Vicente Climent

Anatomic Relations Between the Esophagus and Left Atrium and Relevance for Ablation of Atrial Fibrillation

Background—Esophageal injury is a potential complication after intraoperative or percutaneous transcatheter ablation of the posterior aspect of the left atrium. Understanding the spatial relations between the esophagus and the left atrium is essential to reduce risks. Methods and Results—We examined by gross dissection the course of the esophagus in 15 cadavers. We measured the minimal distance of the esophageal wall to the endocardium of the left atrium with histological studies in 12 specimens. To measure the transmural thickness of the atrial wall, we sectioned another 30 human heart specimens in the sagittal plane at 3 different regions of the left atrium. The esophagus follows a variable course along the posterior aspect of the left atrium; its wall was <5 mm from the endocardium in 40% of specimens. The posterior left atrial wall has a variable thickness, being thickest adjacent to the coronary sinus and thinnest more superiorly. Behind is a layer of fibrous pericardium and fibrofatty tissue of irregular thickness that contains esophageal arteries of 0.4±0.2-mm external diameters. Conclusions—The nonuniform thickness of the posterior left atrial wall and the variable fibrofatty layer between the wall and the esophagus are risk factors that must be considered during ablation procedure. Esophageal arteries and vagus nerve plexus on the anterior surface of the esophagus may be affected by ablative procedures.

How close are the phrenic nerves to cardiac structures? Implications for cardiac interventionalists.

Background: Phrenic nerve injury is a recognized complication following cardiac intervention or surgery. With increasing use of transcatheter procedures to treat drug‐refractory arrhythmias, clarification of the spatial relationships between the phrenic nerves and important cardiac structures is essential to reduce risks.

The terminal crest: morphological features relevant to electrophysiology

Objective: To investigate the detailed anatomy of the terminal crest (crista terminalis) and its junctional regions with the pectinate muscles and intercaval area to provide the yardstick for structural normality. Design: 97 human necropsy hearts were studied from patients who were not known to have medical histories of atrial arrhythmias. The dimensions of the terminal crest were measured in width and thickness from epicardium to endocardium, at the four points known to be chosen as sites of ablation. Results: The pectinate muscles originating from the crest and extending along the wall of the appendage towards the vestibule of the tricuspid valve had a non-uniform trabecular pattern in 80% of hearts. Fine structure of the terminal crest studied using light and scanning electron microscopy consisted of much thicker and more numerous fibrous sheaths of endomysium with increasing age of the patient. 36 specimens of 45 (80%) specimens studied by electron microscopy had a predominantly uniform longitudinal arrangement of myocardial fibres within the terminal crest. In contrast, in all specimens, the junctional areas of the terminal crest with the pectinate muscles and with the intercaval area had crossing and non-uniform architecture of myofibres. Conclusions: The normal anatomy of the muscle fibres and connective tissue in the junctional area of the terminal crest/pectinate muscles and terminal crest/intercaval bundle favours non-uniform anisotropic properties.

Is Thrombogenesis in Atrial Fibrillation Related to Matrix Metalloproteinase-1 and Its Inhibitor, TIMP-1?

Background and Purpose— Decreased matrix metalloproteinase-1 (MMP-1) and increased levels of its inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), reflect impaired matrix degradation with an increase in fibrosis. A prothrombotic state has been described in atrial fibrillation (AF), increasing the risk of stroke and thromboembolism. Because structural abnormalities and remodeling of atria have been observed in AF, we hypothesized that the prothrombotic state in AF may be related to abnormal indexes of matrix degradation. Methods— We studied 48 consecutive patients (30 men; age, 70.5±9.0 years) with chronic nonrheumatic AF who were not on anticoagulation. Plasma levels of MMP-1, TIMP-1, and prothrombin fragment 1+2 (F1+2, an index of thrombogenesis) were measured by enzyme-linked immunosorbent assay. M-mode, 2-dimensional, and Doppler echocardiographic studies were performed in all patients. Research indexes were compared with data from 32 control subjects in sinus rhythm who were of similar age and sex. Results— Patients with AF had lower levels of MMP-1 (P =0.011) but increased levels of TIMP-1 (P =0.033) and F1+2 (P <0.001) and a higher ratio of TIMP-1 to MMP-1 (P =0.009) compared with control subjects. After adjustment for sex, age, hypertension, and diabetes, TIMP-1 levels and the ratio of TIMP-1 to MMP-1 correlated with F1+2 levels (r =0.24, P =0.038; and r =0.26, P =0.023, respectively). In multivariate analysis, there was no independent relationship between MMP-1, TIMP-1, or ratio of TIMP-1 to MMP-1 and the presence of AF. Conclusions— Patients with AF have evidence of impaired matrix degradation, but this was not independently associated with the presence of AF on multivariate analysis. However, an independent relationship was found between the MMP/TIMP system and prothrombotic state (assessed by F1+2 levels).

The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinsonism, and the G2019S mutation of LRRK2 is one of the most prevalent mutations. The deregulation of autophagic processes in nerve cells is thought to be a possible cause of Parkinson’s disease (PD). In this study, we observed that G2019S mutant fibroblasts exhibited higher autophagic activity levels than control fibroblasts. Elevated levels of autophagic activity can trigger cell death, and in our study, G2019S mutant cells exhibited increased apoptosis hallmarks compared to control cells. LRRK2 is able to induce the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells. These data suggest that the G2019S mutation induces autophagy via MEK/ERK pathway and that the inhibition of this exacerbated autophagy reduces the sensitivity observed in G2019S mutant cells.

Plasma von Willebrand factor, soluble thrombomodulin, and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation

Objective: To investigate whether new onset acute atrial fibrillation (AF) of < 48 hours’ duration creates a prothrombotic state in the absence of anticoagulation and to assess the evolution in research indices after spontaneous or pharmacological cardioversion. Methods: 24 patients were recruited with first onset acute non-rheumatic AF, in whom sinus rhythm was restored within 48 hours of arrhythmia onset, without anticoagulant treatment. Atrial mechanical function was assessed by transmitral inflow. Soluble thrombomodulin and von Willebrand factor concentrations (both as indices of endothelial damage or dysfunction) and fibrin D-dimer concentrations (as an index of thrombogenesis) were measured. Blood samples were drawn and echocardiographic studies were performed at days 1, 3, 7, and 30 after cardioversion. Research indices were compared with those of 24 healthy participants, 24 patients with chronic AF, and 24 patients with ischaemic heart disease in sinus rhythm. Results: Patients with AF had higher concentrations of soluble thrombomodulin (acute AF 12.1 (4.1) ng/ml; chronic AF 11.8 (4.6) ng/ml), von Willebrand factor (acute AF 137.2 (36.9) ng/ml; chronic AF 133.1 (25.0) ng/ml), and fibrin D-dimer concentrations (acute AF 2.35 (2.68) μg/ml; chronic AF 1.12 (0.65) μg/ml) than did healthy controls (5.9 (2.7) ng/ml, 86.7 (33.2) ng/ml, and 0.39 (0.28) μg/ml, respectively) and patients with ischaemic heart disease (7.4 (3.7) ng/ml, 110.0 (29.0) ng/ml, and 0.99 (0.73) μg/ml, respectively) (all p < 0.05). Day 30 concentrations of fibrin D-dimer were higher in patients with acute AF than in patients with chronic AF (p  =  0.038) but sTM and von Willebrand factor concentrations were not different (both not significant). There were no significant changes in research indices or echocardiographic parameters after cardioversion (all p > 0.05). Conclusions: There was evidence among patients with acute onset AF of endothelial damage or dysfunction and increased thrombogenesis, which persisted up to 30 days after cardioversion.

Anatomic evaluation of the left phrenic nerve relevant to epicardial and endocardial catheter ablation: Implications for phrenic nerve injury

BACKGROUND/OBJECTIVE The purpose of this study was to clarify the spatial relationship between the left phrenic nerve (LPN) and key cardiac structures in order to minimize the risk of phrenic nerve injury during interventions. METHODS The course and relationship of the LPN to various cardiac structures were examined by gross dissection and histologic sections of 22 human cadavers. RESULTS The nerve descended on the fibrous pericardium along one of three courses: over the anterior surface of the left ventricle (18%), over the lateral margin of the left ventricle (59%), and in a posteroinferior direction (23%). The endocardium of the roof of the left atrial appendage was <4 mm from the LPN in 2 (9%) specimens. The nerve passed <2.5 mm from the epicardium of the apex of the left atrial appendage in 7 (31%) specimens. Regardless of the position of the nerve in relation to the high left ventricular wall, the nerve was <3 mm from the epicardial surface in 8 (36%) specimens and passed <6 mm from the epicardium of the right ventricular outflow tract in 2 (9%) specimens. CONCLUSION During electrophysiologic interventions, the LPN is especially at risk when procedures are performed in the vicinity of the left atrial appendage and high left ventricular wall.

Myoarchitecture and connective tissue in hearts with tricuspid atresia

Objective To compare the atrial and ventricular myoarchitecture in the normal heart and the heart with tricuspid atresia, and to investigate changes in the three dimensional arrangement of collagen fibrils. Methods Blunt dissection and cell maceration with scanning electron microscopy were used to study the architecture of the atrial and ventricular musculature and the arrangement of collagen fibrils in three specimens with tricuspid atresia and six normal human hearts. Results There were significant modifications in the myoarchitecture of the right atrium and the left ventricle, both being noticeably hypertrophied. The middle layer of the ventricle in the abnormal hearts was thicker than in the normal hearts. The orientation of the superficial layer in the left ventricle in hearts with tricuspid atresia was irregular compared with the normal hearts. Scanning electron microscopy showed coarser endomysial sheaths and denser perimysial septa in hearts with tricuspid atresia than in normal hearts. Conclusions The overall architecture of the muscle fibres and its connective tissue matrix in hearts with tricuspid atresia differed from normal, probably reflecting modelling of the myocardium that is inherent to the malformation. This is in concordance with clinical observations showing deterioration in pump function of the dominant left ventricle from very early in life.

Obese subjects with heart failure have lower N-terminal pro-brain natriuretic peptide plasma levels irrespective of aetiology†

N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) may be useful in the diagnosis of heart failure and ventricular dysfunction. Obesity is an independent cardiovascular risk factor. The purpose of this study was to measure NT‐proBNP plasma levels in obese and non‐obese subjects with heart failure and to compare levels in subjects with ischaemic and dilated aetiology.

MORPHOLOGY AND SIGNIFICANCE OF PROGRAMMED CELL DEATH IN THE DEVELOPING LIMB BUD OF THE VERTEBRATE EMBRYO

Cell death constitutes a basic mechanism accounting for many morphogenetic and histogenetic events during normal and abnormal development of embryonic organs and tissues. This article focuses on the major areas of mesodermal cell death occurring during vertebrate limb development. In early stages of limb development, cell death appears to reduce the amount of mesodermal tissue destined to form the anlage of the autopodium. In later stages, cell death plays a role sculpturing the shape of the digits. The morphology of the dying cells corresponds with apoptosis, but internucleosomal DNA fragmentation by endonuclease activation does not appear to be a precocious feature. The cell death program can be inhibited in vivo and in vitro by changing the environmental conditions of the prospective dying cells up to 6–10 h before death. In this review, we survey possible factors controlling the establishment of the cell death program. Information concerning the biochemical basis of cell death in the developing limb is also revised. Finally, the possible role of genes whose pattern of expression is coincident with the dying processes is discussed.