Identification of Two Novel LAMP2 Gene Mutations in Danon Disease.

BACKGROUND: Danon disease is a rare X-linked inherited disorder characterized by massive left ventricular hypertrophy, skeletal muscle dystrophy, and mental retardation. The disease is caused by mutations in the LAMP2 gene encoding for lysosome-associated membrane protein-2. METHODS: Two young male patients with hypertrophic cardiomyopathy, characterized by marked, concentric left ventricular hypertrophy, elevated levels of creatine kinase, and manifest limb-girdle muscular dystrophy in 1 case, were investigated. Genetic screening included direct sequencing of the whole coding sequence of the LAMP2 gene. RESULTS: Genetic analysis identified 2 novel LAMP2 gene mutations. In Family A, a G-A transition (c.962G > A) leading to a nonsense mutation at codon 321 (p.Trp321Ter), and in Family B, a one-nucleotide insertion (c.973insC) leading to a full frame-shift (p.Pro324+24X) was detected in exon 8 of the LAMP2 gene. Family screening identified 8 mutation carriers, with 4 nonpenetrant cases and 3 additional, probably affected family members without DNA diagnosis. The cardiac phenotype was hypertrophic cardiomyopathy in all cases, including female mutation carriers. Five disease-related deaths occurred in the families, at an average age of 33 ± 16 years, which was clearly lower in male than in female patients (28 ± 7 vs 42 ± 25 years). A high prevalence of arrhythmias or conduction abnormalities was also observed. CONCLUSIONS: The reported 2 novel LAMP2 gene mutation carrier families, one of them being one of the largest reported to date, highlight the malignant clinical course of Danon disease, characterized by a high rate of disease-related death at an early age and a high prevalence of arrhythmias or conduction abnormalities.

[Chronic heart failure with impaired left ventricular function (systolic heart failure)]. / Krónikus szívelégtelenség csökkent bal kamra funkcióval (szisztolés szívelégtelenség).

Chronic heart failure is a common public health problem. The disease has a poor prognosis with high mortality rate and the incidence increases continuously. Prognosis of chronic systolic heart failure can be improved by several different medications as well as by special cardiac interventions based on the newly-published European and American guidelines. In case of severe systolic dysfunction, hospitalization and mortality can be reduced using angiotensin converting enzyme inhibitors, angiotensin receptor blocking drugs, beta-receptor blocking agents and aldosterone antagonists, as evidenced in multicentric studies. In selected cases different cardiac interventions, such as intracardial defibrillator and/or cardiac desynchronization device implantation can be used for supporting the failing left ventricle. In terminal stage, special devices (ventricular assist device, intra-aortic balloon pump, arteficial heart) and, finally, heart transplantation can be applied. In this paper, the authors highlight therapeutic options of chronic systolic heart failure referring to recommendations of the latest, 2012 guideline from the European Society of Cardiology.

Hearing disturbances in hypertrophic cardiomyopathy. Is the sensorineural disorder neurogenic or myogenic?

BACKGROUND: In a previous study, we demonstrated that a hidden hearing defect is present in about 50% of patients with hypertrophic cardiomyopathy (HCM). Such defects were found significantly less frequently in age and clinical stage-matched patients with dilated cardiomyopathy (DCM), and were practically absent in patients with valvular aortic stenosis, and in patients taking beta-receptor blockers for different reasons (such as hypertension, ischemic heart disease, etc.). The hearing disturbances were first examined by means of brain-stem evoked response audiometry (BAEP). This method permitted only a rough differentiation between the origins of cochlear (myogenic) and retrocochlear (neurogenic) hearing disturbances, and did not allow us to establish their myogenic or neurogenic nature with certainty. AIMS: Our present aim was to determine whether the hearing disturbances present in HCM and DCM patients are myogenic or neurogenic in origin. METHODS: The neurogenic function of the inner ear was examined by BAEP as before, and the myogenic function by the distortion product otoacoustic emission technique. RESULTS: Myogenic abnormalities were found in 39/69 ears (57%) and neurogenic abnormalities in 19/69 (28%) ears among the HCM cases, as compared with 14/39 (36%) and 8/39 (21%) ears respectively among the DCM cases (p<0.005). Healthy controls displayed the lowest incidence of both types of hearing abnormalities. CONCLUSION: Our results lead us to conclude that myogenic lesions are more frequent than neurogenic lesions in patients with HCM. Both myogenic and neurogenic lesions are more frequent in HCM patients than in DCM patients or healthy controls. It may be hypothesized that abnormal sarcomeric proteins present in the muscular structures of the inner ear in HCM are possibly responsible for the hearing disorders in these patients, and that this is not merely a neurological defect.

Transthoracic echocardiographic evaluation of aortic distensibility in a Takayasu's arteritis patient.

Takayasu's arteritis (TA) is a chronic, nonspecific, rare, and segmental inflammatory disease that primarily affects the aorta and its main branches. In the present case, the aortic elastic properties were decreased (aortic distensibility was practically normal) suggesting that ascending aorta was not affected by TA. For preoperative assessment, a routine transthoracic echocardiography can be a valuable method for the noninvasive functional evaluation of ascending aorta in a patient with TA.

Helicobacter pylori-induced immunological responses in patients with duodenal ulcer and in patients with cardiomyopathies.

The interaction between the bacteria and the host is a key factor determining the clinical consequences of H. pylori infection. The immune system plays an important role in either promoting or preventing the disease. The mucosal production of TNF-alpha, IL-6, IL-8 and IL-10 and the CagA status were investigated in H. pylori-positive patients with duodenal ulcer (DU). The concentrations of these cytokines in gastric antral mucosal specimens from patients infected with H. pylori (n = 40) were determined by ELISA and compared with data on mucosal specimens from H. pylori-negative patients (n = 12). The local TNF-alpha, IL-6 and IL-8 concentrations in the antral biopsy samples were significantly higher (p < 0.001) in the patients infected with H. pylori than in the samples from the H. pylori-negative subjects. CagA positivity was demonstrated in 39 (97.5%) of the 40 patients with DU, and in 41 (70.7%) of H. pylori-positive (58 of 100) healthy blood donors. In complementary studies focusing on extragastric disease, it was found that 57% of patients with ischaemic heart disease were seropositive as concerns H. pylori, and 91% of them had antibodies against human heat shock protein 60, too. This study suggests that, besides the bacterial virulence factor, the host response of an increased mucosal production of inflammatory cytokines can be relevant to the gastric pathophysiology in H. pylori-induced DU. At the same time, in ischaemic heart diseases the role of autoimmune processes induced by H. pylori cannot be excluded.

Comparison of circulating levels of interleukin-6 and tumor necrosis factor-alpha in hypertrophic cardiomyopathy and in idiopathic dilated cardiomyopathy.

It is known from the literature that the circulating levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are elevated in heart failure and idiopathic dilated cardiomyopathy (IDC). Few convincing data are available on the production of cytokines in hypertrophic cardiomyopathy (HC). The levels of circulating IL-6, the soluble form of the IL-6 receptor (sIL-6R), and TNF-alpha in 19 patients with HC, 31 patients with IDC, and 20 healthy subjects (control group) were examined and compared with their clinical parameters. The levels of TNF-alpha and circulating IL-6 proved to be elevated in the sera of patients with IDC. In contrast, the level of TNF-alpha was not elevated in HC, although the levels of IL-6 and sIL-6R were significantly higher than those in the sera of patients with IDC. Although elevated levels of IL-6 may correlate with the extent of left ventricular dysfunction in IDC, the markedly elevated IL-6 levels did not correlate with left ventricular function in HC. The markedly elevated TNF-alpha levels in IDC were associated with the elevated IL-6 levels, probably because of an inflammatory process and/or heart failure. In contrast, in HC, in which the New York Heart Association functional class was actually good, the even higher IL-6 and sIL-6R levels were not associated with a TNF-alpha elevation. In HC, the IL-6 and sIL-6R elevations were due to another mechanism, probably by way of the cardiotrophin-associated gp130 receptor. The sources of IL-6 production in HC are not clear yet.

Comparative study of the roles of cytokines and apoptosis in dilated and hypertrophic cardiomyopathies.

AIMS: In order to gain more insight into the pathogenesis of dilated and hypertrophic cardiomyopathies (DCM and HCM, respectively), we investigated the roles of certain cytokines that regulate apoptosis. METHODS AND RESULTS: ELISA tests, performed to determine the plasma concentrations of tumour necrosis factor-alpha (TNF-alpha), the soluble Fas (sFas), interleukin-6 (IL-6) and the soluble IL-6 receptor (sIL-6R), revealed that DCM patients exhibit elevated concentrations of TNF-alpha, sFas, IL-6 and sIL-6R, while HCM patients have only high IL-6 and sIL-6R levels as compared with healthy individuals. Western blot analysis of the levels of TNF-alpha, IL-6, Bcl-2 and Bax proteins in myocardium samples demonstrated that DCM patients express increased levels of TNF-alpha, IL-6 and Bax, whereas HCM heart lysates display only elevated levels of Bcl-2. Annexin V binding assay of TNF-alpha-treated H9C2 cells indicated that the in vitro cytotoxicity of this cytokine involves apoptotosis and necrosis. CONCLUSION: In accord with previous observations, our data indicate a strong activation of the pro-apoptotic TNF and Fas pathways in DCM patients, and an anti-apoptotic shift in HCM patients. These findings have a bearing on the pathogenesis of cardiomyopathies, since apoptosis may account for certain dysfunctions observed in DCM, while IL-6 may elicit the hypertrophy characteristic of HCM.

[Clinical role of flow velocity of left atrial auricle for prediction of short and long term success of cardioversion in patients with non-valvular atrial fibrillation]. / A bal pitvari fülcse áramlás szerepe a cardioversio rövid és hosszú távú sikerességének elórejelzésében nem valvularis eredetú pitvarfibrilláció fennállásakor.

INTRODUCTION: Echocardiographic parameters for predicting cardioversion (CV) outcome and long-term sinus rhythm (SR) maintenance in patients with nonvalvular atrial fibrillation (AF) are not accurately defined. AIMS: The authors aim was to evaluate the role of left atrial appendage (LAA) flow velocity detected by transesophageal echocardiography before CV for prediction of short and long-term (1 year) outcome of CV in patients with nonvalvular AF. METHODS: One hundred and nine patients (66 males, mean age: 57 +/- 13 years) with nonvalvular AF lasting more than 48 hours but less than 1-year duration underwent transthoracic and transesophageal echocardiography before either electrical or pharmacological CV attempt. RESULTS: Cardioversion was successful in restoring SR rhythm in 83 (76%) and unsuccessful in patients 26 (24%). Mean LAA peak emptying flow was higher in patients with successful than in those with unsuccessful CV (36.7 +/- 14.7 vs 26.3 +/- 9.2 cm/sec; p < 0.01). At multivariate analysis the left LAA emptying velocity > 32 cm/sec was the only independent predictor of CV success. Seventy-four out of the 83 patients with successful CV had a complete follow-up of 1 year. At the end of the 1-year follow-up, 40 of the 74 (54%) patients who underwent successful CV preserved the SR. Mean LAA peak emptying velocity was higher in patients remaining in SR for 1 year than in those with AF relapse (40.3 +/- 15.6 vs 32.2 +/- 12.2 cm/sec cm/sec; p < 0.001). On multivariate analysis, only the mean LAA peak emptying velocity > 39 cm/sec and the use of preventive antiarrhythmic drug treatment predicted the continuous preservation of SR during 1 year. CONCLUSION: In patients with nonvalvular AF, measurement of precardioversion LAA flow velocity profile by transesophageal echo cardiography provides valuable information for prediction of both short and long-term success of CV.