Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Tewari, Shivendra G.; Bugenhagen, Scott M.; Vinnakota, Kalyan C.; Rice, John Jeremy; Janssen, Paul M. L.; Beard, Daniel A.

doi:10.1016/j.yjmcc.2016.04.003

Cited by 27 publications

(54 citation statements)

References 42 publications

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“…The multiscale model is illustrated in Figure 1 . Developed by Tewari et al (2016b) , myofilament mechanoenergetics ( Tewari et al, 2016a , b ) drive biventricular contraction and relaxation ( Lumens et al, 2009 ) coupled to lumped parameter circulations ( Tewari et al, 2013 ). As recently described by Pewowaruk et al (2018) , in order to better represent diastolic ventricular physiology, a varying elastance atrial model was incorporated ( Senzaki et al, 1996 ), in which the atrial pressure changes that drive ventricular filling are calculated as…”

Section: Methodsmentioning

confidence: 99%

“…These studies give evidence of important associations between cellular level and organ level function changes in RVF; however, no causal relationships have been established. A computational model of the cardiovascular system that integrates cellular function (both metabolic and mechanical) and structure into whole organ function has recently been developed ( Tewari et al, 2016a , b ). This model is an important tool to aid in investigating which functional and structural changes at the cellular level cause impaired RV function at the organ level.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

et al. 2018

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Introduction: Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy.Methods: A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α1A-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH.Results: Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload.Conclusion: Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

et al. 2018

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“…Myocardial energy homeostasis is maintained primarily by oxidative phosphorylation of adenosine diphosphate (ADP) in cardiomyocyte mitochondria. A disruption of myocardial energy homeostasis may impair mechanical function of the heart (Tewari et al, 2016b ). Indeed, impaired mitochondrial function can lead to a life-threatening state of heart failure (Neubauer, 2007 ; Brown et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise

et al. 2017

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Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology.

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“…The potential importance of the link between energetic status and mechanical function is highlighted by the fact that maximum CPO is the strongest predictor of mortality in heart failure [1]. Indeed, the hypotheses for mechanisms underlying age-dependent changes to myocardial mechano-energetic function tested here were formulated based on previous theoretical analysis of the link between energy metabolite levels and mechanical function of the heart in cardiac decomposition and failure [6,7]. While these results do not suggest that the phenotypes are identical, they do suggest fundamental similarities in terms of mechanisms impeding myocardial energetics and mechanical-energetic coupling.…”

Section: Discussionmentioning

confidence: 99%

“…CPO is calculated as left ventricular stroke work (mechanical work done per heart beat) multiplied by the heart rate, or as average difference in pressure between the left atrium and the aorta multiplied by the cardiac output, expressed in units of energy per unit time. Processes such as cross-bridge cycling require that ATP is continuously synthesized (and ADP and inorganic phosphate consumed) at sufficient concentrations such that normal functions are not kinetically or thermodynamically impaired [6,7]. Because demand for ATP production in the myocardium is proportional to cardiac work, and because ATP hydrolysis serves as the source of chemical free energy to drive myocardial contraction, it stands to reason that limitations or impairments in myocardial energy metabolism may influence overall cardiac performance represented by CPO.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging

Gao

Jakovljevic

Beard

2019

Preprint

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Changes in the myocardial energetics associated with aging-reductions in creatine phosphate (CrP)/ATP ratio, total creatine, and ATP-mirror changes observed in failing hearts compared to healthy controls. Similarly, both aging and heart failure are associated with significant reductions in cardiac performance and maximal left ventricular cardiac power output (CPO) compared to young healthy individuals. Based on these observations, we hypothesize that reductions in the concentrations cytoplasmic adenine nucleotide, creatine, and phosphate pools that occur with aging impair the myocardial capacity to synthesize ATP at physiological free energy levels, and that the resulting changes to myocardial energetic status impair the mechanical pumping ability of the heart. The purpose of this study is to test theses hypotheses using an age-structured population model for myocardial metabolism in the adult female population and to determine the potential impact of reductions in key myocardial metabolite pools in causing metabolic/energetic and cardiac mechanical dysfunction associated with aging. To test these hypotheses, we developed a population model for myocardial energetics to predict myocardial ATP, ADP, CrP, creatine, and inorganic phosphate concentrations as functions of cardiac work and age in the adult female population. Model predictions support our hypotheses and are consistent with previous experimental observations. The major findings provide a novel theoretical and computational framework for further probing complex relationships between the energetics and performance of the heart with aging. SignificanceNormal mechanical function of the heart requires that ATP be continuously synthesized at a hydrolysis potential of roughly -60 kJ mol -1 . Yet in both the aging and diseased heart the relationships between cardiac work rate and concentrations of ATP, ADP, and inorganic phosphate are altered. Important outstanding questions are: To what extent do changes in metabolite concentrations that occur in aging and heart disease affect metabolic/molecular processes in the myocardium? How are systolic and diastolic functions affected by changes in metabolite concentrations? This study addresses these questions by analyzing relationships between cardiac energy demand and supply using an age-structured population model for human myocardial energetics in women.

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Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Cited by 27 publications

References 42 publications

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging

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