Metabolic Flow Regulation Research Articles

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand‐supply feedback system

Background and objectiveThe myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. MethodsTo investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. ResultsWe found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. ConclusionsModel predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Distinct roles of red-blood-cell-derived and wall-derived mechanisms in metabolic regulation of blood flow.

A theoretical model is used to analyze combinations of RBC-derived and wall-derived (RBC-independent) mechanisms for metabolic blood flow regulation, with regard to their oxygen transport properties. Heterogeneous microvascular network structures are derived from observations in rat mesentery and hamster cremaster. The effectiveness of metabolic blood flow regulation using combinations of RBC-dependent and RBC-independent mechanisms is simulated in these networks under conditions of reduced oxygen delivery and increased oxygen demand. Metabolic regulation by a wall-derived mechanism results in higher predicted total blood flow rate and number of flowing vessels, and lower tissue hypoxic fraction, than regulation by combinations of RBC-derived and wall-derived signals. However, a combination of RBC-derived and wall-derived signals results in a higher predicted median tissue PO2 than either mechanism acting alone. Model results suggest complementary roles for RBC-derived and wall-derived mechanisms of metabolic flow regulation, with the wall-derived mechanism responsible for avoiding hypoxia, and the RBC-derived mechanism responsible for maintaining PO2 levels high enough for optimal tissue function.

Theoretical predictions of metabolic flow regulation in the retina

Purpose: This study uses a theoretical model to investigate the response of retinal blood flow to changes in tissue oxygen demand. The study is motivated by the need for a better understanding of metabolic flow regulation mechanisms in health and disease.Methods: A mathematical model is used to calculate retinal blood flow for different levels of tissue oxygen demand in the presence or absence of regulatory mechanisms. The model combines a compartmental view of the retinal vasculature and a Krogh cylinder description for oxygen delivery to retinal tissue.Results: The model predicts asymmetric behavior in response to changes in tissue oxygen demand. When all regulatory mechanisms are active, the model predicts a 6% decrease in perfusion when tissue oxygen demand is decreased by 50% and a 23% increase in perfusion when tissue oxygen demand is increased by 50%. In the absence of metabolic and carbon dioxide responses, the model predicts a constant level of blood flow that does not respond to changes in oxygen demand, suggesting the importance of these two response mechanisms. The model is not able to replicate the increase in oxygen venous saturation that has been observed in some flicker stimulation studies.Conclusions: The increase in blood flow predicted by the model due to an increase in oxygen demand is not in the same proportion as the change in blood flow observed with the same decrease in oxygen demand, suggesting that vascular regulatory mechanisms may respond differently to different levels of oxygen demand. These results might be useful for interpreting clinical and experimental findings in health and disease.

Ophthalmology and mathematics: crossroad or scientific interface?

Ophthalmology and mathematics: crossroad or scientific interface?

Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation.

In the working heart, coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels (Kv), which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox-sensitive. To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. In mice (wild-type [WT], Kv1.5 null [Kv1.5(-/-)], and Kv1.5(-/-) and WT with inducible, smooth muscle-specific expression of Kv1.5 channels), we measured mean arterial pressure, myocardial blood flow, myocardial tissue oxygen tension, and ejection fraction before and after inducing cardiac stress with norepinephrine. Cardiac work was estimated as the product of mean arterial pressure and heart rate. Isolated arteries were studied to establish whether genetic alterations modified vascular reactivity. Despite higher levels of cardiac work in the Kv1.5(-/-) mice (versus WT mice at baseline and all doses of norepinephrine), myocardial blood flow was lower in Kv1.5(-/-) mice than in WT mice. At high levels of cardiac work, tissue oxygen tension dropped significantly along with ejection fraction. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5(-/-) mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared with those from WT mice. Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunction and tissue hypoxia.

Commentaries on Viewpoint: A paradigm shift for local blood flow regulation

# COMMENT ON “A PARADIGM SHIFT FOR LOCAL BLOOD FLOW REGULATION” {#article-title-2} to the editor: The proposed role of O2− produced by NAD(P)H oxidase acting in concert with changes in mitochondrial O2 on regulating local blood flow hypothesized by Golub and Pittman ([5][1]) could very well

Blood Vessel Adaptation with Fluctuations in Capillary Flow Distribution

Throughout the life of animals and human beings, blood vessel systems are continuously adapting their structures – the diameter of vessel lumina, the thickness of vessel walls, and the number of micro-vessels – to meet the changing metabolic demand of the tissue. The competition between an ever decreasing tendency of luminal diameters and an increasing stimulus from the wall shear stress plays a key role in the adaptation of luminal diameters. However, it has been shown in previous studies that the adaptation dynamics based only on these two effects is unstable. In this work, we propose a minimal adaptation model of vessel luminal diameters, in which we take into account the effects of metabolic flow regulation in addition to wall shear stresses and the decreasing tendency of luminal diameters. In particular, we study the role, in the adaptation process, of fluctuations in capillary flow distribution which is an important means of metabolic flow regulation. The fluctuation in the flow of a capillary group is idealized as a switch between two states, i.e., an open-state and a close-state. Using this model, we show that the adaptation of blood vessel system driven by wall shear stress can be efficiently stabilized when the open time ratio responds sensitively to capillary flows. As micro-vessel rarefaction is observed in our simulations with a uniformly decreased open time ratio of capillary flows, our results point to a possible origin of micro-vessel rarefaction, which is believed to induce hypertension.

Simulation of metabolic blood flow regulation in heterogeneous microvascular networks: Effects of hematocrit variations

A theoretical model is presented for simulating oxygen transport and blood flow regulation in microvascular networks with realistic heterogeneous structures. The distribution of flow and hematocrit is predicted using a model for microvessel hemodynamics, including unequal hematocrit partition at diverging vessel bifurcations. Flow regulation is modeled based on length‐tension characteristics of vascular smooth muscle, and includes myogenic, shear‐dependent and metabolic responses. If the metabolic signal is assumed to originate solely from a red‐blood‐cell‐dependent mechanism, the model predicts unrealistic behavior in two respects. Firstly, a reduction in systemic hematocrit causes a decrease in flow, rather than an increase as expected. Secondly, low flow channels receive a low hematocrit and generate a reduced metabolic signal, causing further flow reduction and leading to uneven oxygenation with hypoxia in some flow channels. These findings suggest that some other mechanism, not dependent on red blood cells, must contribute to metabolic flow regulation. Inclusion in the model of a wall‐derived signal dependent on local oxygen level leads to higher flow in response to hematocrit reduction and more uniform distributions of blood flow and tissue oxygenation. Supported by NIH grant HL070657.

Role of erythrocyte‐ vs. wall‐derived signals in flow regulation in heterogeneous microvascular networks

Postulated mechanisms for metabolic flow regulation are examined using a theoretical model to simulate blood flow, mass transport and vascular responses in heterogeneous microvascular networks. The model accounts for myogenic, shear‐dependent, and metabolic flow regulation. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. Arteriolar tone is assumed to depend on the conducted metabolic signal as well as local wall shear stress and wall tension. In heterogeneous networks, unequal partition of hematocrit at diverging bifurcations can lead to low hematocrit in low‐flow vessels. If the metabolic signal is generated solely by an erythrocyte‐dependent mechanism, such vessels then experience a reduced metabolic signal and may constrict further, leading to further decreases in hematocrit and oxygen delivery. Inclusion of a metabolic signal dependent on oxygen levels at the vessel walls can prevent this effect. The different functional ranges of oxygen tension at which these signals operate suggest a role for both types of signals in flow regulation. Supported by NIH grant HL070657.

Theoretical comparison of wall-derived and erythrocyte-derived mechanisms for metabolic flow regulation in heterogeneous microvascular networks

The objective of this study is to compare the effectiveness of metabolic signals derived from erythrocytes and derived from the vessel wall for regulating blood flow in heterogeneous microvascular networks. A theoretical model is used to simulate blood flow, mass transport, and vascular responses. The model accounts for myogenic, shear-dependent, and metabolic flow regulation. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. Arteriolar tone is assumed to depend on the conducted metabolic signal as well as local wall shear stress and wall tension, and arteriolar diameters are calculated based on vascular smooth muscle mechanics. The model shows that under certain conditions metabolic regulation based on wall-derived signals can be more effective in matching perfusion to local oxygen demand relative to regulation based on erythrocyte-derived signals, resulting in higher extraction and lower oxygen deficit. The lower effectiveness of the erythrocyte-derived signal is shown to result in part from the unequal partition of hematocrit at diverging bifurcations, such that low-flow vessels tend to receive a reduced hematocrit and thereby experience a reduced erythrocyte-derived metabolic signal. The model simulations predict that metabolic signals independent of erythrocytes may play an important role in local metabolic regulation of vascular tone and flow distribution in heterogeneous microvessel networks.

Simulation of metabolism‐perfusion matching in a heterogeneous microvascular network

Microvascular blood flow regulation involves multiple mechanisms designed to maintain adequate perfusion under conditions of varying metabolic demand. The impact of various regulatory factors on metabolism‐perfusion matching was assessed using a heterogeneous microvascular network model that accounted for myogenic, shear, and metabolic flow regulation. Estimates of oxygen extraction under control conditions were compared to an increase in tissue oxygen consumption in combination with a reduction in perfusion. For the values of parameters used, overall oxygen extraction was increased by a factor of 7.19 with a tenfold increase in consumption and a factor of 1.47 when perfusion was reduced by 50%. Combining increased consumption with decreased flow resulted in an increase in extraction by a factor of 9.20 compared to control, suggesting that network regulatory capacity remained intact under these conditions. This has significant implications for the optimization of metabolism‐perfusion matching, since impairment of flow regulation under conditions of increased consumption and decreased perfusion can lead to microvascular perfusion heterogeneity and cause organ failure in critically ill patients.

Mathematical modeling of metabolism‐perfusion matching in a microvascular network

Microvascular blood flow regulation has important implications for optimization of metabolism‐perfusion matching in physiological and pathophysiological conditions such as exercise and sepsis. The purpose of this theoretical study is to assess the impact of various regulatory factors on metabolism‐perfusion matching. A microvascular network model including myogenic, shear, and metabolic flow regulation was developed and utilized to obtain estimates of oxygen extraction under control conditions as compared to a 20% global increase in blood flow accompanied by a 50% increase in oxygen consumption. The exercise state was simulated with preserved flow regulation and sepsis was simulated with impaired metabolic flow regulation. For the values of parameters used, overall oxygen extraction was found to be 28% higher in exercise compared to control values as opposed to only 23% higher in sepsis. This study demonstrates the impact of impaired flow regulation on oxygen delivery and highlights microvascular perfusion abnormalities as a putative mechanism for organ failure in critically ill patients.

Theoretical model of metabolic blood flow regulation: roles of ATP release by red blood cells and conducted responses

A proposed mechanism for metabolic flow regulation involves the saturation-dependent release of ATP by red blood cells, which triggers an upstream conducted response signal and arteriolar vasodilation. To analyze this mechanism, a theoretical model is used to simulate the variation of oxygen and ATP levels along a flow pathway of seven representative segments, including two vasoactive arteriolar segments. The conducted response signal is defined by integrating the ATP concentration along the vascular pathway, assuming exponential decay of the signal in the upstream direction with a length constant of approximately 1 cm. Arteriolar tone depends on the conducted metabolic signal and on local wall shear stress and wall tension. Arteriolar diameters are calculated based on vascular smooth muscle mechanics. The model predicts that conducted responses stimulated by ATP release in venules and propagated to arterioles can account for increases in perfusion in response to increased oxygen demand that are consistent with experimental findings at low to moderate oxygen consumption rates. Myogenic and shear-dependent responses are found to act in opposition to this mechanism of metabolic flow regulation.

Metabolic coronary flow regulation—Current concepts

The concept of metabolic coronary flow control provides a rationale for the close relationship of coronary flow and myocardial metabolic rate of oxygen. The concept is based on the presence of an oxygen (metabolic) sensor coupled functionally to effector mechanisms, which control vascular tone. Four modes of metabolic control models have been proposed. 1) An oxygen sensor located in the wall of coronary vessels coupling to smooth muscle tension. Endothelial prostaglandin production may support this concept. 2) An oxygen sensing mechanism located in the myocardium and changing metabolism in response to changes of local pO(2). Adenosine is a metabolite produced at an accelerated rate when the supply-to-demand relationship for oxygen falls. 3) Sensing of oxygen turnover may be achieved by carbon dioxide production and, potentially, by mitochondrial production of reactive oxygen species. 4) The red blood cell might serve as an oxygen sensor in response to changes of haemoglobin oxygenation. A potential link to vessel relaxation may be red cell ATP release. A large body of experimental evidence supports the notion that K(ATP) channels play a significant role causing smooth muscle hyper-polarization. However, additional yet unknown effector mechanisms must exist, because block of K(ATP) channels does not lead to deterioration of coronary flow control under conditions of exercise. Thus, although several lines of evidence show that metabolic flow regulation is effective during hypoxic conditions,mechanisms mediating normoxic metabolic flow control still await further clarification.

Calcium channel blockade with felodipine does not affect metabolic coronary vasodilation in patients with coronary artery disease.

The effect of calcium channel blockers may affect the feedback mechanism between myocardial metabolic activity and coronary blood flow. To test this hypothesis the effect of calcium channel blockade on metabolic coronary flow regulation was studied. In 10 patients with stable coronary artery disease, coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) were measured both at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), at control and during infusion of felodipine, a vasoselective dihydropyridine. The myocardial oxygen supply-consumption ratio at control (i.e., the slope of the regression line characterizing normal metabolic flow regulation) was 1.58 (95% CI, 1.38-1.80). Following infusion of felodipine, systemic and coronary vascular resistance during sinus rhythm decreased by 20 +/- 11% and 23 +/- 15%, respectively, and coronary venous oxygen saturation increased from 36 +/- 6% at control to 42 +/- 7% (p = 0.047) during infusion of felodipine. The myocardial oxygen supply-consumption ratio, characterizing metabolic flow regulation during felodipine, was 1.52 (95% CI, 1.26-1.78) and thus not different from control. Metabolic coronary flow regulation was not affected by administration of felodipine, although the setpoint of this regulation mechanism might have been offset by the initial drug-induced coronary vasodilation, which persisted during pacing.

Nonpulsatile cardiopulmonary bypass disrupts the flow-metabolism couple in the brain

The effect of cardiopulmonary bypass on the relationship between brain glucose consumption and regional blood flow is unknown. We measured this relationship in pigs subjected to 3 hours of pulsatile or nonpulsatile cardiopulmonary bypass at normothermia and compared the results to the relationship established in a control group of pigs. A total of 10 regions were sampled in both hemispheres of the porcine brain. In control pigs, cerebral blood flow averaged 46 ml/100 gm and the glucose consumption, 21 mumol/100 gm/min. The ratio between blood flow and glucose consumption was close to 2 ml/mumol in all regions. In pulsatile cardiopulmonary bypass both the whole-brain average and the regional values declined, so that the ratio remained the same, about 2 ml/mumol. In nonpulsatile cardiopulmonary bypass regional blood flow remained normal; the average was 49 ml/100 gm/min, whereas the average glucose consumption declined to 16 mumol/100 gm. In regions with high blood flow rates, the ratio between blood flow and glucose consumption increased to about 3 ml/mumol, indicating perfusion in excess of metabolic demand. We conclude that nonpulsatile cardiopulmonary bypass at normothermia affects the metabolic flow regulation in the brain by interfering with the myogenic contractility of cerebral arterioles.