Torsional motion of the left ventricle does not affect ventricular fluid dynamics of both foetal and adult hearts

Left ventricular torsion is caused by shortening and relaxation of the helical fibres in the myocardium, and is thought to be an optimal configuration for minimizing myocardial tissue strains. Characteristics of torsional motion has also been proposed to be markers for cardiac dysfunction. However, its effects on fluid and energy dynamics in the left ventricle have not been comprehensively investigated. To investigate this, we performed image-based flow simulations on five healthy adult porcine and two healthy human foetal left ventricles (representing two different length scales) at different degrees of torsional motions. In the adult porcine ventricles, cardiac features such as papillary muscles and mitral valves, and cardiac conditions such as myocardial infarctions, were also included to investigate the effect of twist. The results showed that, for all conditions investigated, ventricular torsional motion caused minimal changes to flow patterns, and consistently accounted for less than 2% of the energy losses, wall shear stresses, and ejection momentum energy. In contrast, physiological characteristics such as chamber size, stroke volume and heart rate had a much greater influence on flow patterns and energy dynamics. The results thus suggested that it might not be necessary to model the torsional motion to study the flow and energy dynamics in left ventricles.     

Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve leaflet

Aortic valve (AV) calcification is a highly prevalent disease with serious impact on mortality and morbidity. Although exact causes and mechanisms of AV calcification are unclear, previous studies suggest that mechanical forces play a role. Since calcium deposits occur almost exclusively on the aortic surfaces of AV leaflets, it has been hypothesized that adverse patterns of fluid shear stress on the aortic surface of AV leaflets promote calcification. The current study characterizes AV leaflet aortic surface fluid shear stresses using Laser Doppler velocimetry and an in vitro pulsatile flow loop. The valve model used was a native porcine valve mounted on a suturing ring and preserved using 0.15% glutaraldehyde solution. This valve model was inserted in a mounting chamber with sinus geometries, which is made of clear acrylic to provide optical access for measurements. To understand the effects of hemodynamics on fluid shear stress, shear stress was measured across a range of conditions: varying stroke volumes at the same heart rate and varying heart rates at the same stroke volume. Systolic shear stress magnitude was found to be much higher than diastolic shear stress magnitude due to the stronger flow in the sinuses during systole, reaching up to 20 dyn/cm² at mid-systole. Upon increasing stroke volume, fluid shear stresses increased due to stronger sinus fluid motion. Upon increasing heart rate, fluid shear stresses decreased due to reduced systolic duration that restricted the formation of strong sinus flow. Significant changes in the shear stress waveform were observed at 90 beats/min, most likely due to altered leaflet dynamics at this higher heart rate. Overall, this study represents the most well-resolved shear stress measurements to date across a range of conditions on the aortic side of the AV. The data presented can be used for further investigation to understand AV biological response to shear stresses.     

Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.     

Interaction of 0.1-Hz oscillations in heart rate variability and distal blood flow variability

Biophysical features of 0.1-Hz oscillations of heart rate variability (HRV) and distal blood flow (DBF) variability were compared in healthy subjects and patients after acute myocardial infarction (MI). Patients with acute MI (72 men and 53 women; 125 in total) and healthy subjects (23 men and 10 women; 33 in total) aged 30?C83 and 20?C46 years, respectively, participated in the study. The patients were involved in the study for a year after acute MI. The delay in coupling 0.1-Hz oscillations of HRV and DBF variability was estimated. In healthy subjects, the delay in the heart ?? DBF coupling proved to be less than the delay in the DBF ?? heart coupling. Acute MI results mainly in disruption of the heart ?? DBF coupling, which is partially restored by the end of the first year after acute MI, though it remains lower than in healthy subjects. The DBF ?? heart coupling is rapidly restored to the level of healthy subjects within three weeks after acute MI.     

Protective effect of peptide semax (ACTH(4-7)Pro-Gly-Pro) on the rat heart rate after myocardial infarction

Semax, a member of ACTH-derived peptides family, was used in treatment of ischemic stroke in patients. It decreased neurological deficiency and reduced NO hyperproduction in the rat brain caused by acute cerebral hypoperfusion. We suggest that semax is also capable of protecting the rat heart from ischemic damage 28 days after myocardial infarction (MI) induced by left descendent coronary artery occlusion. Semax (150 microg/kg) was given i. p. in the operating day twice: 15 min and 2 hours after coronary occlusion, and once a day for the following 6 days. In 28 days after infarction, the MI group developed cardiac hypertrophy, cell growth was caused mainly by the increase of contractile filaments not supported by the appropriate mitochondrial growth that indicated an impaired energy supply of the cells. Moreover, cardiac hypertrophy was accompanied by decreased mean arterial blood pressure and cardiac contractile function and increased left ventricular end-diastolic pressure. Pharmacological change of cardiac afterload revealed that, in 28 days after MI, the rat heart was not able to change its contractile performance in response to either increase or decrease of systemic blood pressure, and as a result could not maintain its diastolic pressure. All these changes obviously reflect development of heart failure. Semax did not affect cardiac work but partially prevented end-diastolic pressure growth in left ventricle as well as ameliorated cardiomyocyte hypertrophy and disproportionate growth of contractile and mitochondrial apparatus, thus exerting beneficial effect on the left ventricular remodeling and heart failure development late after myocardial infarction.     

Fluid mechanics of the zebrafish embryonic heart trabeculation

Embryonic heart development is a mechanosensitive process, where specific fluid forces are needed for the correct development, and abnormal mechanical stimuli can lead to malformations. It is thus important to understand the nature of embryonic heart fluid forces. However, the fluid dynamical behaviour close to the embryonic endocardial surface is very sensitive to the geometry and motion dynamics of fine-scale cardiac trabecular surface structures. Here, we conducted image-based computational fluid dynamics (CFD) simulations to quantify the fluid mechanics associated with the zebrafish embryonic heart trabeculae. To capture trabecular geometric and motion details, we used a fish line that expresses fluorescence at the endocardial cell membrane, and high resolution 3D confocal microscopy. Our endocardial wall shear stress (WSS) results were found to exceed those reported in existing literature, which were estimated using myocardial rather than endocardial boundaries. By conducting simulations of single intra-trabecular spaces under varied scenarios, where the translational or deformational motions (caused by contraction) were removed, we found that a squeeze flow effect was responsible for most of the WSS magnitude in the intra-trabecular spaces, rather than the shear interaction with the flow in the main ventricular chamber. We found that trabecular structures were responsible for the high spatial variability of the magnitude and oscillatory nature of WSS, and for reducing the endocardial deformational burden. We further found cells attached to the endocardium within the intra-trabecular spaces, which were likely embryonic hemogenic cells, whose presence increased endocardial WSS. Overall, our results suggested that a complex multi-component consideration of both anatomic features and motion dynamics were needed to quantify the trabeculated embryonic heart fluid mechanics.     

Patient-specific CFD models for intraventricular flow analysis from 3D ultrasound imaging: Comparison of three clinical cases

BackgroundAs the intracardiac flow field is affected by changes in shape and motility of the heart, intraventricular flow features can provide diagnostic indications. Ventricular flow patterns differ depending on the cardiac condition and the exploration of different clinical cases can provide insights into how flow fields alter in different pathologies.MethodsIn this study, we applied a patient-specific computational fluid dynamics model of the left ventricle and mitral valve, with prescribed moving boundaries based on transesophageal ultrasound images for three cardiac pathologies, to verify the abnormal flow patterns in impaired hearts. One case (P1) had normal ejection fraction but low stroke volume and cardiac output, P2 showed low stroke volume and reduced ejection fraction, P3 had a dilated ventricle and reduced ejection fraction.ResultsThe shape of the ventricle and mitral valve, together with the pathology influence the flow field in the left ventricle, leading to distinct flow features. Of particular interest is the pattern of the vortex formation and evolution, influenced by the valvular orifice and the ventricular shape. The base-to-apex pressure difference of maximum 2 mmHg is consistent with reported data.ConclusionWe used a CFD model with prescribed boundary motion to describe the intraventricular flow field in three patients with impaired diastolic function. The calculated intraventricular flow dynamics are consistent with the diagnostic patient records and highlight the differences between the different cases. The integration of clinical images and computational techniques, therefore, allows for a deeper investigation intraventricular hemodynamics in patho-physiology.     

Investigation of biophysical features of interaction between 0.1 Hz oscillations in heart rate variability and distal blood flow variability

We studied biophysical features of interaction between 0.1 Hz oscillations in heart rate variability (HRV) and distal blood flow (DBF) variability in healthy subjects and patients after acute myocardial infarction (MI). 125 patients after acute MI (72 male and 53 female) aged between 30 and 83 years and 33 healthy subjects (23 male and 10 female) aged between 20 and 46 years were included in the study. The duration of prospective study of MI patients was one year. We estimated the delay in coupling between 0.1 Hz oscillations in H RV and DBF variability. It is found out that in healthy subjects the delay in coupling from heart rate to DBF is less than delay in coupling from DBF to heart rate. Acute MI results mainly in disruption of coupling from heart rate to DBF. This coupling is partially restored in one year after acute MI, but the delay in coupling remains significantly smaller than in healthy subjects. The features of coupling from DBF to heart rate are restored in MI patients within three weeks after infarction. After this period the delay in this coupling in MI patients is approximately the same as it is in healthy subjects.     

Progression of heart failure after myocardial infarction in the rat

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple "switching on" of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.     

Mechanisms of ventricular arrhythmias elicited by coexistence of multiple electrophysiological remodeling in ischemia: A simulation study

Myocardial ischemia, injury and infarction (MI) are the three stages of acute coronary syndrome (ACS). In the past two decades, a great number of studies focused on myocardial ischemia and MI individually, and showed that the occurrence of reentrant arrhythmias is often associated with myocardial ischemia or MI. However, arrhythmogenic mechanisms in the tissue with various degrees of remodeling in the ischemic heart have not been fully understood. In this study, biophysical detailed single-cell models of ischemia 1a, 1b, and MI were developed to mimic the electrophysiological remodeling at different stages of ACS. 2D tissue models with different distributions of ischemia and MI areas were constructed to investigate the mechanisms of the initiation of reentrant waves during the progression of ischemia. Simulation results in 2D tissues showed that the vulnerable windows (VWs) in simultaneous presence of multiple ischemic conditions were associated with the dynamics of wave propagation in the tissues with each single pathological condition. In the tissue with multiple pathological conditions, reentrant waves were mainly induced by two different mechanisms: one is the heterogeneity along the excitation wavefront, especially the abrupt variation in conduction velocity (CV) across the border of ischemia 1b and MI, and the other is the decreased safe factor (SF) for conduction at the edge of the tissue in MI region which is attributed to the increased excitation threshold of MI region. Finally, the reentrant wave was observed in a 3D model with a scar reconstructed from MRI images of a MI patient. These comprehensive findings provide novel insights for understanding the arrhythmic risk during the progression of myocardial ischemia and highlight the importance of the multiple pathological stages in designing medical therapies for arrhythmias in ischemia.     

Remote Measurements of Heart and Respiration Rates for Telemedicine

Non-contact and low-cost measurements of heart and respiration rates are highly desirable for telemedicine. Here, we describe a novel technique to extract blood volume pulse and respiratory wave from a single channel images captured by a video camera for both day and night conditions. The principle of our technique is to uncover the temporal dynamics of heart beat and breathing rate through delay-coordinate transformation and independent component analysis-based deconstruction of the single channel images. Our method further achieves robust elimination of false positives via applying ratio-variation probability distributions filtering approaches. Moreover, it enables a much needed low-cost means for preventing sudden infant death syndrome in new born infants and detecting stroke and heart attack in elderly population in home environments. This noncontact-based method can also be applied to a variety of animal model organisms for biomedical research.     

A computational framework for adjusting flow during peripheral extracorporeal membrane oxygenation to reduce differential hypoxia

Peripheral veno-arterial extra corporeal membrane oxygenation (VA-ECMO) is an established technique for short-to-medium support of patients with severe cardiac failure. However, in patients with concomitant respiratory failure, the residual native circulation will provide deoxygenated blood to the upper body, and may cause differential hypoxemia of the heart and brain. In this paper, we present a general computational framework for the identification of differential hypoxemia risk in VA-ECMO patients. A range of different VA-ECMO patient scenarios for a patient-specific geometry and vascular resistance were simulated using transient computational fluid dynamics simulations, representing a clinically relevant range of values of stroke volume and ECMO flow. For this patient, regardless of ECMO flow rate, left ventricular stroke volumes greater than 28 mL resulted in all aortic arch branch vessels being perfused by poorly-oxygenated systemic blood sourced from the lungs. The brachiocephalic artery perfusion was almost entirely derived from blood from the left ventricle in all scenarios except for those with stroke volumes less than 5 mL. Our model therefore predicted a strong risk of differential hypoxemia in nearly all situations with some residual cardiac function for this combination of patient geometry and vascular resistance. This simulation highlights the potential value of modelling for optimising ECMO design and procedures, and for the practical utility for personalised approaches in the clinical use of ECMO.     

Right ventricle-pulmonary circulation dysfunction: a review of energy-based approach

Patients with repaired or palliated right heart congenital heart disease (CHD) are often left with residual lesions that progress and can result in significant morbidity. However, right ventricular-pulmonary arterial evaluation and the timing of reintvervention is still subjective. Currently, it relies on symptomology, or RV imaging-based metrics from echocardiography or MR derived parameters including right ventricular (RV) ejection fraction (EF), end-systolic pressure (ESP), and end-diastolic volume (EDV). However, the RV is coupled to the pulmonary vasculature, and they are not typically evaluated together. For example, the dysfunctional right ventricular-pulmonary circulation (RV-PC) adversely affects the RV myocardial performance resulting in decreased efficiency. Therefore, comprehensive hemodynamic assessment should incorporate changes in RV-PC and energy efficiency for CHD patients.The ventricular pressure-volume relationship (PVR) and other energy-based endpoints derived from PVR, such as stroke work (SW) and ventricular elastance (E _es ), can provide a measure of RV performance. However, a detailed explanation of the relationship between RV performance and pulmonary arterial hemodynamics is lacking. More importantly, PVR is impractical for routine longitudinal evaluation in a clinical setting, because it requires invasive catheterization. As an alternative, analytical methods and computational fluid dynamics (CFD) have been used to compute energy endpoints, such as power loss or energy dissipation, in abnormal physiologies.In this review, we review the causes of RV-PA failure and the limitation of current clinical parameters to quantify RV-PC dysfunction. Then, we describe the advantage of currently available energy-based endpoints and emerging energy endpoints, such as energy loss in the Pas or kinetic energy, obtained from a new non-invasive imaging technique, i.e. 4D phase contrast MRI.     

Personalized stent design for congenital heart defects using pulsatile blood flow simulations

Stent size selection and placement are among the most challenging tasks in the treatment of pulmonary artery stenosis in congenital heart defects (CHD). Patient-specific 3D model from CT or MR improves the understanding of the patient’s anatomy and information about the hemodynamics aid in patient risk assessment and treatment planning. This work presents a new approach for personalized stent design in pulmonary artery interventions combining personalized patient geometry and hemodynamic simulations. First, the stent position is initialized using a geometric approach. Second, the stent and artery expansion, including the foreshortening behavior of the stent is simulated. Two stent designs are considered, a regular stent and a Y-stent for bifurcations. Computational fluid dynamics (CFD) simulations of the blood flow in the initial and expanded artery models are performed using patient-specific boundary conditions in form of a pulsatile inflow waveform, 3-element Windkessel outflow conditions, and deformable vessel walls. The simulations have been applied to 16 patient cases with a large variability of anatomies. Finally, the simulations have been clinically validated using retrospective imaging from angiography and pressure measurements. The simulated pressure, volume flow and flow velocity values were on the same order of magnitude as the reference values obtained from clinical measurements, and the simulated stent placement showed a positive impact on the hemodynamic values. Simulation of geometric changes combined with CFD simulations offers the possibility to optimize stent type, size, and position by evaluating different configurations before the intervention, and eventually allow to test customized stent geometries and new deployment techniques in CHD.     

Pericardial and pericardioperitoneal canal relationships to cardiac function in the white sturgeon (Acipenser transmontanus)

Sturgeons are primitive bony fishes and their hearts have structural features found in other primitive fishes. Sturgeons have a pericardioperitoneal canal (PPC), a one-way conduit into the peritoneum. A PPC also occurs in elasmobranchs (sharks and rays) and studies with that group demonstrate that pericardial pressure and pericardial fluid loss via the PPC affect stroke volume. A study of white sturgeon (Acipenser transmontanus) heart function was conducted to test for a comparable PPC and pericardial effects. White sturgeon-elasmobranch heart-function similarities include biphasic ventricular filling, a comparable operational pericardial pressure (-0.03 kPa), and a strongly negative pressure (-0.2 to -0.6 kPa) with complete pericardial fluid withdrawal. Differences include the white sturgeon's relatively smaller atrium and ventricle but a larger conus arteriosus. Although white sturgeon heart size is also smaller, its pericardial volume is disproportionately less (2.4 to 2.7 vs. 3.5 to 5.4 ml kg(-1) in elasmobranchs), meaning it has less scope for increasing stroke volume upon PPC fluid release. These differences may reflect the phylogenetic progression from the less complex operation of the elasmobranch heart, which lacks sympathetic innervation and has a mechanically mediated (PPC) stroke volume, to the condition in the more derived bony fishes which have sympathetic and parasympathetic regulation of both stroke volume and heart rate.     

Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction

A recent study suggests that exogenous ghrelin administration might decrease renal sympathetic nerve activity in conscious rabbits. In the present study, we investigated whether ghrelin administration would attenuate left ventricular (LV) remodeling following myocardial infarction (MI) via the suppression of cardiac sympathetic activity. Ghrelin (100 microg/kg sc, twice daily, n = 15) or saline (n = 15) were administered for 2 wk from the day after MI operation in Sprague-Dawley rats. The effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, histopathological, and gene analysis. In addition, before and after ghrelin (100 microg/kg sc, n = 6) was administered in conscious rats with MI, the autonomic nervous function was investigated by power spectral analysis obtained by a telemetry system. In ghrelin-treated rats, LV enlargement induced by MI was significantly attenuated compared with saline-treated rats. In addition, there was a substantial decrease in LV end-diastolic pressure and increases in the peak rate of the rise and fall of LV pressure in ghrelin-treated MI rats compared with saline-treated MI rats. Furthermore, ghrelin attenuated an increase in morphometrical collagen volume fraction in the noninfarct region, which was accompanied by the suppression of collagen I and III mRNA levels. Importantly, a 2-wk administration of ghrelin dramatically suppressed the MI-induced increase in heart rate and plasma norepinephrine concentration to the similar levels as in sham-operated controls. Moreover, acute administration of ghrelin to MI rats decreased the ratio of the low-to-high frequency spectra of heart rate variability (P < 0.01). In conclusion, these data suggest the potential usefulness of ghrelin as a new cardioprotective hormone early after MI.     

Reduction of myocardial infarct size by fluvastatin

Statins have a variety of cardioprotective properties following chronic treatment. In contrast, little is known about the acute effects. Reperfusion acutely injures the heart by activation of neutrophils as well as endothelial cells. Because statins are known to influence the processes pathogenetically involved, we hypothesized that acute application of statins attenuates the sequelae of cardiac reperfusion. In rats, myocardial infarction (MI) was induced by ligature of the left coronary artery followed by reperfusion. Myocardial blood flow (MBF) was determined by H2 clearance and regional myocardial function (fractional thickening, FT) by pulsed Doppler. MI size was measured by triphenyltetrazolium chloride (TTC) staining, neutrophil extravasation by determination of myeloperoxidase (MPO) activity, and nitric oxide generation via measurement of cGMP. Treatment with fluvastatin, administered intravenously 20 min before the onset of ischemia, significantly attenuated the decline of FT and MBF at the end of the reperfusion period and significantly reduced MI size. Furthermore, fluvastatin induced a significant reduction of MPO activity and an increase of cGMP level compared with the control group. The effect of fluvastatin was completely abolished following pretreatment of NG-nitro-l-arginine methyl ester (l-NAME). These findings suggest that acute application of fluvastatin reduces MI size and attenuates reperfusion injury. We propose that the underlying mechanism is at least partially an inhibition of inflammation and endothelial dysfunction by preventing the activation and extravasation of neutrophils.     

Numerical study of hemodynamics in brain aneurysms treated with flow diverter stents using porous medium theory

Conventional approaches of implementing computational fluid dynamics to study aneurysmal hemodynamics after treatment with a flow diverter stent are computationally expensive. Cumbersome meshing and lengthy simulation runtimes are common. To address these issues, we present a novel volume penalization method that considers flow diverters as heterogeneous porous media. The proposed model requires a considerably smaller number of mesh elements, leading to faster simulation runtimes. Three patient-specific aneurysms were virtually treated with flow diverters and aneurysmal hemodynamics were simulated. The results of the virtual deployments including aneurysmal hemodynamics were compared to corresponding results from conventional approaches. The comparisons showed that the proposed approach led to 9.12 times increase in the speed of simulations on average. Further, aneurysmal kinetic energy and inflow rate metrics for the proposed approach were consistent with those from conventional approaches, differing on average by 3.52% and 3.78%, respectively.     

Novel method to correct displacement profile images and calculate flow vector fields using saturation-tagging MR imaging.

Saturation-tagging Magnetic Resonance (MR) imaging provides a simple and robust means to directly visualize displacement profiles within fluid flow fields. Although useful for velocity quantitation as well as for qualitative depiction of flow patterns in certain well-defined flow fields, the technique is prone to distortions due to oblique flow (misregistration artifact) and ambiguity of fluid vector trajectories in complex flow situations. A novel method is proposed whereby two images are acquired, differing in the temporal position of the phase encoding gradient. Theoretical analysis shows that from the paired images, distortion of the two-dimensional displacement profile can be corrected and fluid velocity vectors extracted, even if the flow directions are unknown. In the simpler case of flow oblique to the gradient principal axes, but with a known trajectory, only one image is necessary to correct the displacement profile distortion and extract the velocity information. MRI experiments in a straight tube model have been carried out to evaluate the feasibility of this method. Good agreement is achieved between the results from MR imaging and those predicted via computer simulation.