New Frank-Starling based contractility and ventricular stiffness indices: clinically applicable alternative to Emax

2013 Summer.Includes bibliographical references.Heart disease is the #1 cause of death in the United States with congestive heart failure (CHF) being a leading component. Load induced CHF, i.e. CHF in response to chronic pressure or volume overload, may be classified either as systolic failure or diastolic failure, depending on the failure mode of the pumping chamber. To assess the severity of systolic failure, there exist clinical indices that quantify chamber contractility, namely: ejection fraction, (dP/dt), Emax (related to the rate of pressure rise in the pumping chamber), and Emax (related to the time-dependent elastance property of the ventricle). Unfortunately, these indices are plagued with limitations due to inherent load dependence or difficulty in clinical implementation. Indices to assess severity of diastolic failure are also limited due to load dependence. The goal of this research is to present (1) a new framework that defines a new contractility index, Tmax, and ventricular compliance 'a', based on Frank-Starling concepts that can be easily applied to human catheterization data, and (2) discusses preliminary findings in patients at various stages of valve disease. A lumped parameter model of the pumping ventricle was constructed utilizing the basic principles of the Frank-Startling law. The systemic circulation was modeled as a three element windkessel block for the arterial and venous elements. Based on the Frank-Starling curve, the new contractility index, Tmax and ventricular compliance 'a' were defined. Simulations were conducted to validate the load independence of Tmax and a computed from a novel technique based on measurements corresponding to the iso-volumetric contraction phase. Recovered Tmax and 'a' depicted load independence and deviated only a few % points from their true values. The new technique was implemented to establish the baseline Tmax and 'a' in normal human subjects from a retrospective meta-data analysis of published cardiac catheterization data. In addition, Tmax and 'a' was quantified in 12 patients with a prognosis of a mix of systolic and diastolic ventricular failure. Statistical analysis showed that Tmax was significantly different between the normal subjects group and systolic failure group (p<0.019) which implies that a decrease in Tmax indeed predicts impending systolic dysfunction. Analysis of human data also shows that the ventricular compliance index 'a' is significantly different between the normal subjects and concentric hypertrophy (p < 0.001). This research has presented a novel technique to recover load independent measures of contractility and ventricular compliance from standard cardiac catheterization data

Forward uncertainty quantification and sensitivity analysis in models of systemic circulation

The intricate nature of the heart and blood circulation is intensively studied in the search for answers and insights capable of maturing the understanding of the cardiovascular system’s physiological and pathophysiological phenomena. Cardiovascular computational models are useful tools for this purpose. They are already widely used by the medical-scientific community, simulating important phenomena such as the dynamics of the systemic circulation and providing valuable information, such as hemodynamic parameters and biomarkers, of common clinical use. However, the clinical application of these models is not straightforward, and for them to be used ubiquitously for decision-making, there is still much to be improved. An important step in this direction is to search for more accurate and reliable models, where the understanding of the relationship between the uncertainties in the input parameters of a model and the precision of its results must be taken into account. In the present work, we verify the effect of the propagation of uncertainties on the input parameters of lumped parameter models and a multi-scale finite element model that simulates the systemic circulation dynamics. For this, we perform forward uncertainty quantification and sensitivity analysis based on the polynomial chaos expansion. The results obtained point to the most influential parameters in the prediction of quantities of interest of clinical relevance. Thus, it is expected that the knowledge acquired on the parameters that must be measured with greater precision and the least influential ones, which can be measured from population-based values or the literature, can help in the calibration and development of more accurate and consistent models.A intrincada natureza do coração e da circulação sanguínea é intensamente estudada na busca de respostas e insights capazes de amadurecer a compreensão dos fenômenos fisiológicos e patofisiológicos do sistema cardiovascular. Modelos computacionais cardiovasculares são ferramentas úteis para este fim e já são amplamente utilizados pela comunidade médico-científica, sendo capazes de simular fenômenos importantes como as dinâmicas da circulação sistêmica e fornecer informações valiosas, como parâmetros hemodinâmicos e biomarcadores, de habitual uso clínico. Entretanto, a aplicação destes modelos em cenários clínicos não se dá facilmente, e para que sejam usados de forma ubíqua para a tomada de decisão ainda há muito o que se aprimorar. Um importante passo neste sentido se dá na busca por modelos mais precisos e confiáveis, onde deve-se tomar em conta o entendimento da relação entre as incertezas nos parâmetros de entrada de um modelo e a precisão de seus resultados. No presente trabalho, verificamos o efeito da propagação de incertezas nos parâmetros de entradas de modelos de parâmetros condensados e um modelo de elementos finitos multi-escala que simulam as dinâmicas da circulação sistêmica. Para isto, realizamos a quantificação de incertezas direta e análise de sensibilidade baseadas na expansão por caos polinomial e os resultados obtidos apontam para os parâmetros mais influentes na predição de quantidades de interesse de relevância clínica. Desta forma, espera-se que os conhecimentos adquiridos sobre os parâmetros que devem ser medidos com maior precisão, bem como os menos influentes, que podem ser medidos a partir de valores de base populacional ou da literatura, possam ajudar na calibragem e desenvolvimento de modelos mais precisos e consistentes.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

In-Vitro and In-Silico Investigations of Alternative Surgical Techniques for Single Ventricular Disease

Single ventricle (SV) anomalies account for one-fourth of all cases of congenital Heart disease. The conventional second and third stage i.e. Comprehensive stage II and Fontan procedure of the existing three-staged surgical approach serving as a palliative treatment for this anomaly, entails multiple complications and achieves a survival rate of 50%. Hence, to reduce the morbidity and mortality rate associated with the second and third stages of the existing palliative procedure, the novel alternative techniques called “Hybrid Comprehensive Stage II” (HCSII), and a “Self-powered Fontan circulation” have been proposed. The goal of this research is to conduct in-vitro investigations to validate computational and clinical findings on these proposed novel surgical techniques. The research involves the development of a benchtop study of HCSII and self-powered Fontan circulation

Model-based quantification of systolic and diastolic left ventricular mechanics

Het linker ventrikel (LV) is de meest gespierde kamer van het hart. Door het gecoördineerd samentrekken van de spiercellen in de LV-wand wordt zuurstofrijk bloed in de aorta gepompt (systolische fase). Daarna ontspannen de spiercellen zich snel waardoor het LV opnieuw met bloed wordt gevuld (diastolische fase). In de kliniek en de onderzoekswereld bestaat er een waaier van modelgebaseerde methoden en concepten om de performantie en de mechanische eigenschappen van het LV te kwantificeren. Invasief bekomen druk- en volumedata laten toe om de systolische en diastolische mechanica van het LV met grote nauwkeurigheid te kennen. In de klinische praktijk wordt echter vaker gebruik gemaakt van (Doppler-) echocardiografie, een snelle en veilige niet-invasieve beeldtechniek. In een eerste deel van dit doctoraatsonderzoek werd een originele methode voorgesteld om, op basis van echocardiografie en klassieke bloeddrukmetingen, de intrinsieke krachtontwikkeling (contractiliteit) van het LV te schatten. De methode werd toegepast bij 2524 mensen die deelnemen aan de Asklepios-studie. De onderzoeksresultaten verschaften ons nieuwe informatie over hoe de evolutie van de krachtontwikkeling verschilt tussen gezonde mannen en vrouwen. De mechanische en vloeistofdynamische fenomenen tijdens de diastole vormden het onderwerp van het tweede deel van het onderzoek. Met behulp van een hydraulisch model van het LV werd nagegaan welke factoren een belangrijke invloed uitoefenen op het gedrag van het LV tijdens de isovolumetrische ontspanningsfase. In dit deel werd eveneens een uitgebreid overzicht gegeven van de meest recente echocardiografische methoden om de diastolische LV-mechanica te begroten. Daarbij werden de bloedstroming, de wandbeweging en de interactie tussen beiden gedetailleerd behandeld

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

Personalising cardiovascular network models in pregnancy: A two‐tiered parameter estimation approach

Uterine artery Doppler waveforms are often studied to determine whether a patient is at risk of developing pathologies such as pre-eclampsia. Many uterine waveform indices have been developed, which attempt to relate characteristics of the waveform with the physiological adaptation of the maternal cardiovascular system, and are often suggested to be an indicator of increased placenta resistance and arterial stiffness.Dopplerwaveforms of four patients, two of whom developed pre-eclampsia, are compared with a comprehensive closed-loop model of pregnancy. The closed-loop model has been previously validated, but has been extended to include an improved parameter estimation technique that utilises systolic and diastolic blood pressure, cardiac output, heart rate, and pulse wave velocity measurements to adapt model resistances, compliances, blood volume, and the mean vessel areas in the main systemic arteries. The shape of the model-predicted uterine artery velocity waveforms showed good agreement with the characteristics observed in the patient Doppler waveforms. The personalised models obtained now allow a prediction of the uterine pressure waveforms in addition to the uterine velocity. This allows for a more detailed mechanistic analysis of the waveforms, e.g. wave intensity analysis, to study existing clinical indices. The findings indicate that to accurately estimate arterial stiffness, both pulse pressure and pulse wave velocities are required. In addition the results predict that patients who developed pre-eclampsia later in pregnancy have larger vessel areas in the main systemic arteries compared to the two patients who had normal pregnancy outcomes

FINDING SIMPLICITY IN THE COMPLEX SYSTEMIC ARTERIAL SYSTEM: BASIS OF INCREASED PULSE PRESSURE

Arterial pulse pressure is critically important to a number of diseases such as isolated systolic hypertension, coronary artery disease and heart failure. Determining the cause of increased pulse pressure has been hampered for two reasons. First, pulse pressure results from contraction of the heart and the load formed by the complex arterial tree. Pressure pulses travel from the heart to the peripheral arteries. As they reach a bifurcation or change in arterial wall properties, some of the pulses get reflected and propagate retrograde towards the heart. Second, two different modeling approaches (0-D and 1-D) describe the arterial system. The Windkessel model ascribed changes in pulse pressure to changes in total arterial compliance (Ctot) and total arterial resistance, whereas the transmission model ascribed them to changes in the magnitude, timing and sites of reflection. Our investigation has addressed both these limitations by finding that a complex arterial system degenerates into a simple 2-element Windkessel model when wavelength of the propagated pulse increases. This theoretical development has yielded three practical results. First, isolated systolic hypertension can be viewed as a manifestation of a system that has degenerated into a Windkessel, and thus increased pulse pressure is due to decreased Ctot. Second, the well-discussed Augmentation Index does not truly describe augmentation of pulse pressure by pulse reflection. Third, the simple 2-element Windkessel can be used to characterize the interaction among heart, arterial system and axial-flow left ventricular assist device analytically. The fact that arterial systems degenerate into Windkessels explains why it becomes much easier to estimate total arterial compliance in hypertension?total arterial compliance is the dominant determinant of pulsatile pressure

MULTISCALE MODELING OF CARDIAC GROWTH AND BAROREFLEX CONTROL

The heart functions within a complex system that adapts its function to any alteration in loading via several mechanisms. For example, the baroreflex is a short-term feedback loop that modulates the heart\u27s function on a beat-to-beat basis to control arterial pressure. On the other hand, cardiac growth is a long-term adaptive response that occurs over weeks or months in response to changes in left ventricular loading. Understanding the mechanisms that drive ventricular growth and biological remodeling is critical to improving patient care. Multiscale models of the cardiovascular system have emerged as effective tools for investigating G&R, offering the ability to evaluate the effects of molecular-level mechanisms on organ-level function. This dissertation presents MyoFE, a multiscale computer model that simulates the left ventricle (LV) pumping blood around a systemic circulation by bridging from molecular to organ-level mechanisms. The model integrates a baroreflex control of arterial pressure using feedback to regulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and thin myofilaments, and vascular tone. MyoFE is extended via a growth algorithm to simulate both concentric growth (wall thickening / thinning) and eccentric growth (chamber dilation / constriction). Specifically, concentric growth is controlled by the time-averaged total stress over the cardiac cycle, while eccentric growth responds to time-averaged intracellular myofiber passive stress. Our integrated model replicated clinical measures of left ventricular growth in two types of valvular diseases - aortic stenosis and mitral regurgitation - at two different levels of severity for each case. Furthermore, our results showed that incorporating the effects of baroreflex control of arterial pressure in simulations of left ventricular growth not only led to more realistic hemodynamics, but also impacted the magnitude of growth. Specifically, our results highlighted the role of regulating venous compliance (vasoconstriction) by the baroreflex immediately after the onset of valvular diseases, which has a significant role on the extent of LV growth in the long term

A one-dimensional hemodynamic model of the coronary arterial tree

One-dimensional (1D) hemodynamic models of arteries have increasingly been applied to coronary circulation. In this study, we have adopted flow and pressure profiles in Olufsen's 1D structured tree as coronary boundary conditions, with terminals coupled to the dynamic pressure feedback resulting from the intra-myocardial stress because of ventricular contraction. We model a trifurcation structure of the example coronary tree as two adjacent bifurcations. The estimated results of blood pressure and flow rate from our simulation agree well with the clinical measurements and published data. Furthermore, the 1D model enables us to use wave intensity analysis to simulate blood flow in the developed coronary model. Six characteristic waves are observed in both left and right coronary flows, though the waves' magnitudes differ from each other. We study the effects of arterial wall stiffness on coronary blood flow in the left circumflex artery (LCX). Different diseased cases indicate that distinct pathological reactions of the cardiovascular system can be better distinguished through Wave Intensity analysis, which shows agreement with clinical observations. Finally, the feedback pressure in terminal vessels and measurement deviation are also investigated by changing parameters in the LCX. We find that larger feedback pressure increases the backward wave and decreases the forward one. Although simplified, this 1D model provides new insight into coronary hemodynamics in healthy and diseased conditions. We believe that this approach offers reference resources for studies on coronary circulation disease diagnosis, treatment and simulation

Arterial pulse wave modeling and analysis for vascular-age studies: a review from VascAgeNet

Aging; Arteriosclerosis; HemodynamicsEnvelliment; Arteriosclerosi; HemodinàmicaEnvejecimiento; Arteriosclerosis; HemodinámicaArterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life.This article is based upon work from COST Action “Network for Research in Vascular Ageing” (VascAgeNet, CA18216), supported by COST (European Cooperation in Science and Technology, www.cost.eu). This work was supported by British Heart Foundation Grants PG/15/104/31913 (to J.A. and P.H.C.), FS/20/20/34626 (to P.H.C.), and AA/18/6/34223, PG/17/90/33415, SPG 2822621, and SP/F/21/150020 (to A.D.H.); Kaunas University of Technology Grant INP2022/16 (to B.P.); European Research Executive Agency, Marie-Sklodowska Curie Actions Individual Fellowship Grant 101038096 (to S.P.); Istinye University, BAP Project Grant 2019B1 (to S.P.); “la Caixa” Foundation Grant LCF/BQ/PR22/11920008 (to A.G.); and National Institute for Health and Care Research Grant AI AWARD02499 and EU Horizon 2020 Grant H2020 848109 (to A.D.H.)