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.

Uptake of [68Ga]-NODAGA-E[(cRGDyK)]2 is related to improvement in pump function in rats with chronic ischemic cardiomyopathy treated with cell therapy

Background An increasing number of patients living with chronic ischemic cardiomyopathy (ICM) are potential candidates for cell therapy, including adipose tissue-derived mesenchymal stromal cells (ASC). However, proper assessment of clinical effects in relation to cellular effector mechanisms, such as angiogenesis, is currently lacking. Purpose To investigate the prognostic value of assessing angiogenesis non-invasively using novel PET imaging in terms of functional outcome after cell therapy in a homologous animal model of ICM. Methods Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery. Four weeks after infarction, the rats were scanned with [18F]-FDG and echocardiography, and based on left ventricular ejection fraction (LVEF) and infarct size randomized to allogeneic ASC treatment (n=14) or saline (n=9). Animals were treated using echo-guided trans-thoracic intramyocardial injections. Follow-up echocardiography was performed four weeks after treatment. Angiogenesis was assessed non-invasively using the [68Ga]-NODAGA-E[(cRGDyK)]2 (RGD) PET-tracer before treatment and two weeks after the treatment (Figure). The output was RGD-uptake by maximum standardized uptake value (SUVmax). Results RGD-uptake in the infarct area significantly decreased in the saline group (p=0.04), while this decline was not significant in the ASC group (p=0.58). There was no effect on LVEF of the cell therapy in this study (p=0.70). When the rats were grouped by RGD-uptake post treatment, the high RGD-uptake group (n=8) improved LVEF compared to the rats with medium or low RGD-uptake (n=15, p=0.04) irrespective of the treatment. This could indicate that non-invasive detection of a high degree of myocardial angiogenesis measured using RGD is predictive of improvement in cardiac pump function in ICM. Conclusions Following injection of ASC or saline, a high RGD-uptake precluded improvement in pump function. This is the first evidence of how uptake of the novel RGD tracer relates to changes in pump function in ICM and the results could affect the design of future clinical trials using regenerative therapy for ICM patients. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Aase and Ejnar Danielsens FondDoctor Sofus Carl Emil Friis and wife Olga Doris Friis' Scholarship Study design, RGD-uptake, and results

Quantitative evaluation of upper urinary tract pump function in pigs with acute unilateral lower ureteral obstruction by 640-slice dynamic volume CT

Background It is a challenging problem to differentiate obstructive hydronephrosis from noninvasive evaluation of renal pelvis and ureteral motility in patients. The purpose of this study was to explore the value of 640-slice dynamic volume CT (DVCT) in the quantitative measurement of upper urinary tract (UUT) pump function after acute unilateral lower ureteral obstruction in pigs. Methods In this study, a perfusion pig model was constructed by constant pressure perfusion testing of the renal pelvis and left nephrostomy. The perfusion and pressure measuring devices were connected to create a state of no obstruction and acute obstruction of the lower part of the left ureter. After successful modelling, continuous dynamic volume scanning of the bilateral renal excretion phase was performed with 640-slice DVCT, and pump functions of the renal pelvis and part of the upper ureter were calculated and analysed. No obstruction or acute obstruction of the lower part of the left ureter was observed. Pump functions of the renal pelvis and part of the upper ureter were determined. Results The results showed that after LUUT fistulostomy, the time difference between the average UUT volume and positive volume value increased gradually, and the calculated flow velocity decreased, which was significantly different from that of the RUUT. The volume difference of the LUUT increased significantly in mild obstruction. In the bilateral control, the volume change rate of the LUUT increased with mild obstruction and decreased with severe obstruction, and there was a significant difference between the left and right sides. Conclusion The continuous dynamic volume scan and measurement of 640-slice DVCT can obtain five pump function datasets of UUT in pigs with acute lower ureteral obstruction.

Pump function of the heart in patients with scoliosis in rest and in stress test

The indices of the pump function of the heart in teenagers with scoliosis of the 3d 4 th degree in rest and during stress test are studied. Disorders of the pump function of the heart take place in rest: the heart rate signficantly increases. During physical exercise in patients with scoliosis the increase of minute blood volume is less pronounced than in healthy persons and is realized by the increase of the heart rate and not by the stroke blood volume. It is less economical form of adaptation of the pump function of the heart to physical exercise. The functional reserves for increasing the minute blood volume, volumetric circulation rate in the response to physical exercise are decreased

Modelling of fibre dispersion and its effects on cardiac mechanics from diastole to systole

Detailed fibre architecture plays a crucial role in myocardial mechanics both passively and actively. Strong interest has been attracted over decades in mathematical modelling of fibrous tissue (arterial wall, myocardium, etc.) by taking into account realistic fibre structures, i.e. from perfectly aligned one family of fibres, to two families of fibres, and to dispersed fibres described by probability distribution functions. It is widely accepted that the fibres, i.e. collage, cannot bear the load when compressed, thus it is necessary to exclude compressed fibres when computing the stress in fibrous tissue. In this study, we have focused on mathematical modelling of fibre dispersion in myocardial mechanics, and studied how different fibre dispersions affect cardiac pump function. The fibre dispersion in myocardium is characterized by a non-rotationally symmetric distribution using a $$\pi $$ π -periodic Von Mises distribution based on recent experimental studies. In order to exclude compressed fibres for passive response, we adopted the discrete fibre dispersion model for approximating a continuous fibre distribution with finite fibre bundles, and then the general structural tensor was employed for describing dispersed active tension. We first studied the numerical accuracy of the integration of fibre contributions using the discrete fibre dispersion approach, then compared different mechanical responses in a uniaxially stretched myocardial sample with varied fibre dispersions. We finally studied the cardiac pump functions from diastole to systole in two heart models, a rabbit bi-ventricle model and a human left ventricle model. Our results show that the discrete fibre model is preferred for excluding compressed fibres because of its high computational efficiency. Both the diastolic filling and the systolic contraction will be affected by dispersed fibres depending on the in-plane and out-of-plane dispersion degrees, especially in systolic contraction. The in-plane dispersion seems affecting myocardial mechanics more than the out-of-plane dispersion. Despite different effects in the rabbit and human models caused by the fibre dispersion, large differences in pump function exist when fibres are highly dispersed at in-plane and out-of-plane. Our results highlight the necessity of using dispersed fibre models when modelling myocardial mechanics, especially when fibres are largely dispersed under pathological conditions, such as fibrosis.

Reduced calf muscle pump function is a risk factor for venous thromboembolism: A population-based cohort study

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998-2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date and patients with reduced CPF (rCPF) were compared to patients with normal CPF. 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included: 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range 0-22.0 years; Table 2). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted HR for incident VTE was 2.0 (95% CI 1.2-3.4) and after adjusting for age, BMI, and CCI, the HR was 1.68 (95% CI 0.98-2.89). The adjusted HR for ipsilateral DVT was evaluated in 3,064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI 1.03-2.84). Mortality was significantly higher in both the bilateral (p<0.001) and unilateral (p<0.001) rCPF groups compared to normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Quantitative Evaluation of Upper Urinary Tract Pump Function in Pigs With Acute Unilateral Lower Ureteral Obstruction by 640-slice Dynamic Volume CT

Background: It is a challenging problem to differentiate obstructive hydronephrosis from non-invasive evaluation of renal pelvis and ureteral motility in patients. The purpose of this study was to explore the value of 640-slice dynamic volume CT (DVCT) in quantitative measurement of upper urinary tract (UUT) pump function after acute unilateral lower ureteral obstruction in pigs. Methods: In this study, perfusion pig model was made by constant pressure perfusion test of renal pelvis and left nephrostomy. The perfusion and pressure measuring devices were connected to create the state of no obstruction, acute obstruction of the lower part of the left ureter. After successful modeling, continuous dynamic volume scanning of bilateral renal excretion phase was performed with 640-slice DVCT, and pump functions of the renal pelvis and part of the upper ureter were calculated and analyzed. No obstruction, acute obstruction of the lower part of the left ureter. Pump functions of the renal pelvis and part of the upper ureter. Results: Results showed after LUUT fistulostomy, the time difference between the average UUTs volume and positive volume value increased gradually, and the calculated flow velocity decreased, which was significantly different from that of the RUUT. The volume difference of the LUUT increased significantly in mild obstruction. In the bilateral control, the volume change rate of the LUUT increased in mild obstruction and decreased in severe obstruction, and there was significant difference between the left and the right side. Conclusion: The continuous dynamic volume scan and measurement of 640-slice DVCT can obtain five pump function data of UUT in pigs with acute lower ureteral obstruction.

Left atrial functional assessment and mortality in patients with severe aortic stenosis with sinus rhythm

Background Aortic valve stenosis (AS) is the most common primary valvular heart disease leading to surgical or percutaneous aortic valve replacement (AVR) in Europe and its prevalence keeps growing. While other risk factors in severe AS are well documented, little is known about the prognostic value of left atrial (LA) function in AS. Our aim is to clarify the relationship between LA function measured at severe AS diagnosis (evaluated by means of volumetric assessment) and all-cause mortality during follow-up. Methods We retrospectively evaluated patients diagnosed with severe AS for the first time at our echocardiography laboratory. We evaluated LA reservoir, conduit and pump function by measuring LA volumes at different timings of cardiac cycle. Treatment strategy was decided according to heart team consensus and patient decision. We divided patients into groups according to terciles of LA reservoir, conduit and pump function. Primary outcome was defined by the occurrence of all-cause mortality during follow-up. Results A total of 408 patients were included in the analysis, with a median follow-up time of 45 months (interquartile range 54 months). 57.9% of patients underwent AVR and 44.9% of patients registered the primary outcome during follow-up. Left atrial emptying fraction (LAEF) was the best LA functional parameter and the best overall parameter in discriminating primary outcome (AUC 0.845, 95%CI 0.81–0.88, P < 0.001). After adjustment for clinical, demographic and echocardiographic variables, cumulative survival of patients with LAEF < 37% and LAEF 37 to 53% relative to patients with LAEF ≥54% remained significantly lower (HR 13.91, 95%CI 6.20–31.19, P < 0.001 and HR 3.40, 95%CI 1.57–7.37, P = 0.002, respectively). After adjustment for AVR, excess risk of LAEF < 37% and LAEF 37 to 53% relative to LAEF ≥54% remained significant (HR 11.71, 95%CI 5.20–26.40, P < 0.001 and HR 3.59, 95%CI 1.65–7.78, P = 0.001, respectively). Conclusions In patients with a first diagnosis of severe AS, LA function, evaluated by means of volumetric assessment, is an independent predictor of all-cause mortality and a more potent predictor of death compared to classical severity parameters. These data can be useful to identify high-risk patients who might benefit of AVR.