Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure.

2'-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca[Formula: see text] transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function. We integrated atomistic simulations of prepowerstroke myosin and actomyosin association, filament-scale Markov state modeling of sarcomere mechanics, cell-scale analysis of myocyte Ca[Formula: see text] dynamics and contraction, organ-scale modeling of biventricular mechanoenergetics, and systems level modeling of circulatory dynamics. Molecular and Brownian dynamics simulations showed that dATP increases the actomyosin association rate by 1.9 fold. Markov state models predicted that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady-state force development at low dATP fractions by 1.3 fold due to mechanosensing and nearest-neighbor cooperativity. This was found to be the dominant mechanism by which small amounts of dATP can improve contractile function at myofilament to organ scales. Together with faster myocyte Ca[Formula: see text] handling, this led to improved ventricular contractility, especially in a failing heart model in which dATP increased ejection fraction by 16% and the energy efficiency of cardiac contraction by 1%. This work represents a complete multiscale model analysis of a small molecule myosin modulator from single molecule to organ system biophysics and elucidates how the molecular mechanisms of dATP may improve cardiovascular function in heart failure with reduced ejection fraction.

Inherent Metabolic Adaptations in Adult Spiny Mouse ( Acomys ) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction.

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( Acomys ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in Acomys compared to the non-regenerative Mus musculus . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus , underscoring the unique metabolic phenotype of Acomys hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys . In conclusion, our study identifies unique metabolic characteristics of Acomys cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes Acomys as a valuable model for studying cardiac ischemic resilience in adult mammals.

Guidelines for mechanistic modeling and analysis in cardiovascular research.

Computational, or in silico, models are an effective, noninvasive tool for investigating cardiovascular function. These models can be used in the analysis of experimental and clinical data to identify possible mechanisms of (ab)normal cardiovascular physiology. Recent advances in computing power and data management have led to innovative and complex modeling frameworks that simulate cardiovascular function across multiple scales. While commonly used in multiple disciplines, there is a lack of concise guidelines for the implementation of computer models in cardiovascular research. In line with recent calls for more reproducible research, it is imperative that scientists adhere to credible practices when developing and applying computational models to their research. The goal of this manuscript is to provide a consensus document that identifies best practices for in silico computational modeling in cardiovascular research. These guidelines provide the necessary methods for mechanistic model development, model analysis, and formal model calibration using fundamentals from statistics. We outline rigorous practices for computational, mechanistic modeling in cardiovascular research and discuss its synergistic value to experimental and clinical data.

Integrated modeling and simulation of recruitment of myocardial perfusion and oxygen delivery in exercise.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins.

Unraveling the Gordian knot of coronary pressure-flow autoregulation.

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today. The purpose of this review is to highlight current knowledge regarding the complex interrelationship between the pathways and mechanisms proposed to dictate the degree of coronary pressure-flow autoregulation. Our group recently likened the intertwined nature of the essential determinants of coronary flow control to the symbolically unsolvable "Gordian knot". To further efforts to unravel the autoregulatory "knot", we consider recent challenges to the local metabolic and myogenic hypotheses and the complicated dynamic structural and functional heterogeneity unique to the heart and coronary circulation. Additional consideration is given to interrogation of putative mediators, role of K+ and Ca2+ channels, and recent insights from computational modeling studies. Improved understanding of how specific vasoactive mediators, pathways, and underlying disease states influence coronary pressure-flow relations stands to significantly reduce morbidity and mortality for what remains the leading cause of death worldwide.

Integrated Functions of Cardiac Energetics, Mechanics, and Purine Nucleotide Metabolism.

Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.

Computational modeling of ventricular-ventricular interactions suggest a role in clinical conditions involving heart failure.

Introduction: The left (LV) and right (RV) ventricles are linked biologically, hemodynamically, and mechanically, a phenomenon known as ventricular interdependence. While LV function has long been known to impact RV function, the reverse is increasingly being realized to have clinical importance. Investigating ventricular interdependence clinically is challenging given the invasive measurements required, including biventricular catheterization, and confounding factors such as comorbidities, volume status, and other aspects of subject variability. Methods: Computational modeling allows investigation of mechanical and hemodynamic interactions in the absence of these confounding factors. Here, we use a threesegment biventricular heart model and simple circulatory system to investigate ventricular interdependence under conditions of systolic and diastolic dysfunction of the LV and RV in the presence of compensatory volume loading. We use the end-diastolic pressure-volume relationship, end-systolic pressure-volume relationship, Frank Starling curves, and cardiac power output as metrics. Results: The results demonstrate that LV systolic and diastolic dysfunction lead to RV compensation as indicated by increases in RV power. Additionally, RV systolic and diastolic dysfunction lead to impaired LV filling, interpretable as LV stiffening especially with volume loading to maintain systemic pressure. Discussion: These results suggest that a subset of patients with intact LV systolic function and diagnosed to have impaired LV diastolic function, categorized as heart failure with preserved ejection fraction (HFpEF), may in fact have primary RV failure. Application of this computational approach to clinical data sets, especially for HFpEF, may lead to improved diagnosis and treatment strategies and consequently improved outcomes.

Higher mitochondrial oxidative capacity is the primary molecular differentiator in muscle of rats with high and low intrinsic cardiorespiratory fitness.

OBJECTIVE: Cardiorespiratory fitness (CRF) is tightly linked with health and longevity and is implicated in metabolic flexibility and substrate metabolism. The high capacity runner (HCR) and low capacity runner (LCR) rat lines are a genetically heterogeneous rat model selected and bred for CRF that reflect CRF in humans by exhibiting differences in nutrient handling. This study aims to differentiate the intrinsic substrate preference of the HCR compared to LCR rats to better understand the intersection of mitochondrial respiration and intrinsic CRF. METHODS: We performed bulk skeletal muscle RNA-Sequencing on male and female HCR and LCR rats and assessed the effect of rat line on mitochondrial gene expression pathways using the MitoCarta3.0 database. In a separate cohort of rats, mitochondria were isolated from skeletal and cardiac muscle and maximal oxidation rates were measured using an Oroboros O2k when provided either pyruvate or fatty acid substrates. RESULTS: The expression of mitochondrial genes are significantly upregulated in HCR skeletal muscle in both male and female rats. In respirometry experiments, fatty acid oxidative capacities were greater in HCR compared to LCR, and male compared to female rats, as a function of both mitochondrial quality and mitochondrial density. This effect was greater in the skeletal muscle than in the heart. Pyruvate oxidation did not differ significantly between lines. CONCLUSIONS: The capacity for increased fatty acid oxidation in the HCR rat is a result of selection for running capacity and is likely a key contributor to the healthy metabolic phenotype of individuals with high CRF.

Portal Venous Remodeling Determines the Pattern of Cirrhosis Decompensation: A Systems Analysis.

INTRODUCTION: As liver disease progresses, scarring results in worsening hemodynamics ultimately culminating in portal hypertension. This process has classically been quantified through the portosystemic pressure gradient (PSG), which is clinically estimated by hepatic venous pressure gradient (HVPG); however, PSG alone does not predict a given patient's clinical trajectory regarding the Baveno stage of cirrhosis. We hypothesize that a patient's PSG sensitivity to venous remodeling could explain disparate disease trajectories. METHODS: We created a computational model of the portal system in the context of worsening liver disease informed by physiologic measurements from the field of portal hypertension. We simulated progression of clinical complications, HVPG, and transjugular intrahepatic portosystemic shunt placement while only varying a patient's likelihood of portal venous remodeling. RESULTS: Our results unify hemodynamics, venous remodeling, and the clinical progression of liver disease into a mathematically consistent model of portal hypertension. We find that by varying how sensitive patients are to create venous collaterals with rising PSG we can explain variation in patterns of decompensation for patients with liver disease. Specifically, we find that patients who have higher proportions of portosystemic shunting earlier in disease have an attenuated rise in HVPG, delayed onset of ascites, and less hemodynamic shifting after transjugular intrahepatic portosystemic shunt placement. DISCUSSION: This article builds a computational model of portal hypertension which supports that patient-level differences in venous remodeling may explain disparate clinical trajectories of disease.

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5-7). Hypoxemia (PaO2 < 40 mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60 mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25 mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.

Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Reduced cardiac muscle power with low ATP simulating heart failure.

For patients with heart failure, myocardial ATP level can be reduced to one-half of that observed in healthy controls. This marked reduction (from ≈8 mM in healthy controls to as low as 3-4 mM in heart failure) has been suggested to contribute to impaired myocardial contraction and to the decreased pump function characteristic of heart failure. However, in vitro measures of maximum myofilament force generation, maximum shortening velocity, and the actomyosin ATPase activity show effective KM values for MgATP ranging from ≈10 µM to 150 µM, well below the intracellular ATP level in heart failure. Thus, it is not clear that the fall of myocardial ATP observed in heart failure is sufficient to impair the function of the contractile proteins. Therefore, we tested the effect of low MgATP levels on myocardial contraction using demembranated cardiac muscle preparations that were exposed to MgATP levels typical of the range found in non-failing and failing hearts. Consistent with previous studies, we found that a 50% reduction in MgATP level (from 8 mM to 4 mM) did not reduce maximum force generation or maximum velocity of shortening. However, we found that a 50% reduction in MgATP level caused a 20%-25% reduction in maximal power generation (measured during muscle shortening against a load) and a 20% slowing of cross-bridge cycling kinetics. These results suggest that the decreased cellular ATP level occurring in heart failure contributes to the impaired pump function of the failing heart. Since the ATP-myosin ATPase dissociation constant is estimated to be submillimolar, these findings also suggest that MgATP concentration affects cross-bridge dynamics through a mechanism that is more complex than through the direct dependence of MgATP concentration on myosin ATPase activity. Finally, these studies suggest that therapies targeted to increase adenine nucleotide pool levels in cardiomyocytes might be beneficial for treating heart failure.

Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms.

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The modelling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural haemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modelling framework, and associated model simulations are compared with experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally probable metabolic mechanism among the seven tested models, in which production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow. Finally, the identified model is validated based on comparisons of simulations with data on the myocardial perfusion response to conscious exercise that were not used for model identification. KEY POINTS: Although several competing hypotheses exist, we lack knowledge of specific nature of the metabolic mechanism(s) governing regional myocardial perfusion. Moreover, we lack an understanding of how parallel myogenic, adrenergic/autonomic and metabolic mechanisms work together to regulatory oxygen delivery in the beating heart. We have developed a multiscale modelling framework to test competing hypotheses against experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The analysis identifies a maximally probable metabolic mechanism among seven tested models, in which the production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow.

Systems analysis of the mechanisms governing the cardiovascular response to changes in posture and in peripheral demand during exercise.

Blood flows and pressures throughout the human cardiovascular system are regulated in response to various dynamic perturbations, such as changes to peripheral demands in exercise, rapid changes in posture, or loss of blood from hemorrhage, via the coordinated action of the heart, the vasculature, and autonomic reflexes. To assess how the systemic and pulmonary arterial and venous circulation, the heart, and the baroreflex work together to effect the whole-body responses to these perturbations, we integrated an anatomically-based large-vessel arterial tree model with the TriSeg heart model, models capturing nonlinear characteristics of the large and small veins, and baroreflex-mediated regulation of vascular tone and cardiac chronotropy and inotropy. The model was identified by matching data from the Valsalva maneuver (VM), exercise, and head-up tilt (HUT). Thirty-one parameters were optimized using a custom parameter-fitting tool chain, resulting in an unique, high-fidelity whole-body human cardiovascular systems model. Because the model captures the effects of exercise and posture changes, it can be used to simulate numerous clinical assessments, such as HUT, the VM, and cardiopulmonary exercise stress testing. The model can also be applied as a framework for representing and simulating individual patients and pathologies. Moreover, it can serve as a framework for integrating multi-scale organ-level models, such as for the heart or the kidneys, into a whole-body model. Here, the model is used to analyze the relative importance of chronotropic, inotropic, and peripheral vascular contributions to the whole-body cardiovascular response to exercise. It is predicted that in normal physiological conditions chronotropy and inotropy make roughly equal contributions to increasing cardiac output and cardiac power output during exercise. Under upright exercise conditions, the nonlinear pressure-volume relationship of the large veins and sympathetic-mediated venous vasoconstriction are both required to maintain preload to achieve physiological exercise levels. The developed modeling framework is built using the open Modelica modeling language and is freely distributed.

Phenotyping heart failure using model-based analysis and physiology-informed machine learning.

To phenotype mechanistic differences between heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction, a closed-loop model of the cardiovascular system coupled with patient-specific transthoracic echocardiography (TTE) and right heart catheterization (RHC) data was used to identify key parameters representing haemodynamics. Thirty-one patient records (10 HFrEF, 21 HFpEF) were obtained from the Cardiovascular Health Improvement Project database at the University of Michigan. Model simulations were tuned to match RHC and TTE pressure, volume, and cardiac output measurements in each patient. The underlying physiological model parameters were plotted against model-based norms and compared between HFrEF and HFpEF. Our results confirm the main mechanistic parameter driving HFrEF is reduced left ventricular (LV) contractility, whereas HFpEF exhibits a heterogeneous phenotype. Conducting principal component analysis, k -means clustering, and hierarchical clustering on the optimized parameters reveal (i) a group of HFrEF-like HFpEF patients (HFpEF1), (ii) a classic HFpEF group (HFpEF2), and (iii) a group of HFpEF patients that do not consistently cluster (NCC). These subgroups cannot be distinguished from the clinical data alone. Increased LV active contractility ( p<0.001 ) and LV passive stiffness ( p<0.001 ) at rest are observed when comparing HFpEF2 to HFpEF1. Analysing the clinical data of each subgroup reveals that elevated systolic and diastolic LV volumes seen in both HFrEF and HFpEF1 may be used as a biomarker to identify HFrEF-like HFpEF patients. These results suggest that modelling of the cardiovascular system and optimizing to standard clinical data can designate subgroups of HFpEF as separate phenotypes, possibly elucidating patient-specific treatment strategies. KEY POINTS: Analysis of data from right heart catheterization (RHC) and transthoracic echocardiography (TTE) of heart failure (HF) patients using a closed-loop model of the cardiovascular system identifies key parameters representing haemodynamic cardiovascular function in patients with heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). Analysing optimized parameters representing cardiovascular function using machine learning shows mechanistic differences between HFpEF groups that are not seen analysing clinical data alone. HFpEF groups presented here can be subdivided into three subgroups: HFpEF1 described as 'HFrEF-like HFpEF', HFpEF2 as 'classic HFpEF', and a third group of HFpEF patients that do not consistently cluster. Focusing purely on cardiac function consistently captures the underlying dysfunction in HFrEF, whereas HFpEF is better characterized by dysfunction in the entire cardiovascular system. Our methodology reveals that elevated left ventricular systolic and diastolic volumes are potential biomarkers for identifying HFrEF-like HFpEF patients.

Quantitative analysis of mitochondrial ATP synthesis.

We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized 1 H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the 1 H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo 1 H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between 1 H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with 1 H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. DATA CONCLUSION: We validated the use of localized 1 H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.