical, structural and regulatory. Observed abnormalities of its activity have been associated with worsening of heart failure (HF). AIM: Evaluation of desmin activity detected with immunohistochemical (IHC) and immunofluorescent (IF) staining in cardiomyocytes in patients with chronic HF. METHODS: The study population comprised 37 patients (mean age 46.5+/-15.28 years, 83.8% males) with diagnosed HF of unknown aetiology, who underwent myocardial biopsy. Coronary angiography was performed to exclude presence of significant coronary artery disease. Heart failure was diagnosed based on clinical assessment and echocardiography showing left ventricular ejection fraction below 45%. RESULTS: The IHC and IF evaluation of cardiomyocyte desmin showed that these methods were consistent with respect to classification of 31 specimens (83.8%), while being discrepant in 6 (16.2%) cases. Desmin detection in myocardial biopsy specimens with IHC staining showed normal amounts of this protein in 11 (29.8%) cases, excess in 18 (48.6%) patients and deficiency in 8 (21.6%) cases, whereas in IF stained specimens respective values were 12 (32.4%), 15 (40.6%) and 10 (27%). No significant differences were found between all desmin groups (i.e. normal level, excessive and deficiency) evaluated with IHC and IF staining (p=0.39; p=0.25; p=0.31, respectively). CONCLUSIONS: The IHC and IF methods allow evaluation of desmin activity in cardiomyocytes and division into three types of expression. Both methods have high consistency. The IHC, which is the more available method, seems to be a sufficient assay.

[Reversible dilated cardiomyopathy in a patient with acute, advanced heart failure and intense endothelial inflammatory reaction in endomyocardial biopsy--a case report]. / Odwracalna kardiomiopatia rozstrzeniowa u chorego z ostra i ciezka niewydolnoscia serca oraz nasilona odpowiedzia zapalna sródblonka w biopsji endomiokardialnej.

Inflammatory response of the endothelium has been increasingly recognized in the aetiopathogenesis of sporadic dilated cardiomyopathy (DCM). It has been shown that up to 2/3 of patients with DCM have immunohistological evidence of enhanced activation of the endothelium. We present a case of a middle-aged patient with a history of hypertension and hyperlipidaemia who developed sudden significant left ventricular dysfunction following flu-like syndrome. Endomyocardial biopsy revealed no myocarditis, but immunohistological features of endothelial activation were present. Additionally, increasing titers of IgG antibodies against PvB19 were observed. During 18 months of standard heart failure treatment along with statin therapy, we observed a significant recovery of left ventricular systolic function, and in this way, reversible dilated cardiomyopathy.