Impact of surgical ventricular restoration on ventricular shape, wall stress, and function in heart failure patients

Surgical ventricular restoration (SVR) was designed to treat patients with aneurysms or large akinetic walls and dilated ventricles. Yet, crucial aspects essential to the efficacy of this procedure like optimal shape and size of the left ventricle (LV) are still debatable. The objective of this study is to quantify the efficacy of SVR based on LV regional shape in terms of curvedness, wall stress, and ventricular systolic function. A total of 40 patients underwent magnetic resonance imaging (MRI) before and after SVR. Both short-axis and long-axis MRI were used to reconstruct end-diastolic and end-systolic three-dimensional LV geometry. The regional shape in terms of surface curvedness, wall thickness, and wall stress indexes were determined for the entire LV. The infarct, border, and remote zones were defined in terms of end-diastolic wall thickness. The LV global systolic function in terms of global ejection fraction, the ratio between stroke work (SW) and end-diastolic volume (SW/EDV), the maximal rate of change of pressure-normalized stress (dσ*/dt(max)), and the regional function in terms of surface area change were examined. The LV end-diastolic and end-systolic volumes were significantly reduced, and global systolic function was improved in ejection fraction, SW/EDV, and dσ*/dt(max). In addition, the end-diastolic and end-systolic stresses in all zones were reduced. Although there was a slight increase in regional curvedness and surface area change in each zone, the change was not significant. Also, while SVR reduced LV wall stress with increased global LV systolic function, regional LV shape and function did not significantly improve.     

Transmural cardiac strains in the lateral wall of the ovine left ventricle

The constant-volume property of contracting cardiac muscle has been invoked in models of heart wall mechanics that predict that systolic subendocardial left ventricular (LV) wall thickening must significantly exceed subepicardial thickening. To examine this prediction, we implanted arrays of radiopaque markers to measure lateral equatorial wall transmural strains and global and regional LV geometry in seven sheep and studied the four-dimensional dynamics of these arrays using biplane videofluoroscopy (60 Hz) in anesthetized intact animals 1 and 8 wk after surgery. A transmural gradient of systolic lateral wall thickening was observed at 1 wk (P = 0.009; linear regression) but was no longer present at 8 wk (P = 0.243). Referenced to end diastole, group mean (+/-SD) end-systolic radial subepicardial, midwall, and subendocardial wall thickening strains were, respectively, 0.08 +/- 0.08, 0.14 +/- 0.08, and 0.22 +/- 0.12 at 1 wk and 0.19 +/- 0.07 (P = 0.02; 1 vs. 8 wk), 0.20 +/- 0.04, and 0.23 +/- 0.07 at 8 wk. With the exception of an 8-ml (7%) increase in end-diastolic volume (P = 0.04) from 1 to 8 wk, LV shape and hemodynamics were otherwise unchanged. We conclude that equivalent hemodynamics can be generated by the left ventricle with or without a transmural gradient of systolic wall thickening in this region; thus such a gradient is unlikely to be a fundamental property of the contracting LV myocardium. We discuss some implications of these findings regarding mechanisms involved in systolic wall thickening.     

Contribution of myocardium overlying the anterolateral papillary muscle to left ventricular deformation

Previous studies of transmural left ventricular (LV) strains suggested that the myocardium overlying the papillary muscle displays decreased deformation relative to the anterior LV free wall or significant regional heterogeneity. These comparisons, however, were made using different hearts. We sought to extend these studies by examining three equatorial LV regions in the same heart during the same heartbeat. Therefore, deformation was analyzed from transmural beadsets placed in the equatorial LV myocardium overlying the anterolateral papillary muscle (PAP), as well as adjacent equatorial LV regions located more anteriorly (ANT) and laterally (LAT). We found that the magnitudes of LAT normal longitudinal and radial strains, as well as major principal strains, were less than ANT, while those of PAP were intermediate. Subepicardial and midwall myofiber angles of LAT, PAP, and ANT were not significantly different, but PAP subendocardial myofiber angles were significantly higher (more longitudinal as opposed to circumferential orientation). Subepicardial and midwall myofiber strains of ANT, PAP, and LAT were not significantly different, but PAP subendocardial myofiber strains were less. Transmural gradients in circumferential and radial normal strains, and major principal strains, were observed in each region. The two main findings of this study were as follows: 1) PAP strains are largely consistent with adjacent LV equatorial free wall regions, and 2) there is a gradient of strains across the anterolateral equatorial left ventricle despite similarities in myofiber angles and strains. These findings point to graduated equatorial LV heterogeneity and suggest that regional differences in myofiber coupling may constitute the basis for such heterogeneity.     

Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy

Ventricular loading conditions are crucial determinants of cardiac function and prognosis in heart failure. B-type natriuretic peptide (BNP) is mainly stored in the ventricular myocardium and is released in response to an increased ventricular filling pressure. We examined, therefore, the hypothesis that BNP serum concentrations are related to ventricular wall stress. Cardiac magnetic resonance imaging (MRI) was used to assess left ventricular (LV) mass and cardiac function of 29 patients with dilated cardiomyopathy and 5 controls. Left ventricular wall stress was calculated by using a thick-walled sphere model, and BNP was assessed by immunoassay. LV mass (r = 0.73, p < 0.001) and both LV end-diastolic (r = 0.54, p = 0.001) and end-systolic wall stress (r = 0.66, p < 0.001) were positively correlated with end-diastolic volume. LV end-systolic wall stress was negatively related to LV ejection fraction (EF), whereas end-diastolic wall stress was not related to LVEF. BNP concentration correlated positively with LV end-diastolic wall stress (r = 0.50, p = 0.002). Analysis of variance revealed LV end-diastolic wall stress as the only independent hemodynamic parameter influencing BNP (p < 0.001). The present approach using a thick-walled sphere model permits determination of mechanical wall stress in a clinical routine setting using standard cardiac MRI protocols. A correlation of BNP concentration with calculated LV stress was observed in vivo. Measurement of BNP seems to be sufficient to assess cardiac loading conditions. Other relations of BNP with various hemodynamic parameters (e.g., EF) appear to be secondary. Since an increased wall stress is associated with cardiac dilatation, early diagnosis and treatment could potentially prevent worsening of the outcome.     

Heterogeneous expression of connexin 43 in the myocardium of rabbit right ventricular outflow tract

The right ventricular outflow tract (RVOT) has been demonstrated as an important focus in idiopathic ventricular arrhythmias. However, the role of the gap junction in this region in arrhythmic events has not been fully investigated. The purpose of this study was to evaluate the expression and distribution of the gap junction protein connexin 43 (Cx43) in the myocardium of the RVOT area of normal adult rabbits. Tissue samples were obtained from 6 regions of normal rabbit heart, i.e. the left ventricle (LV) free wall, the LV papillary muscle, the RVOT free wall, and the RVOT septum which was subdivided into the RV side, the central layer, and the LV side. Immunohistochemical analysis was performed to investigate the characteristics of Cx43 distribution in the RVOT area. In the LV free wall and papillary muscle, Cx43 was abundantly, homogeneously, and approximately equally expressed in end-to-end- and side-to-side intercellular connections. In the free wall of the RVOT, Cx43 expression was poor compared to both these LV regions and side-to-side cell connections were predominant. Cx43 was as richly and homogeneously distributed in the central layer and LV side of the RVOT septum as in the two LV regions. However, in the RV side of the RVOT septum, its distribution was scant and an unstained area was noted. The heterogeneous expression of Cx43 in the RVOT area may serve as substrate for idiopathic ventricular arrhythmia.     

Left ventricular effects on right ventricular developed pressure.

The possibility that left ventricular (LV) performance might affect right ventricular (RV) function through the myocardium was examined by using isolated, flow-perfused, paced rabbit hearts beating isovolumically. Reducing LV volume from its optimal volume to zero caused a 5.7% decrease (N = 10, P less than 0.001) in right ventricular developed pressure (RVDP). Ligating the anterior ventricular branches of the left coronary artery which in the rabbit supply the LV free wall resulted in an additional 9.3% decrease in RVDP (N = 5, P = 0.05) within 3 min of ligation. Finally, cutting the LV free wall from the atrioventricular orifice to the apex (thereby preventing any developed LV free wall force during systole) caused a 45% further decrease in RVDP (N = 2, P less than 0.02). Cineradiographic study showed that the alterations in RVDP resulting from changes in LV volume and coronary occlusion correlated significantly (N = 5, P less than 0.01) with the magnitude of septal bulging into the RV cavity during systole. The results indicate that alteration in LV free wall function and changes in LV volume can directly effect RVDP through the myocardium.     

Left ventricular myocardal activation under ventricular paced beats in chickens Gallus gallus domesticus

The aim of the study was to advance our knowledge regarding the activation process of the ventricular myocardium in birds in which Purkinje fibres penetrate into the ventricular wall to reach the epicardium. A depolarization pattern of the left ventricular free wall was studied in chickens (Gallus gallus) during ventricular paced beats. Duration of the activation process of the left ventricular free wall is significantly increased during ventricular ectopic excitation as compared with sinus rhythm. Its lowest increase occurs during subendocardial pacing of the middle part of the left ventricle, but its greatest increase is observed during subepicardial pacing of the left ventricular base. Multifocality and mosaicity of depolarization of the left ventricular free wall myocardium in chicken are expressed in a considerably less degree during ventricular paced beats in comparison with sinus rhythm. During ventricular paced beats, excitation of the left ventricular free wall is mostly due to the successive spreading of the depolarization wave from pacing sites.     

Ventricular remodeling induced by retinoic acid supplementation in adult rats

Retinoic acid (RA) plays a role in regulating cardiac geometry and function throughout life. The aim of this study was to analyze the cardiac effects of RA in adult rats. Wistar rats were randomly allocated to a control group (n = 18) receiving standard rat chow and a group treated with RA (n = 14) receiving standard rat chow supplemented with RA for 90 days. All animals were evaluated by echocardiography, isolated papillary muscle function, and morphological studies. Whereas the RA-treated group developed an increase in both left ventricular (LV) mass and LV end-diastolic diameter, the ratio of LV wall thickness to LV end-diastolic diameter remained unchanged when compared with the control group. In the isolated papillary muscle preparation, RA treatment decreased the time to peak developed tension and increased the maximum velocity of isometric relengthening, indicating that systolic and diastolic function was improved. Although RA treatment produced an increase in myocyte cross-sectional area, the myocardial collagen volume fraction was similar to controls. Thus our study demonstrates that small physiological doses of RA induce ventricular remodeling resembling compensated volume-overload hypertrophy in rats.     

A 2D FE model of the heart demonstrates the role of the pericardium in ventricular deformation

During pulmonary artery constriction (PAC), an experimental model of acute right ventricular (RV) pressure overload, the interventricular septum flattens and inverts. Finite element (FE) analysis has shown that the septum is subject to axial compression and bending when so deformed. This study examines the effects of acute PAC on the left ventricular (LV) free wall and the role the pericardium may play in these effects. In eight open-chest anesthetized dogs, LV, RV, aortic, and pericardial pressures were recorded under control conditions and with PAC. Model dimensions were derived from two-dimensional echocardiography minor-axis images of the heart. At control (pericardium closed), FE analysis showed that the septum was concave to the LV; stresses in the LV, RV, and septum were low; and the pericardium was subject to circumferential tension. With PAC, RV end-diastolic pressure exceeded LV pressure and the septum inverted. Compressive stresses developed circumferentially in the septum out to the RV insertion points, forming an arch-like pattern. Sharp bending occurred near the insertion points, accompanied by flattening of the LV free wall. With the pericardium open, the deformations and stresses were different. The RV became much larger, especially with PAC. With PAC, the arch-like circumferential stresses still developed in the septum, but their magnitudes were reduced, compared with the pericardium-closed case. There was no free wall inversion and flattening was less. From these FE results, the pericardium has a significant influence on the structural behavior of the septum and the LV and RV free walls. Furthermore, the deformation of the heart is dependent on whether the pericardium is open or closed.     

Intramyocardial Injections to De-Stiffen the Heart: A Subject-Specific in Silico Approach

We hypothesized that minimally invasive injections of a softening agent at strategic locations in stiff myocardium could de-stiffen the left ventricle (LV) globally. Physics-based finite element models of the LV were created from LV echocardiography images and pressures recorded during experiments in four swine. Results confirmed animal models of LV softening by systemic agents. Regional de-stiffening of myocardium led to global de-stiffening of LV. The mathematical set up was used to design LV global de-stiffening by regional softening of myocardium. At an end diastolic pressure of 23 mmHg, when 8 ml of the free wall was covered by intramyocardial injections, end diastolic volume (EDV) increased by 15.0%, whereas an increase up to 11 ml due to intramyocardial injections in the septum and free wall led to a 26.0% increase in EDV. Although the endocardial intramyocardial injections occupied a lower LV wall volume, they led to an EDV (44 ml) that was equal compared to intramyocardial injections in the mid-wall (44 ml) and larger compared to intramyocardial injections in the epicardium (41 ml). Using an in silico set up, sites of regional myocardium de-stiffening could be planned in order to globally soften overly stiff LV in heart failure with preserved ejection fraction. This novel treatment is built on subject-specific data. Hypothesis-testing of these simulation findings in animal models is warranted.     

Regional metabolic rate of exogenous glucose in the isoprenaline and dobutamine stimulated canine myocardium as estimated by the 2-deoxy-d[1-14C]glucose method

The effect of β-adrenoceptor stimulation by isoprenaline and dobutamine on the transmural distribution pattern of regional myocardial metabolic rate of exogenous glucose (RMMRGlc) was studied in the anesthetized closed chest dog using the 2-deoxy-d[1-¹⁴C]glucose method. In a previous series a lumped constant (LC) value of 0.93 ± 0.47 (1 SD) was measured for [¹⁴C]2-deoxyglucose in the canine myocardium. In the control group (N = 12) RMMRGlc was significantly higher in the subendocardial layer of the left ventricular free wall than in both the middle and subepicardial layer, where it was quite evenly distributed (P ⩽ 0.05). With i.v. dobutamine (N = 8) RMMRGlc was significantly lower in the midportion of left ventricular free wall than in the subepicardial layer (P ⩽ 0.05), but it was not different from the inner wall section. Significant differences between the subepicardial and subendocardial portions of the left ventricular free wall could not be found, either. In the isoprenaline group (N = 9) no transmural gradients of RMMRGlc were observed in the left ventricular myocardium. In all groups, both the interventricular septum and the right ventricular free wall exhibited homogeneous distribution patterns of RMMRGlc.It is concluded that transmural distribution patterns of exogenous glucose utilization probably reflect corresponding gradients in energy demands of the left ventricular wall. Redistribution of RMMRGlc in the isoprenaline and dobutamine groups may result from altered working conditions, a change in local inotropic state of the left ventricular myocardium, or from regional differences in the proportions of substrate utilization, and from regional differences in adrenoceptor density.     

Influence of the pericardium on right and left ventricular filling in the dog

We compared the influence of the pericardium on left and right ventricular (LV, RV) filling by measuring LV and RV pressures and segment lengths (SL, LV free wall, and RV inflow and outflow tracts) in six open-chest, pentobarbital sodium-anesthetized dogs before and after pericardiectomy. End-diastolic pressure (EDP) was varied by partial caval occlusion and dextran infusion. At each site the ln EDP-SL relation was fitted by linear regression and characterized by its slope and 1-Torr EDP intercept. The slope and 1-Torr intercept of the LV ln EDP-SL relation changed variably after pericardiectomy, but in each dog a change occurred that shifted this relation downward. In contrast, the RV inflow tract slope invariably decreased significantly after pericardiectomy, whereas its intercept was unchanged in all but one dog. The RV outflow tract results were similar to the inflow tract but less consistent. By the use of the raw EDP-SL data points, we calculated that the absolute contribution of the pericardium to EDP (i.e., the effective pericardial surface pressure) was similar at the three sites. However, as EDP values increased the proportional contribution of the pericardium to right ventricular end-diastolic pressure (RVEDP) increased, whereas that to left ventricular end-diastolic pressure (LVEDP) remained relatively constant. As a result, at the higher EDP values tested, the pericardium was responsible for a larger proportion of RVEDP than LVEDP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired distensibility of the left ventricle after stiffening of the right ventricle.

Acute and chronic alterations of right ventricular (RV) wall properties can change left ventricular (LV) performance. We investigated whether and how stiffening of the RV free wall alters LV diastolic distensibility. We used cross-circulated isolated hearts, in which the LV and RV were independently controllable. Stiffness of the RV free wall was altered by intramuscular injections of glutaraldehyde into the RV free wall after right coronary artery ligation. We measured circumferential and longitudinal regional lengths in the septum and LV free wall. During data acquisition, RV volume was held constant. After the RV free wall was stiffened by glutaraldehyde, the LV diastolic pressure-volume relation shifted upward and became steeper. Importantly, stiffening of the RV free wall increased the diastolic regional area in the septum and LV free wall under constant LV volume. The augmented regional dimensions may result in enhanced regional tension under constant LV volume and may be related to the observed increase in LV diastolic intracavitary pressure. The impaired LV diastolic distensibility by stiffening of the RV free wall may be at least partly explained by myocardial stretch, probably due to LV deformation.     

The impact of endurance exercise training on left ventricular systolic mechanics

Although exercise training-induced changes in left ventricular (LV) structure are well characterized, adaptive functional changes are incompletely understood. Detailed echocardiographic assessment of LV systolic function was performed on 20 competitive rowers (10 males and 10 females) before and after endurance exercise training (EET; 90 days, 10.7 +/- 1.1 h/wk). Structural changes included LV dilation (end-diastolic volume = 128 +/- 25 vs. 144 +/- 28 ml, P < 0.001), right ventricular (RV) dilation (end-diastolic area = 2,850 +/- 550 vs. 3,260 +/- 530 mm2, P < 0.001), and LV hypertrophy (mass = 227 +/- 51 vs. 256 +/- 56 g, P < 0.001). Although LV ejection fraction was unchanged (62 +/- 3% vs. 60 +/- 3%, P = not significant), all direct measures of LV systolic function were altered. Peak systolic tissue velocities increased significantly (basal lateral S'Delta = 0.9 +/- 0.6 cm/s, P = 0.004; and basal septal S'Delta = 0.8 +/- 0.4 cm/s, P = 0.008). Radial strain increased similarly in all segments, whereas longitudinal strain increased with a base-to-apex gradient. In contrast, circumferential strain (CS) increased in the LV free wall but decreased in regions adjacent to the RV. Reductions in septal CS correlated strongly with changes in RV structure (DeltaRV end-diastolic area vs. DeltaLV septal CS; r2 = 0.898, P < 0.001) and function (Deltapeak RV systolic velocity vs. DeltaLV septal CS, r2 = 0.697, P < 0.001). EET leads to significant changes in LV systolic function with regional heterogeneity that may be secondary to concomitant RV adaptation. These changes are not detected by conventional measurements such as ejection fraction.     

SERCA2a activity correlates with the force-frequency relationship in human myocardium

The present investigation addresses whether protein expression and function of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban (PLB) correlate in failing and nonfailing human myocardium. SERCA2a activity and protein expression, PLB phosphorylation, and the force-frequency relationship (FFR) have been determined in right atrium (RA) and left ventricle (LV) from nonfailing (NF, n = 12) and terminally failing [dilated cardiomyopathy (DCM), n = 12] human hearts. Only in LV of DCM hearts was SERCA2a activity significantly decreased [maximal turnover rate (V(max)) = 196 +/- 11 and 396 +/- 30 nmol. mg(-1). min(-1) in LV and RA, respectively], whereas protein expression of SERCA2a in the different chambers was unchanged in NF (3.9 +/- 0.3 and 3.2 +/- 0.4 densitometric units in LV and RA, respectively) and DCM hearts (4.8 +/- 0.8 and 3.4 +/- 0.1 densitometric units in LV and RA, respectively). Phosphorylation of PLB was higher in LV than in RA in NF (Ser(16): 180.5 +/- 19.0 vs. 56.8 +/- 6.0 densitometric units; Thr(17): 174.6 +/- 11.2 vs. 37.4 +/- 8.9 densitometric units) and DCM hearts (Ser(16): 132.0 +/- 5.4 vs. 22.4 +/- 3.5 densitometric units; Thr(17): 131.2 +/- 10.9 vs. 9.2 +/- 2.4 densitometric units). SERCA2a function, but not protein expression, correlated well with the functional parameters of the FFR in DCM and NF human hearts. Regulation of SERCA2a function depends on the phosphorylation of PLB at Ser(16) and Thr(17). However, direct SERCA2a regulation might also be affected by an unknown mechanism.     

Enhanced inotropic response to dobutamine in strength-trained subjects with left ventricular hypertrophy.

To determine whether strength-trained individuals with physiological concentric left ventricular (LV) hypertrophy exhibit enhanced inotropic responses to catecholamines, we studied 11 bodybuilders, aged 33.0 +/- 2 (SE) yr old, and 10 sedentary healthy subjects, aged 31.3 +/- 2.4 yr old, at baseline and during infusion of incremental doses of dobutamine after atropine. The bodybuilders had larger LV mass, posterior wall and septal wall thicknesses, and wall thickness-to-radius ratio, assessed with two-dimensional echocardiography, than did the sedentary subjects. There was a significant correlation between LV mass and lean body mass irrespective of training status. Baseline LV fractional shortening was similar in the two groups. There was a greater inotropic response to dobutamine in the strength-trained individuals, as evidenced by a steeper slope of the fractional shortening-end-systolic wall stress relationship with a higher y-axis intercept and by a shallower end-systolic wall stress-end systolic diameter relationship without changes in end-diastolic diameter. The heart rate response to dobutamine was attenuated in the strength-trained athletes. There was a significant correlation (r = 0.604, P < 0.05) between the inotropic sensitivity to dobutamine and LV mass normalized for lean body mass in the bodybuilders. The data suggest that concentric LV physiological hypertrophy in the resistance-trained individuals is associated with enhanced inotropic but not chronotropic responses to catecholamines.     

Regional nonuniformity of normal adult human left ventricle

Regional nonuniformity is a feature of both diseased and normal left ventricles (LV). With the use of magnetic resonance (MR) myocardial tagging, we performed three-dimensional strain analysis on 87 healthy adults in local cardiac and fiber coordinate systems (radial, circumferential, longitudinal, and fiber strains) to characterize normal nonuniformities and to test the validity of wall thickening as a parameter of regional function. Regional morphology included wall thickness and radii of curvature measurements. With respect to transmural nonuniformity, subendocardial strains exceeded subepicardial strains. Going from base to apex, wall thickness and circumferential radii of curvature decreased, whereas longitudinal radii of curvature increased. All of the strains increased from LV base to apex, resulting in a higher ejection fraction (EF) at the apex than at the base (70.9 +/- 0.4 vs. 62.4 +/- 0.4%; means +/- SE, P < 0.0001). When we looked around the circumference of the ventricle, the anterior part of the LV was the flattest and thinnest and showed the largest wall thickening (46.6 +/- 1.2%) but the lowest EF (64.7 +/- 0.5%). The posterior LV wall was thicker, more curved, and showed a lower wall thickening (32.8 +/- 1.0%) but a higher EF (71.3 +/- 0.5%). The regional contribution of the LV wall to the ejection of blood is thus highly variable and is not fully characterized by wall thickening alone. Differences in regional LV architecture and probably local stress are possible explanations for this marked functional nonuniformity.     

A finite element model of the human left ventricular systole

Local wall stress is the pivotal determinant of the heart muscle's systolic function. Under in vivo conditions, however, such stresses cannot be measured systematically and quantitatively. In contrast, imaging techniques based on magnetic resonance (MR) allow the determination of the deformation pattern of the left ventricle (LV) in vivo with high accuracy. The question arises to what extent deformation measurements are significant and might provide a possibility for future diagnostic purposes. The contractile forces cause deformation of LV myocardial tissue in terms of wall thickening, longitudinal shortening, twisting rotation and radial constriction. The myocardium is thereby understood to act as a densely interlaced mesh. Yet, whole cycle image sequences display a distribution of wall strains as function of space and time heralding a significant amount of inhomogeneity even under healthy conditions. We made similar observations previously by direct measurement of local contractile activity. The major reasons for these inhomogeneities derive from regional deviations of the ventricular walls from an ideal spheroidal shape along with marked disparities in focal fibre orientation. In response to a lack of diagnostic tools able to measure wall stress in clinical routine, this communication is aimed at an analysis and functional interpretation of the deformation pattern of an exemplary human heart at end-systole. To this end, the finite element (FE) method was used to simulate the three-dimensional deformations of the left ventricular myocardium due to contractile fibre forces at end-systole. The anisotropy associated with the fibre structure of the myocardial tissue was included in the form of a fibre orientation vector field which was reconstructed from the measured fibre trajectories in a post mortem human heart. Contraction was modelled by an additive second Piola-Kirchhoff active stress tensor. As a first conclusion, it became evident that longitudinal fibre forces, cross-fibre forces and shear along with systolic fibre rearrangement have to be taken into account for a useful modelling of systolic deformation. Second, a realistic geometry and fibre architecture lead to typical and substantially inhomogeneous deformation patterns as they are recorded in real hearts. We therefore, expect that the measurement of systolic deformation might provide useful diagnostic information.     

Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy

The neuregulin-1 (NRG1)/ErbB system has emerged as a paracrine endothelium-controlled system in the heart, which preserves left ventricular (LV) performance in pathophysiological conditions. Here, we analyze the activity and function of this system in pregnancy, which imparts a physiological condition of LV hemodynamic overload. NRG1 expression and ErbB receptor activation were studied by Western blot analyses in rats and mice at different stages of pregnancy. LV performance was evaluated by transthoracic echocardiography, and myocardial performance was assessed from twitches of isolated papillary muscles. NRG1/ErbB signaling was inhibited by oral treatment of animals with the dual ErbB1/ErbB2 tyrosine kinase inhibitor lapatinib. Analyses of LV tissue revealed that protein expression of different NRG1 isoforms and levels of phosphorylated ErbB2 and ErbB4 significantly increased after 1-2 wk of pregnancy. Lapatinib prevented phosphorylation of ErbB2 and ERK1/2, but not of ErbB4 and protein kinase B (Akt), revealing that lapatinib only partially inhibited NRG1/ErbB signaling in the LV. Lapatinib did not prevent pregnancy-induced changes in LV mass and did not cause apoptotic cell death or fibrosis in the LV. Nevertheless, lapatinib led to premature maternal death of ～25% during pregnancy and it accentuated pregnancy-induced LV dilatation, significantly reduced LV fractional shortening, and induced abnormalities of twitch relaxation (but not twitch amplitude) of isolated papillary muscles. This is the first study showing that the NRG1/ErbB system is activated, and plays a modulatory role, during physiological hemodynamic overload associated with pregnancy. Inhibiting this system during physiological overload may cause LV dysfunction in the absence of myocardial cell death.     

Contribution of myocardium hydraulic skeleton to left ventricular wall interaction and synergy in dogs

The most premature motion change after coronary occlusion is early diastolic thinning of the ischemic left ventricular (LV) wall, with concomitant thickening of the normoperfused wall. We aimed 1). to demonstrate that these early changes are the result of the absence of fluid within the ischemic myocardium (hydraulic skeleton) rather than to cell anoxia and 2). to quantitate the contribution of the lack of hydraulic skeleton to left ventricular asynergy of contraction in seven anesthetized dogs submitted to acute, short-lasting circumflex artery (Cx) occlusion (ischemia) and to perfusion of the Cx with an oxygen-free solution (anoxia). We analyzed the time course of regional work index (WI, area of the LV pressure-wall thickness loop) and regional efficiency (defined as the ratio of WI to the maximum possible work). Interwall asynergy was defined as the difference between the regional efficiency of the anterior and posterior walls. After 9-10 s, posterior wall efficiency decreased 37 +/- 6% with anoxia and 72 +/- 3% with ischemia (P < 0.025), and interwall asynergy was 0 +/- 6% with anoxia and 32 +/- 5% with ischemia (P < 0.05). The contribution of absent hydraulic skeleton to interwall asynergy (calculated as the difference between %asynergy in anoxia and %asynergy in ischemia) was 30 +/- 8% (P < 0.05). In conclusion, the earliest wall motion change observed after acute coronary occlusion, namely ischemic wall thinning concomitant with normoperfused wall thickening during isovolumic relaxation, is the result of the absence of intracoronary fluid. The lack of hydraulic skeleton within the myocardium contributes approximately 30% to interwall asynergy.