Burst-Like Transcription of Mutant and Wildtype -Alleles as Possible Origin of Cell-to-Cell Contractile Imbalance in Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) has been related to many different mutations in more than 20 different, mostly sarcomeric proteins. While development of the HCM-phenotype is thought to be triggered by the different mutations, a common mechanism remains elusive. Studying missense-mutations in the ventricular beta-myosin heavy chain (β-MyHC, ) we hypothesized that significant contractile heterogeneity exists among individual cardiomyocytes of HCM-patients that results from cell-to-cell variation in relative expression of mutated vs.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1.

Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes.

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers.

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level.

Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: results from a multicentre international randomized trial (PREVENT-HF).

Aims: Previous experimental and clinical studies have consistently suggested that right ventricular (RV) apical pacing has important adverse effects. Ventricular pacing (VP), however, is required, and cannot be reduced in many patients with atrioventricular (AV) block. The PREVENT-HF study was an international randomized trial that explored differences in left ventricular (LV) remodelling during RV apical vs.

The left and right ventricle of a patient with a R723G mutation of the beta-myosin heavy chain and severe hypertrophic cardiomyopathy show no differences in the expression of myosin mRNA.

Background: In familial hypertrophic cardiomyopathy (FHC), asymmetric left ventricular (LV) hypertrophy has been considered to be the predominant phenotypic expression, whereas right ventricular (RV) involvement is still ambiguous. In most cases, the right ventricle remains unaffected until secondary pulmonary hypertension develops. Several FHC-causing mutations of genes encoding sarcomere-related proteins have been identified which are transmitted in an autosomal-dominant manner.

Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance.

The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W).

Relationship between adiponectin and left atrium size in uncomplicated obese patients: adiponectin, a link between fat and heart.

Background: It is well known that obesity is a risk factor for severe cardiovascular complications, such as coronary heart disease, heart failure, stroke, venous thromboembolic disease, and atrial fibrillation. Left ventricle (LV) and left atrium (LA) enlargement is a characteristic feature of these patients with the consequent cardiovascular risk. Factors other than hemodynamic may influence LA remodeling.

Association between sleep-disordered breathing, aminoterminal pro-brain natriuretic peptide (NT-proBNP) levels and insulin resistance in morbidly obese young women.

Objective: Sleep-disordered breathing (SDB) is often encountered in morbid obesity (MO) in conjunction with insulin resistance (IR) and several cardio-vascular risk factors. Aminoterminal pro-brain natriuretic peptide (NT-proBNP) is a promising marker for left ventricular dysfunction (LVD) in MO. The aim of this study was to look for possible correlations between SDB, IR, heart structure and function indexes and NT-proBNP levels in MO female subjects.

Quantification of mutant versus wild-type myosin in human muscle biopsies using nano-LC/ESI-MS.

A liquid chromatography/electrospray ionization mass spectrometry (nano-LC/ESI-MS) approach is described by which abundance of proteins (e.g., of beta-myosin heavy chain; MW 223 kDa) carrying a point mutation can be determined in tissue samples where the mutant protein is coexpressed with its wild-type forms.

Correlation between insulin resistance surrogates and echocardiographic findings in asymptomatic patients with morbid obesity: a cross-sectional study.

Objective: To assess the relationship between insulin resistance (IR) and left ventricular diastolic dysfunction (LVDD) in asymptomatic patients with morbid obesity (MO).

Methods: The study cohort consisted of 231 patients (165 women and 66 men) with MO (mean body mass index [BMI] of 46.0 kg/m2) and a control group of 93 age-and sex-matched apparently healthy control subjects (56 women and 37 men; mean BMI of 24.

Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: rationale and design of the PREVENT-HF study.

Aims: Right ventricular (RV) pacing has been shown to cause heart failure symptoms in patients with and without previous systolic left ventricular (LV) dysfunction. The aim here was to evaluate the preventive effect of biventricular pacing vs. RV apical pacing in patients with indication for permanent ventricular pacing.

[Natural history of and risk factors for idiopathic atrial fibrillation recurrence (FAP Registry)].

Introduction And Objectives: The natural history of idiopathic atrial fibrillation is not well understood. The aim of this study was to investigate the frequency of and risk factors for disease recurrence.

Methods: The study involved 115 patients with a first episode of paroxysmal atrial fibrillation of unknown origin who were included the FAP registry, which contains data from 11 district hospitals in Catalonia, Spain.

Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells.

Disease-causing mutations in cardiac myosin heavy chain (beta-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa(50)) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations.

[Hypertrophic cardiomyopathy. Genetic basis and clinical implications].

Thanks to advances in molecular biology during the last decade, the etiology of hypertrophic cardiomyopathy has been elucidated. Although more than 150 causal mutations of 9 genes that encode contractile proteins have been identified, many of the pathogenetic mechanisms remain unclear. In this review we discuss the current state of knowledge of the functional effects of some mutations, particularly two of the most lethal beta-myosin mutations -Arg403Gln and Arg723Gly (Barcelona mutation)- and their contributions to the pathogenesis of hypertrophy, sudden death and ischemia.

[Late T-lymphocyte and monocyte activation in coronary restenosis. Evidence for a persistent inflammatory/immune mechanism?].

Aims: This study was made to determine if restenosis after percutaneous coronary angioplasty is associated with acute or chronic inflammatory/immunologic activity, and explored possible relationships with latent infection.

Patients And Method: Forty-six consecutive patients underwent elective PTCA and 6 months of angiographic follow-up. Peripheral venous blood samples were obtained at baseline, 24-48 h, and 4-6 months post-intervention.

[Genes and coronary heart disease].

The causes of atherosclerotic cardiovascular disease have been intensely scrutinized for the last few decades. Since the classic risk factors have been found to be incomplete predictors of the disease, additional risk factors based on molecular genetics are now being sought. Polymorphisms are gene variations that have only modest effects on the function of coded proteins or enzymes.

[Clinical profile of idiopathic paroxsysmal atrial fibrillation. (FAP registry)].

Objective: To assess the relative frequency and clinical profile of paroxysmal lone atrial fibrillation in comparison with that of secondary atrial fibrillation.

Patients And Method: A prospective multicenter study (FAP Register) was designed to include 300 patients with symptomatic paroxysmal atrial fibrillation admitted to the emergency ward of 11 secondary hospitals of Catalonia.

Results: Lone atrial fibrillation was found in 67 patients (22.

Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene.

Mutations causing hypertrophic cardiomyopathy have been described in nine genes encoding sarcomeric proteins. We report a new mutation in three families, with a C-->G transversion in nucleotide 12 307 of the beta-myosin heavy chain gene, located at the essential light chain interacting region, resulting in the replacement of arginine by glycine at amino acid residue 723. PCR amplification of the selected regions followed by single strand conformation polymorphism analysis, DNA sequencing of the polymorphic patterns and restriction analysis were used to detect the mutation.

[Guidelines for the diagnosis and management of heart failure and cardiogenic shock. Informe del Grupo de Trabajo de Insuficiencia Carddiacade la Sociedad Espanñola de Cardiología].

Guidelines for the Diagnosis and Management of Heart Failure and Cardiogenic Shock have been developed by the Working Group on Heart Failure of the Spanish Society of Cardiology, in collaboration with other Scientific Sections and members of the society. The aim of this report is to promote a more consistent and effective clinical practice according to the principles of evidence based medicine or the recommendations widely accepted by the scientific community. At the same time the aim is to give guidance for epidemiological surveys, heart failure registers clinical assays and clinical quality assessment, and to contribute to cost containment.

[Treatment of cardiac arrhythmia with radiofrequency in pediatrics].

Objective: The use of radiofrequency ablation of cardiac arrhythmias in pediatrics requires demonstration that the technique is effective and devoid of significant complications. In this study we present our experience in the ablation of cardiac arrhythmias in children and adolescents.

Patients And Methods: Between January 1992 and January 1997 we performed a total of 1,543 radiofrequency ablation procedures.

[Hemodynamic deterioration in patients submitted to ablation of the atrioventricular node].

Introduction: Radiofrequency ablation of the atrioventricular conduction system has become an established therapy for patients with drug-refractory atrial fibrillation. We observed 14 patients with hemodynamic deterioration related to worsening of mitral regurgitation after the procedure.

Patients And Methods: We retrospectively evaluated 256 consecutive patients with drug-refractory atrial fibrillation referred for radiofrequency ablation of the AV node and implantation of a pacemaker.

Radiofrequency ablation of anteroseptal, para-Hisian, and mid-septal accessory pathways using a simplified femoral approach.

Feasibility of RF ablation using a simplified two-catheter technique from a femoral approach was studied in 97 consecutive patients with a manifest or concealed accessory pathway located at the anteroseptal, mid-septal, and para-Hisian areas. RF was applied at the site with the shortest V-delta interval or the earliest retrograde atrial activation during orthodromic tachycardia or right ventricular pacing. Ablation was initially successful in 88 of 97 patients (91%).