Investigation into the two-way interaction of coronary flow and heart function in coronary artery disease predicted by a computational model of autoregulation of coronary flow.

This study presents a closed-loop computational model to investigate the interplay between heart function, coronary flow, and systemic circulation during exercise, with a specific focus on the impact of coronary artery stenosis. The model incorporates a lumped representation of the heart, main arteries, and coronary arteries, establishing a closed circulatory system. The simulation investigates the autoregulation of coronary flow in response to myocardial oxygen demands during physical exercise by incorporating sympathetic and parasympathetic functions. This study establishes a closed supply-demand loop and investigates the effect of coronary flow deficiency on heart function and systemic circulation in coronary artery diseases during exercise. In coronary artery diseases with low stenosis, heart function and systemic flow resemble those of a healthy person. However, as stenosis intensifies with physical exercise, an additional regulatory mechanism (reg2) is activated. This mechanism adjusts coronary flow by reducing myocardial contractility (E) and increasing heart rate (HR) while maintaining cardiac output (CO). The study results indicate that, at the highest exercise intensity for a healthy individual (HR = 150), the value of E increases from 6 to 8.65mmHg/ml. Meanwhile, for a patient with 85 % coronary artery stenosis in the same exercise intensity, the HR increases to 200, and the value of E decreases to 3.45mmHg/ml. The results also demonstrate that the initiation of the (reg2) mechanism at rest occurs at 83 % stenosis, while at the highest exercise intensity, this mechanism commences at 67 % stenosis.

Computational Multi-Scale Modeling of Drug Delivery into an Anti-Angiogenic Therapy-Treated Tumor.

The present study develops a numerical model, which is the most complex one, in comparison to previous research to investigate drug delivery accompanied by the anti-angiogenesis effect. This paper simulates intravascular blood flow and interstitial fluid flow using a dynamic model. The model accounts for the non-Newtonian behavior of blood and incorporates the adaptation of the diameter of a heterogeneous microvascular network derived from modeling the evolution of endothelial cells toward a circular tumor sprouting from two-parent vessels, with and without imposing the inhibitory effect of angiostatin on a modified discrete angiogenesis model. The average solute exposure and its uniformity in solid tumors of different sizes are studied by numerically solving the convection-diffusion equation. Three different methodologies are considered for simulating anti-angiogenesis: modifying the capillary network, updating the transport properties, and considering both microvasculature and transport properties modifications. It is shown that anti-angiogenic therapy decreases drug wash-out in the periphery of the tumor. Results show the decisive role of microvascular structure, particularly its distribution, and interstitial transport properties modifications induced via vascular normalization on the quality of drug delivery, such that it is improved by 39% in uniformity by the second approach in R = 0.2 cm.

Investigation of the evolution of tumor-induced microvascular network under the inhibitory effect of anti-angiogenic factor, angiostatin: A mathematical study.

Anti-angiogenesis as a treatment strategy for normalizing the microvascular network of tumors is of great interest among researchers, especially in combination with chemotherapy or radiotherapy. According to the vital role that angiogenesis plays in tumor growth and in exposing the tumor to therapeutic agents, this work develops a mathematical framework to study the influence of angiostatin, a plasminogen fragment that shows the anti-angiogenic function, in the evolutionary behavior of tumor-induced angiogenesis. Angiostatin-induced microvascular network reformation is investigated in a two-dimensional space by considering two parent vessels around a circular tumor by a modified discrete angiogenesis model in different tumor sizes. The effects of imposing modifications on the existing model, i.e., the matrix-degrading enzyme effect, proliferation and death of endothelial cells, matrix density function, and a more realistic chemotactic function, are investigated in this study. Results show a decrease in microvascular density in response to the angiostatin. A functional relationship exists between angiostatin's ability to normalize the capillary network and tumor size or progression stage, such that capillary density decreases by 55%, 41%, 24%, and 13% in tumors with a non-dimensional radius of 0.4, 0.3, 0.2, and 0.1, respectively, after angiostatin administration.

Numerical Investigation on the Anti-Angiogenic Therapy-Induced Normalization in Solid Tumors.

This study numerically analyzes the fluid flow and solute transport in a solid tumor to comprehensively examine the consequence of normalization induced by anti-angiogenic therapy on drug delivery. The current study leads to a more accurate model in comparison to previous research, as it incorporates a non-homogeneous real-human solid tumor including necrotic, semi-necrotic, and well-vascularized regions. Additionally, the model considers the effects of concurrently chemotherapeutic agents (three macromolecules of IgG, F(ab')2, and F(ab')) and different normalization intensities in various tumor sizes. Examining the long-term influence of normalization on the quality of drug uptake by necrotic area is another contribution of the present study. Results show that normalization decreases the interstitial fluid pressure (IFP) and spreads the pressure gradient and non-zero interstitial fluid velocity (IFV) into inner areas. Subsequently, wash-out of the drug from the tumor periphery is decreased. It is also demonstrated that normalization can improve the distribution of solute concentration in the interstitium. The efficiency of normalization is introduced as a function of the time course of perfusion, which depends on the tumor size, drug type, as well as normalization intensity, and consequently on the dominant mechanism of drug delivery. It is suggested to accompany anti-angiogenic therapy by F(ab') in large tumor size (Req=2.79 cm) to improve reservoir behavior benefit from normalization. However, IgG is proposed as the better option in the small tumor (Req=0.46 cm), in which normalization finds the opportunity of enhancing uniformity of IgG average exposure by 22%. This study could provide a perspective for preclinical and clinical trials on how to take advantage of normalization, as an adjuvant treatment, in improving drug delivery into a non-homogeneous solid tumor.