Construção de um dispositivo de simulação do escoamento pulsátil em artérias

Pós-graduação em Engenharia Mecânica - FEIS

Isolated right atrial appendage (RAA) rupture in blunt trauma – a case report and an anatomic study comparing RAA and right atrium (RA) wall thickness

Abstract Background Heart chambers rupture in blunt trauma is uncommon and is associated with a high mortality. The determinant factors, and the incidence of isolated heart chambers rupture remains undetermined. Isolated rupture of the right atrium appendage (RAA) is very rare, with 8 cases reported in the reviewed literature. The thin wall of the RAA has been presumed to render this chamber more prone to rupture in blunt trauma. Objective To report a case of isolated RAA rupture in blunt trauma, and to compare right atrium (RA) and RAA wall thickness in a necropsy study. Methods The thickness of RA and RAA wall of hearts from cadavers of fatal penetrating head trauma victims was measured. Our case of isolated RAA rupture is presented. The main findings of the 8 cases reported in the literature, and the findings of our case, were organized in a table. Result The comparison of the data showed that wall thickness of the RAA (0.53 ± 0.33 mm) was significantly thinner than that of RA (1.11 ± 0.42 mm) (p < 0.05). Comments In all these 9 cases of isolated RAA rupture, cardiac tamponade occurred, RAA rupture was diagnosed intraoperatively and sutured, and the patients survived. Main mechanisms hypothesized for heart chamber rupture include mechanical compression coincident with phases of cardiac cycle, leading to high hydrostatic pressure inside the chamber. Published series include numerous cases of RA rupture, and only a few cases of RAA rupture. Conclusion Thus, our data suggests that wall thickness is not a determinant factor for RA or RAA rupture in blunt trauma.

Computational analyses on the structure-function relation in ion channels

Ion channels are protein molecules, embedded in the lipid bilayer of the cell membranes. They act as powerful sensing elements switching chemicalphysical stimuli into ion-fluxes. At a glance, ion channels are water-filled pores, which can open and close in response to different stimuli (gating), and one once open select the permeating ion species (selectivity). They play a crucial role in several physiological functions, like nerve transmission, muscular contraction, and secretion. Besides, ion channels can be used in technological applications for different purpose (sensing of organic molecules, DNA sequencing). As a result, there is remarkable interest in understanding the molecular determinants of the channel functioning. Nowadays, both the functional and the structural characteristics of ion channels can be experimentally solved. The purpose of this thesis was to investigate the structure-function relation in ion channels, by computational techniques. Most of the analyses focused on the mechanisms of ion conduction, and the numerical methodologies to compute the channel conductance. The standard techniques for atomistic simulation of complex molecular systems (Molecular Dynamics) cannot be routinely used to calculate ion fluxes in membrane channels, because of the high computational resources needed. The main step forward of the PhD research activity was the development of a computational algorithm for the calculation of ion fluxes in protein channels. The algorithm - based on the electrodiffusion theory - is computational inexpensive, and was used for an extensive analysis on the molecular determinants of the channel conductance. The first record of ion-fluxes through a single protein channel dates back to 1976, and since then measuring the single channel conductance has become a standard experimental procedure. Chapter 1 introduces ion channels, and the experimental techniques used to measure the channel currents. The abundance of functional data (channel currents) does not match with an equal abundance of structural data. The bacterial potassium channel KcsA was the first selective ion channels to be experimentally solved (1998), and after KcsA the structures of four different potassium channels were revealed. These experimental data inspired a new era in ion channel modeling. Once the atomic structures of channels are known, it is possible to define mathematical models based on physical descriptions of the molecular systems. These physically based models can provide an atomic description of ion channel functioning, and predict the effect of structural changes. Chapter 2 introduces the computation methods used throughout the thesis to model ion channels functioning at the atomic level. In Chapter 3 and Chapter 4 the ion conduction through potassium channels is analyzed, by an approach based on the Poisson-Nernst-Planck electrodiffusion theory. In the electrodiffusion theory ion conduction is modeled by the drift-diffusion equations, thus describing the ion distributions by continuum functions. The numerical solver of the Poisson- Nernst-Planck equations was tested in the KcsA potassium channel (Chapter 3), and then used to analyze how the atomic structure of the intracellular vestibule of potassium channels affects the conductance (Chapter 4). As a major result, a correlation between the channel conductance and the potassium concentration in the intracellular vestibule emerged. The atomic structure of the channel modulates the potassium concentration in the vestibule, thus its conductance. This mechanism explains the phenotype of the BK potassium channels, a sub-family of potassium channels with high single channel conductance. The functional role of the intracellular vestibule is also the subject of Chapter 5, where the affinity of the potassium channels hEag1 (involved in tumour-cell proliferation) and hErg (important in the cardiac cycle) for several pharmaceutical drugs was compared. Both experimental measurements and molecular modeling were used in order to identify differences in the blocking mechanism of the two channels, which could be exploited in the synthesis of selective blockers. The experimental data pointed out the different role of residue mutations in the blockage of hEag1 and hErg, and the molecular modeling provided a possible explanation based on different binding sites in the intracellular vestibule. Modeling ion channels at the molecular levels relates the functioning of a channel to its atomic structure (Chapters 3-5), and can also be useful to predict the structure of ion channels (Chapter 6-7). In Chapter 6 the structure of the KcsA potassium channel depleted from potassium ions is analyzed by molecular dynamics simulations. Recently, a surprisingly high osmotic permeability of the KcsA channel was experimentally measured. All the available crystallographic structure of KcsA refers to a channel occupied by potassium ions. To conduct water molecules potassium ions must be expelled from KcsA. The structure of the potassium-depleted KcsA channel and the mechanism of water permeation are still unknown, and have been investigated by numerical simulations. Molecular dynamics of KcsA identified a possible atomic structure of the potassium-depleted KcsA channel, and a mechanism for water permeation. The depletion from potassium ions is an extreme situation for potassium channels, unlikely in physiological conditions. However, the simulation of such an extreme condition could help to identify the structural conformations, so the functional states, accessible to potassium ion channels. The last chapter of the thesis deals with the atomic structure of the !- Hemolysin channel. !-Hemolysin is the major determinant of the Staphylococcus Aureus toxicity, and is also the prototype channel for a possible usage in technological applications. The atomic structure of !- Hemolysin was revealed by X-Ray crystallography, but several experimental evidences suggest the presence of an alternative atomic structure. This alternative structure was predicted, combining experimental measurements of single channel currents and numerical simulations. This thesis is organized in two parts, in the first part an overview on ion channels and on the numerical methods adopted throughout the thesis is provided, while the second part describes the research projects tackled in the course of the PhD programme. The aim of the research activity was to relate the functional characteristics of ion channels to their atomic structure. In presenting the different research projects, the role of numerical simulations to analyze the structure-function relation in ion channels is highlighted.

A robust reference signal generator for synchronized ventricular assist devices

Ventricular assist devices (VADs) are blood pumps that offer an option to support the circulation of patients with severe heart failure. Since a failing heart has a remaining pump function, its interaction with the VAD influences the hemodynamics. Ideally, the heart's action is taken into account for actuating the device such that the device is synchronized to the natural cardiac cycle. To realize this in practice, a reliable real-time algorithm for the automatic synchronization of the VAD to the heart rate is required. This paper defines the tasks such an algorithm needs to fulfill: the automatic detection of irregular heart beats and the feedback control of the phase shift between the systolic phases of the heart and the assist device. We demonstrate a possible solution to these problems and analyze its performance in two steps. First, the algorithm is tested using the MIT-BIH arrhythmia database. Second, the algorithm is implemented in a controller for a pulsatile and a continuous-flow VAD. These devices are connected to a hybrid mock circulation where three test scenarios are evaluated. The proposed algorithm ensures a reliable synchronization of the VAD to the heart cycle, while being insensitive to irregularities in the heart rate.

Analysis of Pressure Head-Flow Loops of Pulsatile Rotodynamic Blood Pumps

The clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. A commonly used method for restoring pulsatility with rotodynamic blood pumps (RBPs) is to modulate the speed profile, synchronized to the cardiac cycle. This introduces additional parameters that influence the (un)loading of the heart, including the timing (phase shift) between the native cardiac cycle and the pump pulses, and the amplitude of speed modulation. In this study, the impact of these parameters upon the heart-RBP interaction was examined in terms of the pressure head-flow (HQ) diagram. The measurements were conducted using a rotodynamic Deltastream DP2 pump in a validated hybrid mock circulation with baroreflex function. The pump was operated with a sinusoidal speed profile, synchronized to the native cardiac cycle. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. The HQ loops displayed characteristic shapes depending on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS ]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift.

A patient-specific study of type-B aortic dissection: evaluation of true-false lumen blood exchange

BACKGROUND Aortic dissection is a severe pathological condition in which blood penetrates between layers of the aortic wall and creates a duplicate channel - the false lumen. This considerable change on the aortic morphology alters hemodynamic features dramatically and, in the case of rupture, induces markedly high rates of morbidity and mortality. METHODS In this study, we establish a patient-specific computational model and simulate the pulsatile blood flow within the dissected aorta. The k-ω SST turbulence model is employed to represent the flow and finite volume method is applied for numerical solutions. Our emphasis is on flow exchange between true and false lumen during the cardiac cycle and on quantifying the flow across specific passages. Loading distributions including pressure and wall shear stress have also been investigated and results of direct simulations are compared with solutions employing appropriate turbulence models. RESULTS Our results indicate that (i) high velocities occur at the periphery of the entries; (ii) for the case studied, approximately 40% of the blood flow passes the false lumen during a heartbeat cycle; (iii) higher pressures are found at the outer wall of the dissection, which may induce further dilation of the pseudo-lumen; (iv) highest wall shear stresses occur around the entries, perhaps indicating the vulnerability of this region to further splitting; and (v) laminar simulations with adequately fine mesh resolutions, especially refined near the walls, can capture similar flow patterns to the (coarser mesh) turbulent results, although the absolute magnitudes computed are in general smaller. CONCLUSIONS The patient-specific model of aortic dissection provides detailed flow information of blood transport within the true and false lumen and quantifies the loading distributions over the aorta and dissection walls. This contributes to evaluating potential thrombotic behavior in the false lumen and is pivotal in guiding endovascular intervention. Moreover, as a computational study, mesh requirements to successfully evaluate the hemodynamic parameters have been proposed.

Effects of Thoratec pulsatile ventricular assist device (PVAD) timing on the abdominal aortic wave intensity pattern

Arterial waves are seen as possible independent mediators of cardiovascular risks, and the wave intensity analysis (WIA) has therefore been proposed as a method for patient selection for ventricular assist device (VAD) implantation. Interpreting measured wave intensity (WI) is challenging and complexity is increased by the implantation of a VAD. The waves generated by the VAD interact with the waves generated by the native heart, and this interaction varies with changing VAD settings. Eight sheep were implanted with a pulsatile VAD (PVAD) through ventriculo-aortic cannulation. The start of PVAD ejection was synchronized to the native R-wave and delayed between 0 % - 90 % of the cardiac cycle in 10 % steps or phase shifts (PS). Pressure and velocity signals were registered, using a combined Doppler and pressure wire positioned in the abdominal aorta, and used to calculate the WI. Depending on the PS, different wave interference phenomena occurred. Maximum unloading of the left ventricle (LV) coincided with constructive interference and maximum blood flow pulsatility, and maximum loading of the LV coincided with destructive interference and minimum blood flow pulsatility. We believe, that non-invasive WIA could potentially be used clinically to assess the mechanical load of the LV, and to monitor the peripheral hemodynamics such as blood flow pulsatility and risk of intestinal bleeding.

Pulsatile blood flow-split in aortic arch dissection

Abnormalities of the aortic arch, as the most proximal site of the cardiovascular system, are of great interest due to its major role in blood distribution to all downstream members. Wall dissection is one of the disorders that an aorta may suffer due to hypertension or degradation of aortic wall properties. A geometrical change of the aortic arch caused by the dissected wall, and consequently the blood flow path, makes the time-varying flow curves to be different in comparison to the healthy aortic arch. This phenomenon modifies wall shear stress (WSS) history during the cardiac cycle. In the current work, the pulsatile blood flow in a typical Stanford A (DeBakey II) dissected aorta is simulated by CFD technique, STAR-CCM+. The boundary conditions are calculated based on a combination of the impedance boundary condition and the auto-regulation concept in the cardiovascular system.

Accommodation and intraocular pressure

The relationship between accommodation and intraocular pressure (lOP) has not been addressed as a research question for over 20 years, when measurement of both of these parameters was less advanced than today. Hence the central aim of this thesis was to evaluate the effects of accommodation on lOP. The instrument of choice throughout this thesis was the Pulsair EasyEye non-contact tonometer (NCT) due principally to its slim-line design which allowed the measurement of lOP in one eye and simultaneous stimulation of accommodation in the other eye. A second reason for using the Pulsair EasyEye NCT was that through collaboration with the manufacturers (Keeler, UK) the instrument's operational technology was made accessible. Hence, the principle components underpinning non-contact lOP measures of 0.1mmHg resolution (an order of magnitude greater than other methods) were made available. The relationship between the pressure-output and corneal response has been termed the pressure-response relationship, aspects of which have been shown to be related to ocular biometric parameters. Further, analysis of the components of the pressure-response relationship together with high-speed photography of the cornea during tonometry has enhanced our understanding of the derivation of an lOP measure with the Pulsair EasyEye NCT. The NCT samples the corneal response to the pressure pulse over a 19 ms cycle photoelectronically, but computes the subject's lOP using the data collected in the first 2.34 ms. The relatively instantaneous nature of the lOP measurement renders the measures susceptible to variations in the steady-state lOP caused by the respiratory and cardiac cycles. As such, the variance associated with these cycles was minimised by synchronising the lOP measures with the cardiac trace and maintaining a constant pace respiratory cycle at 15 breathes/minute. It is apparent that synchronising the lOP measures with the peak, middle or trough of the cardiac trace significantly reduced the spread of consecutive measures. Of the 3 locations investigated, synchronisation with the middle location demonstrated the least variance (coeflicient of variation = 9.1%) and a strong correlation (r = 0.90, p = <0.001) with lOP values obtained with Goldmann contact tonometry (n = 50). Accordingly lOP measures synchronised with the middle location of the cardiac cycle were taken in the RE while the LE fixated low (L; zero D), intermediate (I; 1.50 D) and high (H; 4 D) accommodation targets, Quasi-continuous measures of accommodation responses were obtained during the lOP measurement period using the portable infrared Grand Seiko FR-5000 autorefractor. The lOP reduced between L and I accommodative levels by approximately 0.61 mmHg (p <0.00 I). No significant reduction in IOP between L and H accommodation levels was elicited (p = 0.65) (n = 40). The relationship between accommodation and lOP was characterised by substantial inter-subject variations. Myopes demonstrated a tendency to show a reduction in IOP with accommodation which was significant only with I accommodation levels when measured with the NCT (r = 0.50, p = 0.01). However, the relationship between myopia and lOP change with accommodation reached significance for both I (r = 0.61, p= 0.003) and H (r = 0.531, p= 0.0 1) accommodation levels when measured with the Ocular blood Flow Analyser (OBFA). Investigation of the effects of accommodation on the parameters measured by the OBFA demonstrated that with H accommodation levels the pulse amplitude (PA) and pulse rate (PR) responses differed between myopes and emmetropes (PA: p = 0.03; PR: p = 0.004). As thc axial length increased there was a tendency for the pulsatile ocular blood flow (POBF) to reduce with accommodation, which was significant only with H accommodation levels (r = 0.38, p = 0.02). It is proposed that emmetropes arc able to regulate the POBF responses to changes in ocular perfusion pressure caused by changes in lOP with I (r = 0.77, p <0.001) and H (r = 0.73, p = 0.001) accommodation levels. However, thc relationship between lOP and POBF changes in the myopes was not correlated for both I (r = 0.33, p = 0.20) and H (r = 0.05, p = 0.85) accommodation levels. The thesis presents new data on the relationships between accommodation, lOP and parameters of the OBFA,: and provides evidence for possible lOP and choroidal blood flow regulatory mechanisms. Further the data highlight possible deficits in the vascular regulation of the myopic eye during accommodation, which may play a putative role in the aetiology of myopia development.

The development and investigation of a novel pulsatile heart assist device

Cardiovascular diseases (CVD) contributed to almost 30% of worldwide mortality; with heart failure being one class of CVD. One popular and widely available treatment for heart failure is the intra-aortic balloon pump (IABP). This heart assist device is used in counterpulsation to improve myocardial function by increasing coronary perfusion, and decreasing aortic end-diastolic pressure (i.e. the resistance to blood ejection from the heart). However, this device can only be used acutely, and patients are bedridden. The subject of this research is a novel heart assist treatment called the Chronic Intermittent Mechanical Support (CIMS) which was conceived to offer advantages of the IABP device chronically, whilst overcoming its disadvantages. The CIMS device comprises an implantable balloon pump, a percutaneous drive line, and a wearable driver console. The research here aims to determine the haemodynamic effect of balloon pump activation under in vitro conditions. A human mock circulatory loop (MCL) with systemic and coronary perfusion was constructed, capable of simulating various degrees of heart failure. Two prototypes of the CIMS balloon pump were made with varying stiffness. Several experimental factors (balloon inflation/deflation timing, Helium gas volume, arterial compliance, balloon pump stiffness and heart valve type) form the factorial design experiments. A simple modification to the MCL allowed flow visualisation experiments using video recording. Suitable statistical tests were used to analyse the data obtained from all experiments. Balloon inflation and deflation in the ascending aorta of the MCL yielded favourable results. The sudden balloon deflation caused the heart valve to open earlier, thus causing longer valve opening duration in a cardiac cycle. It was also found that pressure augmentation in diastole was significantly correlated with increased cardiac output and coronary flowrate. With an optimum combination (low arterial compliance and low balloon pump stiffness), systemic and coronary perfusions were increased by 18% and 21% respectively, while the aortic end-diastolic pressure (forward flow resistance) decreased by 17%. Consequently, the ratio of oxygen supply and demand to myocardium (endocardial viability ratio, EVR) increased between 33% and 75%. The increase was mostly attributed to diastolic augmentation rather than systolic unloading.

On arterial contractility, energetic requirements of the cardiovascular system, and the formation of arterial sclerosis

The aorta has been viewed as a passive distribution manifold for blood whose elasticity allows it to store blood during cardiac ejection (systole), and release it during relaxation (diastole). This capacitance, or compliance, lowers peak cardiac work input and maintains peripheral sanguine irrigation throughout the cardiac cycle. The compliance of the human and canine circulatory systems have been described either as constant throughout the cycle (Toy et al. 1985) or as some inverse function of pressure (Li et al. 1990, Cappelo et al. 1995). This work shows that a compliance value that is higher during systole than diastole (equivalent to a direct function of pressure) leads to a reduction in the energetic input to the cardiovascular system (CV), even when accounting for the energy required to change compliance. This conclusion is obtained numerically, based on a 3-element lumped-parameter model of the CV, then demonstrated in a physical model built for the purpose. It is then shown, based on the numerical and physical models, on analytical considerations of elastic tubes, and on the analysis of arterial volume as a function of pressure measured in vivo (Armentano et al. 1995), that the mechanical effects of a presupposed arterial contraction are consistent with those of energetically beneficial changes in compliance during the cardiac cycle. Although the amount of energy potentially saved with rhythmically contracting arteries is small (mean 0.55% for the cases studied) the importance of the phenomenon lies in its possible relation to another function of the arterial smooth muscle (ASM): synthesis of wall matrix macromolecules. It is speculated that a reduction in the rate of collagen synthesis by the ASM is implicated in the formation of arteriosclerosis. ^

Quantitative analysis of pre- and post-operative valvular annulus deformations following valvular insufficiency

Valvular insufficiency is a growingly common valvular heart disease that frequently is associated with regurgitation. Atrioventricular incompetency can lead to overall ventricular and atrial enlargement, volume overload, heart impairment and, if not treated, can culminate in heart failure. With the advances in technology and the increasing interest in devices that have lower post-operative burden on patients, transcatheter mitral and tricuspid valve repair systems are going through a phase of rapid development and growing use. In this work, we aimed to quantitatively assess the morphology of mitral and tricuspid annuli in patients who underwent transcatheter valve repair with MitraClip/TriClip, before and after the intervention, using three-dimensional transoesophageal echocardiography images, in order to evaluate the geometrical changes of the annulus following the intervention. For our purposes, firstly, we implemented a tool for the visualization and navigation of the volumetric data across the cardiac cycle. Then, in order to track the annulus over the cardiac cycle, we extracted five rotational slices from the volume data, selected two initial points on each slice, and tracked these points across the cardiac cycle using KLT algorithm. In a first stage we led a parameters optimization for the tracking method, and we studied the sensitivity of the KLT algorithm to the initialization points, that are manually chosen by the user. In a second stage, we analysed 10 subjects (5 for mitral regurgitation and 5 for tricuspid regurgitation), tracking their annulus before and after valve repairment. In conclusion, we found in all our 10 subjects that immediately after the intervention there is a shortening of the major diameters of the valves, mainly the shortest diameter, due to the clip application, that leads to a reduction of the perimeter and the area of the annulus.

Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice

The precise role of cell cycle-dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We report that loss of p27(KIP1) in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p27(KIP1)+/+ myocytes, the percentage of neonatal p27(KIP1)-/- myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G(0)/G(1) cells. The expressions of proliferating cell nuclear antigen, G(1)/S and G(2)/M phase-acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p27(KIP1)-/- mice, concomitant with a substantial decrease in the expressions of G(1) phase-acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and alpha-skeletal actin were detectable at significant levels in neonatal and adult p27(KIP1)-/- mouse hearts but were undetectable in p27(KIP1)+/+ hearts. In addition, loss of p27(KIP1) was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27(KIP1) results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy.

Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors

Like most other cells in the body, foetal and neonatal cardiac myocytes are able to divide and proliferate. However, the ability of these cells to undergo cell division decreases progressively during development such that adult myocytes are unable to divide. A major problem arising from this inability of adult cardiac myocytes to proliferate is that the mature heart is unable to regenerate new myocardial tissue following severe injury, e.g. infarction, which can lead to compromised cardiac pump function and even death. Studies in proliferating cells have identified a group of genes and proteins that controls cell division. These proteins include cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs), which interact with each other to form complexes that are essential for controlling normal cell cycle progression. A variety of other proteins, e.g. the retinoblastoma protein (pRb) and members of the E2F family of transcription factors, also can interact with, and modulate the activities of, these complexes. Despite the major role that these proteins play in other cell types, little was known until recently about their existence and activities in immature (proliferating) or mature (non-proliferating) cardiac myocytes. The reason(s) why cardiac myocytes lose their ability to divide during development remains unknown, but if strategies were developed to understand the mechanisms underlying cardiac myocyte growth, it could open up new avenues for the treatment of cardiovascular disease. In this article, we shall review the function of the cell cycle machinery and outline some of our recent findings pertaining to the involvement of the cell cycle in modulating cardiac myocyte growth and hypertrophy.