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). All three mutations are associated with hypertrophic cardiomyopathy and are located in the converter region of the myosin head domain. We determined several mechanical parameters of single skinned slow fibers isolated from Musculus soleus biopsies of hypertrophic cardiomyopathy patients and healthy controls. Major findings of this study for mutation R723G were i), a >40% increase in fiber stiffness in rigor with a 2.9-fold increase in stiffness per myosin head (S( *)(rigor R723G) = 0.84 pN/nm S( *)(rigor WT) = 0.29 pN/nm); and ii), a significant increase in force per head (F( *)(10 degrees C), 1.99 pN vs. 1.49 pN = 1.3-fold increase; F( *)(20 degrees C), 2.56 pN vs. 1.92 pN = 1.3-fold increase) as well as stiffness per head during isometric steady-state contraction (S( *)(active10 degrees C), 0.52 pN/nm vs. 0.28 pN/nm = 1.9-fold increase). Similar changes were found for mutation R719W (2.6-fold increase in S( *)(rigor); 1.8-fold increase in F( *)(10 degrees C), 1.6-fold in F( *)(20 degrees C); twofold increase in S( *)(active10 degrees C)). Changes in active cross-bridge cycling kinetics could not account for the increase in force and active stiffness. For the above estimates the previously determined fraction of mutated myosin in the biopsies was taken into account. Data for wild-type myosin of slow soleus muscle fibers support previous findings that for the slow myosin isoform S( *) and F( *) are significantly lower than for fast myosin e.g., of rabbit psoas muscle. The data indicate that two mutations, R723G and R719W, are associated with an increase in resistance to elastic distortion of the individual mutated myosin heads whereas mutation I736T has essentially no effect. The data strongly support the notion that major elastic distortion occurs within the converter itself. Apparently, the compliance depends on specific residues, e.g., R719 and R723, presumably located at strategic positions near the long alpha-helix of the light chain binding domain. Because amino acids 719 and 723 are nonconserved residues, cross-bridge stiffness may well be specifically tuned for different myosins.

[Clinical profile of idiopathic paroxsysmal atrial fibrillation. (FAP registry)]. / Perfil clínico de la fibrilación auricular paroxística idiopática (registro FAP).

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 (22.3%) while systemic hypertension was present in 33.7% of the cases; mitral or aortic valvular disease in 12% and coronary heart disease in 9.7%. As compared with patients with evidence of cardiac or systemic etiology, patients with isolated paroxysmal atrial fibrillation were younger (mean age of 55 vs 65 years of age; p = 0.0001), dyspnea was less frequent (p = 0.007); had a tendency to appear at night; left atrial size was smaller (p < 0.001) and response to treatment of sinusal rhythm was not different. CONCLUSIONS: Relative frequency of paroxysmal lone atrial fibrillation was only second to hypertension, which appears to be the most important pathogenic factor in our population. The clinical profile shows similarities in secondary fibrillation

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. A total of 23 individuals were diagnosed as carriers, and seven were obligate carriers or had been clinically diagnosed. The Arg723Gly mutation was associated with a malignant phenotype. Ten out of 30 affected members died suddenly or needed an implantable cardioverter-defibrillator at a mean age of 42, and seven members developed progressive heart failure, leading to death or heart transplant in five, at a mean age of 50 years. Echocardiography showed non-obstructive left ventricular hypertrophy in affected members older than 20 (sensitivity 68%). Mean survival of affected members was 51 years. In conclusion, a new mutation Arg723Gly in beta-myosin heavy chain gene is reported which shortens life expectancy because of sudden death and end-stage heart failure.

[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]. / Guías del diagnóstico, clasificación y tratamiento de la insuficiencia cardíaca y del shock cardiogénico. Informe del Grupo de Trabajo de Insuficiencia Cardíaca de la Sociedad Española 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. These twelve guidelines have been designed for doctors in general practice as well as specialists. Criteria for diagnosis and classification of heart failure (systolic and diastolic heart failure, left or right, acute or chronic) are defined. The more appropriate use of clinical or high technology laboratory studies are recommended as well as the most efficient strategies nowadays for the management of chronic stable, unstable or refractory heart failure, or acute heart failure and cardiogenic shock.

[Hemodynamic deterioration in patients submitted to ablation of the atrioventricular node]. / Deterioro hemodinámico en pacientes sometidos a ablación del nodo auriculoventricular.

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. Because we found hemodynamic deterioration related to worsening mitral regurgitation, we compared the clinical history, electrophysiologic and echocardiographic data from the patients with hemodynamic deterioration and worsening mitral regurgitation (group A) with those without hemodynamic deterioration (group B). RESULTS: Fourteen out of 256 patients (group A) undergoing ablation of the atrioventricular conduction system deteriorated with acute pulmonary edema (3 patients) or congestive heart failure (11 patients) at a mean of 6 weeks after the ablation procedure. Four of these patients were referred for mitral valve surgery. The length of the procedure and the number of applications during ablation were similar in both groups. Compared with group B patients, group A patients had significantly higher left ventricular end-diastolic diameters (64 +/- 6 mm vs 56 +/- 9 mm; p < 0.05) at baseline despite similar left ventricular end-systolic diameters, fractional shortening and grade of mitral regurgitation (1.15 +/- 1.05 vs 1.11 +/- 0.97). Moreover, whereas no change was observed in left ventricular end-diastolic diameter, left ventricular end-systolic diameter, fractional shortening and grade of mitral regurgitation in group B patients after ablation, group A patients experienced a significant increase in left ventricular end-diastolic diameter (64 +/- 6 mm vs 72 +/- 9 mm; p < 0.01) and grade of mitral regurgitation (1.15 +/- 1.05 vs 2.90 +/- 1.15; p < 0.01). In patients operated on no ablation related structural damage to the mitral valve apparatus could be detected. The worsening of the mitral regurgitation was related to dilation of the mitral valve annulus. CONCLUSIONS: Hemodynamic deterioration together with progression of mitral regurgitation is a potential complication of ablation of the atrioventricular conduction system.

[Treatment of cardiac arrhythmia with radiofrequency in pediatrics]. / Tratamiento de arritmias cardíacas con radiofrecuencia en pediatría.

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. Of these, 130 were performed in 117 patients younger than 18 years of age (58 were younger than 14 years old). Indication for ablation was the presence of drug refractory recurrent paroxysmal supraventricular tachycardia in 112 patients and permanent ventricular preexcitation in 5 asymptomatic patients. Final diagnosis in the 112 symptomatic patients was: 4 atrial tachycardias, 21 atrio-ventricular nodal reentrant tachycardias, 53 Wolff-Parkinson-White (WPW) syndromes, 33 orthodromic tachycardias using a concealed accessory pathway and 1 idiopathic left ventricular tachycardia. RESULTS: The initial ablation procedure was effective in 109/117 patients (93%) with a total duration of 90 +/- 31 minutes, using 16 +/- 11 minutes of radioscopy and a median of 4 radiofrequency applications. During follow-up, recurrence occurred in 9 patients (8%). In 7 of them and in 6 of those with an unsuccessful initial procedure, a second effective procedure was performed in 11/13 patients. Finally, radiofrequency ablation was effective in 111/117 patients (95%). We observed a single complication in a 15 year old girl who presented a thrombosis of the right femoral artery requiring balloon recanalization. Comparison of these results with those in the adult population showed no difference in terms of effectiveness, recurrences or complications. CONCLUSIONS: Radiofrequency ablation of cardiac arrhythmias in pediatric and young patients can be safely and effectively done. Results are similar to those obtained in adults suggesting that indications for ablation can also be similar.

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%). Success rate was 94% (16/17) for anteroseptal, 94% (39/43) for para-Hisian, and 89% (33/37) for mid-septal accessory pathways, without differences between manifest and concealed pathways for any of the locations. Mean number of RF pulses was 8 +/- 5 for anteroseptal, 6 +/- 6 for mid-septal, and 12 +/- 13 for para-Hisian accessory pathways. Two patients (2%) required implantation of a permanent pacemaker for complete AV block. At a mean follow-up of 27 +/- 14 months, four patients with previous manifest preexcitation experienced resumption of intermittent preexcitation, but only one required a second successful procedure for recurrence of palpitations. RF ablation can be used effectively and without impairment of normal AV conduction in the majority of patients with anteroseptal, para-Hisian, and mid-septal accessory pathways using a simplified two-catheter technique from a femoral approach.

[Long term follow-up in patients with the permanent form of junctional reciprocating tachycardia treated with radiofrequency ablation]. / Seguimiento a largo plazo de pacientes con la forma permanente de taquicardia recíproca de la unión tipo Coumel tratados mediante ablación con radiofrecuencia.

OBJECTIVES: This study sought to determine the long-term follow-up, safety and efficacy of radiofrequency catheter ablation in patients with the permanent form of junctional reciprocating tachycardia. We assessed the reversibility of tachycardia-related left ventricular dysfunction and we detailed the location and electrophysiologic characteristics of these atrioventricular decremental pathways. BACKGROUND: Permanent junctional reciprocating tachycardia is an infrequent form on reciprocating tachycardia, commonly incessant and usually drug-refractory. The electrocardiographic hallmarks include an RP interval > PR with inverted P waves in leads II, III, aVF and V3-V6. During tachycardia, retrograde ventriculo-atrial conduction occurs over an accessory pathway with decremental conduction properties, located predominantly in the posteroseptal zone. It is known that long lasting and incessant tachycardia may result in tachycardia-related severe ventricular dysfunction, the so called tachycardiomyopathy. PATIENTS AND METHODS: We included 24 patients (9 males, 15 females; mean age 42 +/- 22 years) with the diagnosis of permanent junctional reciprocating tachycardia at electrophysiologic study. Six patients had tachycardia-related left ventricular dysfunction. Radiofrequency energy was delivered at the site of earliest retrograde atrial activation during reciprocating tachycardia (n = 22) or ventricular pacing (n = 2). All patients were followed at the outpatient clinic and serial echocardiograms were performed in those who presented depressed left ventricular function. RESULTS: Radiofrequency catheter ablation was performed in 24 decremental accessory pathways. Earliest retrograde atrial activation was right posteroseptal in 22 patients (92%), right midseptal in 1 (4%) and right posterolateral in 1 (4%). Twenty-three accessory pathways were successfully ablated with a mean of 5 +/- 3 (median, 4) radiofrequency applications of a mean duration of 48 +/- 13 s. Only the midseptal accessory pathway could not be ablated. After a mean follow-up of 21 +/- 16 months (median, 15; range 2 to 64) 22 patients remain asymptomatic. There were recurrences in 4 patients after the initial successful ablation (three during the first month and one during the second month after the procedure), two were ablated in a second ablation procedure, one patient required a third procedure and one required a fourth. All patients with left ventricular dysfunction experienced an improvement after ablation. Mean preablation left ventricular ejection fraction in patients with tachycardiomyopathy was 28 +/- 6% (median, 27) and raised to 51 +/- 16% (median, 47) after ablation (p < 0.02). CONCLUSIONS: Our study supports the concept that radiofrequency catheter ablation is a safe and useful treatment for patients with permanent junctional reciprocating tachycardia. Radiofrequency current should be the treatment of choice in these patients because this arrhythmia is usually drug-refractory. The majority of accessory pathways with decremental conduction properties are localized in the posteroseptal zone. Cessation of the arrhythmia after successful ablation results in recovery of left ventricular dysfunction.

Enhanced detection criteria in implantable defibrillators.

INTRODUCTION: Enhanced detection criteria in third-generation implantable defibrillators have been implemented to avoid inappropriate therapy of fast supraventricular arrhythmias. We prospectively analyzed the use of these criteria in patients with an implantable defibrillator with electrogram storing capability. METHODS AND RESULTS: In 82 consecutive patients with a Guidant-CPI implantable defibrillator, sudden onset > 9% and stability < 40 msec were systematically programmed in zone 1 of therapy together with a sustained rate duration security mechanism. All detected tachycardia episodes were analyzed. The study population consisted of 59 patients who had at least one episode of tachycardia detected in zone 1 during follow-up. The tachycardia rate in zone 1 never exceeded 210 beats/min. Twenty patients had no episodes during follow-up, and three patients had episodes detected exclusively in zone 2 of therapy. Supraventricular arrhythmias were detected frequently in the ventricular tachycardia zone (193 of 690 tachycardia episodes in 23 of 59 patients). Use of sudden onset was very effective in detecting sinus tachycardias (65 of 67 episodes), and stability was very useful in detecting atrial fibrillation (31 of 32 episodes). However, sensitivity in detecting ventricular tachycardia was only 90% (451 of 497 episodes). Application of the sustained rate duration criterion allowed appropriate treatment of all ventricular tachycardia episodes, increasing sensitivity to 100%; however, specificity in appropriate nontreatment of supraventricular decreased from 96% to 83%. Subsequent analysis of different algorithms applied to our data showed that sudden onset > 9% and stability < 40 msec was the algorithm with the best specificity and sensitivity. CONCLUSION: Programming sudden onset and stability detection criteria with a sustained rate duration safety net for triggering tachycardia therapy results in appropriate device management in most patients with supraventricular and slow (< 210 beats/min) ventricular tachycardias.

Atrial fibrillation induced by atrioventricular nodal reentrant tachycardia.

In 4 patients with recurrent episodes of paroxysmal atrial fibrillation as the only documented arrhythmia, electrophysiologic study showed that atrial fibrillation originated after a very fast transition from atrioventricular nodal reentrant tachycardia. Recognition of atrioventricular nodal reentrant tachycardia as the triggering factor for atrial fibrillation has important therapeutic consequences.

Radiofrequency ablation of concealed left free-wall accessory pathways without coronary sinus catheterization: results in 100 consecutive patients.

INTRODUCTION: Feasibility of radiofrequency (RF) ablation using a two-catheter technique without coronary sinus catheterization was studied in 100 consecutive patients with a single concealed left free-wall accessory pathway. METHODS AND RESULTS: Tachycardia was induced by electrical stimulation in the right atrium/right ventricle, and the presence of a concealed left free-wall accessory pathway was suggested electrocardiographically (negative P wave in leads I and/or aVL during orthodromic tachycardia) or by earlier atrial activation in the pulmonary artery compared to the high right atrium. Mapping of the mitral annulus was performed during right ventricular pacing or orthodromic tachycardia, and RF energy was applied at the site with the earliest retrograde atrial activation. Ablation was considered effective if tachycardia could not be induced, and if VA dissociation or exclusive retrograde nodal conduction was observed. Ablation was initially successful in 98 of 100 patients. Mean number of radiofrequency pulses were 3.2 +/- 2. Mean fluoroscopy time and total procedure time was 14 +/- 9 and 107 +/- 32 minutes, respectively. There were no complications related to the procedure. At a mean follow-up of 22 +/- 13 months, two patients experienced tachycardia recurrence and required a second procedure, which was successful. CONCLUSIONS: Our results suggest that RF catheter ablation of concealed left free-wall accessory pathways can be safely, effectively, and rapidly performed using a simplified two-catheter technique with no need for coronary sinus catheterization.

[Radiofrequency ablation of occult left accessory pathways without catheterization of the coronary sinus]. / Ablación mediante radiofrecuencia de vías accesorias ocultas izquierdas sin cateterismo del seno coronario.

BACKGROUND: Radiofrequency catheter ablation of concealed left-sided accessory pathways conventionally implies the introduction of several catheters for the assessment of electrophysiological properties as well as for the localization of the accessory pathways. PATIENTS AND METHODS: Feasibility of radiofrequency ablation using a simplified two-catheter technique without coronary sinus catheterization was prospectively studied in 95 consecutive patients with a single concealed left free-wall accessory pathway. A 6F quadripolar catheter was introduced into the right atrium/right ventricle and tachycardia was induced by electrical stimulation. The presence of a concealed left-sided accessory pathway was suggested electrocardiographically (negative P wave in I and/or aVL during orthodromic tachycardia) or by earlier atrial activation in the pulmonary artery compared to the right atrium. Mapping of the mitral annulus and ablation were performed during orthodromic tachycardia or ventricular pacing using a 7F steerable catheter. Radiofrequency energy was applied at sites with the shortest VA interval. The procedure was considered effective if tachycardia could not be induced and if VA dissociation or exclusive nodal VA conduction were observed. RESULTS: The procedure was initially successful in 93 out of 95 patients (98%). Mean number of applications were 3.2 +/- 2. Mean fluoroscopy time and total procedure duration were 14 +/- 9 and 108 +/- 33 minutes respectively. At a mean follow-up of 21 +/- 13 months, 2 patients required a second session because of tachycardia recurrence. CONCLUSIONS: Radiofrequency catheter ablation of concealed left-sided accessory pathways can be safely, effectively and rapidly performed using a two-catheter technique without coronary sinus catheterization.

[Guideline 1. Diagnosis of heart failure and ventricular dysfunction]. / Guía 1. Diagnóstico de la insuficiencia cardíaca y la disfunción ventricular.

The criteria required for the diagnosis of the four clinical aspects of the congestive heart failure, that are needed for the correct management of patients are discussed: the diagnosis of the syndrome, mechanism (systolic or diastolic dysfunction), ethology and functional capacity. The "initial evaluation" of patients presenting with symptoms of heart failure is described to encourage an structured diagnostic approach and the cost/effective use of diagnostic methods.

[Guideline 6. Cardiogenic shock]. / Guía 6. Shock cardiogénico.

The criteria required for the clinical and hemodynamic diagnosis of cardiogenic shock are described. The management of shock is briefly reviewed.

[Guideline 7. Intensive treatment of unstable heart failure. Indications for heart transplantation]. / Guía 7. Tratamiento intensivo de la insuficiencia cardíaca inestable. Indicaciones del trasplante cardíaco.

Unstable heart failure is defined as class IV cardiac failure with symptoms that do not respond to empiric treatment, which causes hypotension, renal failure, hyponatremia and/or symptomatic ventricular arrhythmias. It may be reversible or refractory. Refractory or "end-stage" heart failure is an indication for heart transplant, provided that: a) all reversible ethiologic factors have been corrected; and b) aggressive treatment in the intensive care unit under hemodynamic monitoring has not been able to stabilize heart failure.

[Guideline 8. Guidelines for diagnosis and treatment of congestive heart failure and shock (DRG 127). Hospitalization criteria]. / Guía 8. Criterios de hospitalización.

The recommendations for hospital admission are discussed. The need to avoid needless hospitalizations is emphasized.