Although myocardial architecture has been investigated extensively, as yet no evidence exists for the anatomic segregation of discrete myocardial pathways. We performed post-mortem diffusion tensor imaging on 14 pig hearts. Pathway tracking was done from 22 standardized voxel groups from within the left ventricle, the left ventricular papillary muscles, and the right ventricular outflow tract. We generated pathways with comparable patterns in the different hearts when tracking from all chosen voxels. We were unable to demonstrate discrete circular or longitudinal pathways, nor to trace any solitary tract of myocardial cells extending throughout the ventricular mass. Instead, each pathway possessed endocardial, midwall, and epicardial components, merging one into another in consistent fashion. Endocardial tracks, when followed towards the basal or apical parts of the left ventricle, changed smoothly their helical and transmural angulations, becoming continuous with circular pathways in the midwall, these circular tracks further transforming into epicardial tracks, again by smooth change of the helical and transmural angles. Tracks originating from voxels in the papillary muscles behaved similarly to endocardial tracks. This is the first study to show myocardial pathways that run through the mammalian left and right ventricles in a highly reproducible manner according to varying local helical and transmural intrusion angles. The patterns generated are an inherent feature of the three-dimensional arrangement of the individual myocytes aggregated within the walls, differing according to the regional orientation and branching of individual myocytes. We found no evidence to support the existence of individual muscles or bands.

The three-dimensional architecture of the right ventricular myocardium is a major determinant of function, but as yet no investigator-independent methods have been used to characterize either the normal or hypertrophied state. We aimed to assess and compare, using diffusion tensor magnetic resonance imaging, the normal architecture with the arrangement induced by chronic hypertrophy. We randomized 20 female 5 kg piglets into pulmonary trunk banding (N ¼ 16) and sham operation (N ¼ 4). Right ventricular hypertrophy was assessed after 8 weeks. The excised and fixed hearts were subject to diffusion tensor imaging to determine myocyte helical angles, and the presence of any reproducible tracks formed by the aggregated myocytes. All banding animals developed significant right ventricular hypertrophy, albeit that no difference was observed in terms of helical angles or myocardial pathways between the banded animals and sham group animals. Helical angles varied from $70 degrees endocardially to À50 degrees epicardially. Very few tracks were circular, with helical angles approximating zero. Reproducible patterns of chains of aggregated myocytes were observed in all hearts, regardless of group. The architecture of the myocytes aggregated in the walls of the right ventricle is comparable to that found in the left ventricle in terms of endocardial and epicardial helical angles, however the right ventricle both in the normal and the hypertrophied state lacks the extensive zone of circular myocytes seen in the mid-portion of the left ventricular walls. Without such beneficial architectural remodelling, the porcine right ven-*Correspondence to:

Sevoflurane is a cerebral vasodilator in patients with cerebral tumours. Sevoflurane increases CBF and decreases CVR in a dose-dependent manner. CO2-reactivity is preserved during 1.5% and 2.5% sevoflurane.

BackgroundPulmonary arterial hypertension is usually fatal due to right ventricular failure and is frequently associated with co-existing left ventricular dysfunction. Endothelin-1 is a powerful pro-fibrotic mediator and vasoconstrictor that is elevated in pulmonary arterial hypertension. Endothelin receptor blockers are commonly used as pulmonary vasodilators, however their effect on biventricular injury, remodeling and function, despite elevated isolated right ventricular afterload is unknown.MethodsElevated right ventricular afterload was induced by progressive pulmonary artery banding. Seven rabbits underwent pulmonary artery banding without macitentan; 13 received pulmonary artery banding + macitentan; and 5 did not undergo inflation of the pulmonary artery band (sham-operated controls). Results: Right and left ventricular collagen content was increased with pulmonary artery banding compared to sham-operated controls and ameliorated by macitentan. Right ventricular fibrosis signaling (connective tissue growth factor and endothelin-1 protein levels); extra-cellular matrix remodeling (matrix-metalloproteinases 2 and 9), apoptosis and apoptosis-related peptides (caspases 3 and 8) were increased with pulmonary artery banding compared with sham-operated controls and decreased with macitentan.ConclusionIsolated right ventricular afterload causes biventricular fibrosis, right ventricular apoptosis and extra cellular matrix remodeling, mediated by up-regulation of endothelin-1 and connective tissue growth factor signaling. These pathological changes are ameliorated by dual endothelin receptor blockade despite persistent elevated right ventricular afterload.

Recent studies point toward the existence of a significant population of cardiomyocytes that intrude transmurally, in addition to those aligned tangentially. Our aim was to investigate the extent of transmural angulation in the porcine left ventricle using diffusion tensor magnetic resonance imaging (DTMRI). Hearts from eight 15 kg pigs were arrested in diastole. The ventricles were filled with polymer to maintain the enddiastolic dimensions. All hearts were examined using DTMRI to assess the distribution of transmural angulation of the cardiomyocytes at 12 predetermined locations covering the entirety of the left ventricle. We found significant differences between the regions, as well as within the transmural subcomponents. In eight out of the 12 predetermined mural segments, the highest mean transmural angle was located sub-endocardially. The greatest mean transmural angles were found in the anterior basal region, specifically 14.9 6 6.0-degree angle, with the greatest absolute value being 34.3-degree angle. This is the first study to show the significant heterogeneities in the distribution of helical and transmural angles within the entirety of the left ventricular walls, not only for different depths within the ventricular walls, but also between different ventricular regions. The results show unequivocally that not all the contractile elements are aligned exclusively in tangential fashion within the left ventricle. The main function of the transmurally intruding component is most likely to equalize and normalize shortening of the cardiomyocytes at all depths within the myocardium, but our findings also support the

The right ventricle (RV) tolerates acute pulmonary valvular regurgitation fairly well, however, in the long-term dilatation and failure often ensues. There is little known of the structural and functional myocardial alterations following this pathophysiology, and therefore animal models are sought. We aimed to develop an animal experimental model for RV dilatation emphasizing feasibility, reproducibility and human compatibility. Free pulmonary valve insufficiency and RV dilatation were created with a novel external suture plication technique in nine 5 kg piglets. Six matched animals served as controls. After 10 weeks cardiac dimensions and physiology were assessed with in vivo cardiovascular MRI and conductance technique. RV end-diastolic volume increased 31% in the intervention group (P=0.03). The regurgitation fraction was 37% in the intervention group compared to -2% in controls (P<0.001). Conductance measurements showed preserved RV contractile function, but significant left ventricular diastolic impairment. This study is the first to show that pulmonary valve regurgitation, RV dilatation and functional impairment can be achieved by external leaflet plication. Compared to known methods, the advantages of this model are: 1) no induction of stenosis over time, 2) no risk of stent migration, and 3) very simple and reproducible.

Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular‐ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure‐load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)‐induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle‐tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro‐fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge‐point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up‐regulation of regional transforming growth factor‐β1 (TGF β1) and apoptosis signaling. A group of PAH rats who received the TGF β blocker SB431542 showed improved RV function and reduced regional hinge‐point myocardial fibrosis. RV pressure‐loading and PAH lead to biventricular TGF β1 signaling, fibrosis and apoptosis, predominantly at the septal hinge‐point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV‐LV interactions through the septal hinge‐points to induce LV fibrosis and dysfunction.

Surgical relief for pulmonary stenosis is efficient in relieving outflow obstruction; however, this efficiency is achieved at the cost of pulmonary regurgitation, leading to right ventricular dilatation and tricuspid regurgitation. When required, pulmonary valve replacement is performed most frequently >20 years after the initial surgery. Lifelong follow-up of patients treated surgically for pulmonary stenosis is emphasised in this group of patients, who might otherwise consider themselves cured.