A model of left ventricular function in the denervated heart

A model has been formulated for the function of the denervated left ventricle. Using the model it is possible to generate realistic waveforms for aortic flow, aortic pressure, left ventricular volume and left ventricular pressure over a wide range of simulated haemodynamic conditions. The effect of changes in contractile state is introduced through the concept of left ventricular pumping capacity. Model results compare well with similar data obtained from denervated hearts in open-chest dogs anaesthetized with halothane under positive pressure ventilation. Simulation of changes in contractile state shows excellent agreement with data published by previous investigators.     

Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling

Angiotensin II type 2 receptor (AT(2)R) overexpression (AT(2)TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT(2)TG are mediated via the bradykinin subtype 2 receptor (B(2)R). Fourteen transgenic mice overexpressing the AT(2)R (AT(2)TG mice), 10 mice with a B(2)R deletion (B(2)KO mice), 13 AT(2)TG mice with B(2)R deletion (AT(2)TG/B(2)KO mice), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging at baseline and days 1, 7, and 28 after MI induced by 1 h of occlusion of the left anterior descending artery followed by reperfusion. Short-axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in AT(2)TG mice compared with the other three strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between AT(2)TG and AT(2)TG/B(2)KO mice; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or B(2)KO mice. Both strains lacking B(2)R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28. Attenuation of postinfarct remodeling by overexpression of AT(2)R is not directly mediated via a B(2)R pathway. However, B(2)R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in AT(2)TG mice and in limiting collagen deposition during postinfarct remodeling.     

Impact of overweight on left ventricular function in type 2 diabetes mellitus

Background

Coexistence of left ventricular (LV) longitudinal myocardial systolic dysfunction with LV diastolic dysfunction could lead to heart failure with preserved ejection fraction (HFpEF). Diabetes mellitus (DM) is known as a significant factor associated with HFpEF. Although the mechanisms of DM-related LV myocardial injury are complex, it has been postulated that overweight contributes to the development of LV myocardial injury in type 2 diabetes mellitus (T2DM) patients. However, the precise impact of overweight on LV longitudinal myocardial systolic function in T2DM patients remains unclear.

Methods

We studied 145 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease. LV longitudinal myocardial systolic function was assessed by global longitudinal strain (GLS), which was defined as the average peak strain of 18-segments obtained from standard apical views. Overweight was defined as body mass index (BMI) ≥ 25 kg/m². Ninety age-, gender- and LVEF-matched healthy volunteers served as controls.

Results

GLS of overweight T2DM patients was significantly lower than that of non-overweight patients (17.9 ± 2.4% vs. 18.9 ± 2.6%, p < 0.05), whereas GLS of both overweight and non-overweight controls was similar (19.8 ± 1.3% vs. 20.4 ± 2.1%, p = 0.38). Furthermore, multiple regression analysis revealed that for T2DM patients, BMI was the independent determinant parameters for GLS as well as LV mass index.

Conclusions

Overweight has a greater effect on LV longitudinal myocardial systolic function in T2DM patients than on that in non-DM healthy subjects. Our finding further suggests that the strict control of overweight in T2DM patients may be associated with prevention of the development of HFpEF.

     

Computational modeling of left heart diastolic function: examination of ventricular dysfunction

A computational model that accounts for blood-tissue interaction under physiological flow conditions was developed and applied to a thin-walled model of the left heart. This model consisted of the left ventricle, left atrium, and pulmonary vein flow. The input functions for the model included the pulmonary vein driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The Immersed Boundary Method was used for the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology, and the fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). This model was used to examine the flow fields in the left heart under abnormal diastolic conditions of delayed ventricular relaxation, delayed ventricular relaxation with increased ventricular stiffness, and delayed ventricular relaxation with an increased atrial contraction. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions, and to the results from simulations of normal diastolic function in this model [1]. Cases involving impairment of diastolic function were modeled with changes to the input functions for fiber relaxation/contraction of the chambers. The three cases of diastolic dysfunction investigated agreed with the changes in diastolic flow fields seen clinically. The effect of delayed relaxation was to decrease the early filling magnitude, and this decrease was larger when the stiffness of the ventricle was increased. Also, increasing the contraction of the atrium during atrial systole resulted in a higher late filling velocity and atrial pressure. The results show that dysfunction can be modeled by changing the relationships for fiber resting-length and/or stiffness. This provides confidence in future modeling of disease, especially changes to chamber properties to examine the effect of local dysfunction on global flow fields.     

Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling

The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated (n = 12); 2) wild type, treated with the AT1-R blocker losartan (10-20 mg.kg(-1).day(-1) in drinking water) from day 1 to day 28 post-MI (n = 10); 3) cardiac overexpression of the AT2-R [AT2-transgenic (TG); n = 14]; 4) AT2-TG treated with losartan (n = 13); and 5) AT2-TG and null for the AT1a-R [AT2-TG/AT1 knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and end-systolic volume (EDVI and ESVI) and mass indexed to weight on days 0, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium-enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Infarct size was similar among groups. Systolic blood pressure was lowest in AT2-TG/AT1KO. By day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in AT2-TG/AT1KO at day 28. The AT2-TG/AT1KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The AT1-R and AT2-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of AT1-R is equivalent to AT2-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT1a-R is additive to AT2-R overexpression, due, at least in part, to blood pressure lowering.     

Interaction between left ventricular wall motion and intraventricular flow propagation in acute and chronic ischemia

Myocardial ischemia has been associated with left ventricular (LV) postsystolic shortening. The combination of tissue Doppler imaging and high frame-rate acquisition of two-dimensional color flow makes it possible to study the interaction between LV wall motion and intraventricular flow propagation. The aim of this study was to examine in a clinical model the impact that acute myocardial ischemia and prior myocardial infarct might have on LV flow patterns and to explain the underlying mechanisms from the tissue Doppler data. LV flow propagation and tissue velocities during early diastole were studied in 18 healthy individuals, 17 patients with prior anterior myocardial infarct, and 16 patients before and during percutaneous coronary intervention (PCI) of the left anterior descending artery. Normal individuals had intraventricular flow propagation toward the apex during isovolumic relaxation. During this early diastolic time phase, myocardial velocities measured at mid- and apical septal segment were directed away from the apex. Before PCI, patients without myocardial infarction had similar findings as in normal individuals. In contrast, each patient with either prior myocardial infarction or PCI-induced acute ischemia had flow propagation opposite to normal individuals, and tissue velocities reversed toward the apex during early diastole. Reversal of early diastolic LV flow propagation in acute and chronic anterior myocardial ischemia reflects postsystolic shortening in the dyskinetic apical and septal myocardial segments.     

Continuous measurement of glucose utilization in heart myoblasts

Understanding quantitative aspects of cell energy metabolism and how it is influenced by environment is central to biology, medicine, and biotechnology. Most methods used for measuring metabolic fluxes associated with energy metabolism require considerable personnel effort or high maintenance instrumentation. The microphysiometer is a commercially available instrument that measures acid extrusion rates, which are commonly used for drug screening. With the addition of oxygen sensors, the instrument can also be used to measure cell oxygen consumption rates and thereby calculate glycolytic fluxes. In the work described here, oxygen consumption and acid extrusion rates were used to measure glucose utilization by the H9c2 rat heart myoblast cell line and these results are compared with fluxes measured with a radiometric assay. Both assays were used to investigate changes in H9c2 energy metabolism due to cell stimulation with carbachol and insulin. The results demonstrate the utility of the microphysiometer method for measuring both transient and sustained changes in partitioning of glucose utilization between glycolysis and oxidation in live cells.     

应用Tei指数评价高血压心脏病患者左心室整体功能的研究

目的:探讨超声对高血压心脏病患者左心室整体功能评价的临床价值.方法:69例高血压心脏病患者分为3组:A组26例左室壁厚度正常,B组23例仅室间隔增厚,C组20例室间隔与左室后壁均增厚,同时选择正常健康者D组48人为对照.常规行超声心动图检查,测量并计算出二尖瓣口血流频谱舒张早期和舒张晚期血流峰值之比(E/A)、左室射血分数(LVEF)及Tei指数等评价参数.结果:高血压心脏病A、B组LVEF值均在正常范围,C组LVEF值有所下降,但与对照组比较差异均无统计学意义(P>0.05),但E/A值均较对照组减小(P<0.05);高血压心脏病A、B和C组Tei指数分别为(0.49±0.15)、(0.56±0.10)和(0.56±0.10),高于正常对照组的(0.32±0.08)(P<0.05).结论:在LVEF正常情况下Tei指数能更早地全面反映高血压心脏病患者左心功能下降情况,并且不受心率、心室几何形态,心室收缩和舒张压等因素的影响,为临床早期干预治疗防止心衰发生提供了依据.     

Synchrony of sarcomeric movement regulates left ventricular pump function in the in vivo beating mouse heart

Sarcomeric contraction in cardiomyocytes serves as the basis for the heart’s pump functions. It has generally been considered that in cardiac muscle as well as in skeletal muscle, sarcomeres equally contribute to myofibrillar dynamics in myocytes at varying loads by producing similar levels of active and passive force. In the present study, we expressed α-actinin–AcGFP in Z-disks to analyze dynamic behaviors of sequentially connected individual sarcomeres along a myofibril in a left ventricular (LV) myocyte of the in vivo beating mouse heart. To quantify the magnitude of the contribution of individual sarcomeres to myofibrillar dynamics, we introduced the novel parameter “contribution index” (CI) to measure the synchrony in movements between a sarcomere and a myofibril (from −1 [complete asynchrony] to 1 [complete synchrony]). First, CI varied markedly between sarcomeres, with an average value of ∼0.3 during normal systole. Second, when the movements between adjacent sarcomeres were asynchronous (CI < 0), a sarcomere and the ones next to the adjacent sarcomeres and farther away moved in synchrony (CI > 0) along a myofibril. Third, when difference in LV pressure in diastole and systole (ΔLVP) was lowered to <10 mm Hg, diastolic sarcomere length increased. Under depressed conditions, the movements between adjacent sarcomeres were in marked asynchrony (CI, −0.3 to −0.4), and, as a result, average CI was linearly decreased in association with a decrease in ΔLVP. These findings suggest that in the left ventricle of the in vivo beating mouse heart, (1) sarcomeres heterogeneously contribute to myofibrillar dynamics due to an imbalance of active and passive force between neighboring sarcomeres, (2) the force imbalance is pronounced under depressed conditions coupled with a marked increase in passive force and the ensuing tug-of-war between sarcomeres, and (3) sarcomere synchrony via the distal intersarcomere interaction regulates the heart''s pump function in coordination with myofibrillar contractility.     

Right and left ventricular wall deformation patterns in normal and left heart hypoplasia chick embryos

The vertebrate embryonic ventricle transforms from a smooth-walled single tube to trabeculated right ventricular (RV) and left ventricular (LV) chambers during cardiovascular morphogenesis. We hypothesized that ventricular contraction patterns change from globally isotropic to chamber-specific anisotropic patterns during normal morphogenesis and that these deformation patterns are influenced by experimentally altered mechanical load produced by chronic left atrial ligation (LAL). We measured epicardial RV and LV wall strains during normal development and left heart hypoplasia produced by LAL in Hamburger-Hamilton stage 21, 24, 27, and 31 chick embryos. Normal RV contracted isotropically until stage 24 and then contracted preferentially in the circumferential direction. Normal LV contracted isotropically at stage 21, preferentially in the longitudinal direction at stages 24 and 27, and then in the circumferential direction at stage 31. LAL altered both RV and LV strain patterns, accelerated the onset of preferential RV circumferential strain patterns, and abolished preferential LV longitudinal strain (P < 0.05 vs. normal). Mature patterns of anisotropic RV and LV deformation develop coincidentally with morphogenesis, and changes in these deformation patterns reflect altered cardiovascular function and/or morphogenesis.     

Relationship between glucose utilization and growth rate in Bacillus subtilis

The effect of growth rate on the rate of glucose utilization has been examined with a sporogenic and a weakly sporogenic strain of Bacillus subtilis by means of the continuous culture technique. Cultures were grown aerobically on a mineral salts medium with glucose as the carbon and energy source. During both nitrogen and l-tryptophan limitation, the rate of glucose consumption (milligrams of glucose per hour per milligrams of cells) decreased when the growth rate was decreased. The coupling between the rate of glucose disappearance and the growth rate was estimated as 76 to 86% during nitrogen limitation and as 60 to 78% during tryptophan limitation. Sporulation had no detectable influence on the coupling.     

Effects of pericardial constraint and ventricular interaction on left ventricular hemodynamics in the unloaded heart

Pericardial constraint and ventricular interaction influence left ventricular (LV) performance when preload is high. However, it is unclear if these constraining forces modulate LV filling when the heart is unloaded, such as during upright posture, in humans. Fifty healthy individuals underwent right heart catheterization to measure pulmonary capillary wedge (PCWP) and right atrial pressure (RAP). To evaluate the effects of pericardial constraint on hemodynamics, transmural filling pressure (LVTMP) was defined as PCWP-RAP. Beat-to-beat blood pressure (BP) waveforms were recorded, and stroke volume (SV) was derived from the Modelflow method. After measurements at -30 mmHg lower body negative pressure (LBNP), which approximates the upright position, LBNP was released, and beat-to-beat measurements were performed for 15 heartbeats. At -30 mmHg LBNP, RAP and PCWP were significantly decreased. During the first six beats of LBNP release, heart rate (HR) was unchanged, while BP increased from the fourth beat. RAP increased faster than PCWP resulting in an acute decrease in LVTMP from the fourth beat. A corresponding drop in SV by 3% was observed with no change in pulse pressure. From the 7th to 15th beats, LVTMP and SV increased steadily, followed by a decreased HR due to the baroreflex. A decreased TMP, but not PCWP, caused a transient drop in SV with no changes in HR or pulse pressure during LBNP release. These results suggest that the pericardium constrains LV filling during LBNP release, enough to cause a small but significant drop of SV, even at low cardiac filling pressure in healthy humans.     

Maintenance of left ventricular function (90%) after twenty-four-hour heart preservation with deferoxamine.

During 24-h in vitro heart preservation and reperfusion, irreversible tissue damage occurs caused by reactive oxygen intermediates, such as superoxide radicals, singlet oxygen, hydrogen peroxide, hydroperoxyl, hydroxyl radicals, as well as the peroxynitrite radical. Reduction of the related oxidative damage of reperfused ischemic tissue by free radical scavengers and metal chelators is of primary importance in maintaining heart function. We assessed whether deferoxamine (DFR) added to a cardioplegia solution decreased free radical formation during 24-h cold (5 degrees C) heart preservation and normothermic reperfusion (37 degrees C) in the Langendorff isolated perfused rat heart. The deferoxamine treated hearts were significantly (p less than .001) better preserved than the control hearts after 24 h of preservation with regard to recovery of left ventricular diastolic pressure, contractility (+dP/dt), relaxation (-dP/dt), creatine kinase release, and lipid peroxidation. DFR preserved cell membrane integrity and maintained 93% of left ventricular contractility. The evidence suggests that DFR reduces lipid peroxidation damage by reducing free radical formation and thereby maintaining normal coronary perfusion flow and myocardial function.     

Mesenchymal stem cells from ischemic heart disease patients improve left ventricular function after acute myocardial infarction

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 x 10(5) cells in 20 microl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/scid mice. Sham-operated mice were used as the control (n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 +/- 2% vs. 36 +/- 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 +/- 3% vs. 16 +/- 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 +/- 0.3% of injected cells) expressed von Willebrand factor (16.9 +/- 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.     

Characterization of the phospholemman knockout mouse heart: depressed left ventricular function with increased Na-K-ATPase activity

Phospholemman (PLM, FXYD1), abundantly expressed in the heart, is the primary cardiac sarcolemmal substrate for PKA and PKC. Evidence supports the hypothesis that PLM is part of the cardiac Na-K pump complex and provides the link between kinase activity and pump modulation. PLM has also been proposed to modulate Na/Ca exchanger activity and may be involved in cell volume regulation. This study characterized the phenotype of the PLM knockout (KO) mouse heart to further our understanding of PLM function in the heart. PLM KO mice were bred on a congenic C57/BL6 background. In vivo conductance catheter measurements exhibited a mildly depressed cardiac contractile function in PLM KO mice, which was exacerbated when hearts were isolated and Langendorff perfused. There were no significant differences in action potential morphology in paced Langendorff-perfused hearts. Depressed contractile function was associated with a mild cardiac hypertrophy in PLM KO mice. Biochemical analysis of crude ventricular homogenates showed a significant increase in Na-K-ATPase activity in PLM KO hearts compared with wild-type controls. SDS-PAGE and Western blot analysis of ventricular homogenates revealed small, nonsignificant changes in Na- K-ATPase subunit expression, with two-dimensional gel (isoelectric focusing, SDS-PAGE) analysis revealing minimal changes in ventricular protein expression, indicating that deletion of PLM was the primary reason for the observed PLM KO phenotype. These studies demonstrate that PLM plays an important role in the contractile function of the normoxic mouse heart. Data are consistent with the hypothesis that PLM modulates Na-K-ATPase activity, indirectly affecting intracellular Ca and hence contractile function.     

C-type natriuretic peptide and its relation to non-invasive indices of left ventricular function in patients with chronic heart failure

C-type natriuretic peptide (CNP) significantly increases in chronic heart failure (CHF) patients as a function of clinical severity. Aim of this study was to evaluate in CHF patients the relationship between circulating CNP concentrations and echo-Doppler conventional indices of left ventricular (LV) function as well as less load independent parameters as dP/dt. LV ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) and LV dP/dt were evaluated together with plasma CNP levels in 38 patients with CHF and in 63 controls. CNP levels resulted significantly higher in CHF patients than in controls (7.19+/-0.59 pg/ml vs. 2.52+/-0.12 pg/ml, p<0.0001). A significant correlation between dP/dt and CNP levels (r=-0.61, p<0.0001) was observed. A good correlation with EF (r=-0.55, p<0.001) and a less significant relation with LVEDD (r=0.316, p<0.05) were also reported. When patients were divided according to dP/dt values a very significant difference in CNP levels was observed: Group I (<600, n=25) vs. Group II (>600, n=13): 8.46+/-0.69 and 4.75+/-0.75 pg/ml, respectively, p<0.001. This is the first study that reports a correlation between CNP and dP/dt in CHF patients, thus suggesting a possible role on cardiac contractility.