Jos A. E. Spaan

Oxygen and coronary vascular resistance during autoregulation and metabolic vasodilation in the dog

The hypothesis that tissue oxygen tension controls coronary vascular resistance during changes in perfusion pressure and oxygen consumption was expressed in a simplified mathematical form capable of making quantitative predictions. The predictive value of this formulation of the hypothesis was tested in experiments on anaesthetized mongrel dogs subjected to constant‐pressure perfusion of the left main coronary artery, with measurements of coronary blood flow and arterio‐venous oxygen content differences. Coronary venous oxygen content was used as an index of tissue oxygenation. The responses of coronary blood flow and arterio‐venous oxygen content difference, made over a range of perfusion pressures (which caused autoregulation) and heart rates (which caused metabolic regulation) were predicted qualitatively by the model. Coronary vascular conductance was positively related to metabolic rate only during metabolic regulation (heart rate changes); during autoregulation the relationship between these two variables was inverse. Coronary vascular conductance and resistance values taken from both interventions (both perfusion pressure and heart rate variations) were closely related to coronary venous oxygen content and calculated PO2. These findings suggest that further examination of oxygen tension, as the controller of the coronary vascular bed under physiological conditions should be considered.

Dynamic response of the coronary circulation to a rapid change in its perfusion in the anaesthetized goat

1. We tested predictions of a mathematical formulation of a hypothesis of dynamic control of coronary blood flow by tissue oxygen tension. 2. The rate of change of adjustment of the coronary circulation to a step change in arterial perfusion was analysed in the cannulated main stem preparation of the anaesthetized goat. The variable studied was the ratio between driving pressure and coronary flow, each averaged per heart beat. The response of this ratio was measured following a sudden change in perfusion pressure with constant‐pressure perfusion and a sudden change in flow with constant‐flow perfusion. 3. The rate of change of the pressure‐flow ratio was quantified by t50, the time required to establish half of the completed response. For a pressure decrease t50 was 4.9 +/‐ 0.2 s (n = 35) (mean +/‐ S.E.M., n = number of individual measurements), 11.3 +/‐ 1.2 s (n = 25) for a flow decrease, 14.5 +/‐ 1.6 (n = 34) for a pressure increase and 25.1 +/‐ 2.3 (n = 19) for a flow increase. 4. No effect of the level of flow or pressure on t50 was found for a decrease in perfusion. Furthermore, with a flow increase, the t50 value did not depend on the level of flow, which is in agreement with the outcome of earlier experiments where the response to a change in heart rate was measured. With a pressure increase, the mean t50 value of the pressure‐flow ratio was lower at high perfusion pressure but the difference with low perfusion pressure was not significant (P = 0.11). 5. The t50 value in the cases of an increase in pressure and flow are similar to those found for a change of heart rate in an earlier study. 6. Unlike step changes of metabolic rate, some of the measured responses to mechanical step changes were not predicted by the oxygen hypothesis. It is suggested that the increased rate of coronary adjustment induced by the reduction of coronary perfusion is due to arteriolar smooth muscle mechanics which apparently differ in strength depending on the direction of change of the arteriolar dimensions. 7. This suggestion is strengthened by the results of experiments in which smooth muscle responses were abolished with adenosine.

System analysis of the dynamic response of the coronary circulation to a sudden change in heart rate

In this study the response of driving pressure/flow ratio on an abrupt change in heart rate was analysed. The difference between the response obtained with constant pressure and constant flow perfusion was also studied. The responses show a fast initial reversed phase followed by a slow phase caused by regulation. To test whether the initial phase could be the result of mechanical changes in the coronary circulation, a model for regulation was extended by the addition of four different mechanical models originating from the literature. These extended models were able to explain the fast initial phase. However, the mechanical model consisting of an intramyocardial compliance (C=0·08 ml mm Hg−1 100 g−1) with a variable venous resistance, and the model consisting of a waterfall and a small compliance (C=0·007 ml mm Hg−1 100 g−1) both explained these responses best. The analysis showed that there is no direct relationship between rate of change of vascular tone and rate of change of pressure/flow ratio. However, on the basis of the two extended models, it can be predicted that the half-time for the response of regulation to be complete is about 9s with constant pressure perfusion and 15 s with constant flow perfusion.

Coronary Circulation Mechanics

The use of linear models is very common in studying the mechanical events of the coronary circulation. In this chapter some of the these linear models are discussed. However, special attention is devoted to a nonlinear model. This nonlinear model consists of an arteriolar, capillary, and a venular compartment, each composed of transmural pressure-dependent resistances and compliances. With this model, the influence of pressure-dependent resistances and compliances on the arterial signals is analyzed. This analysis shows that the phasic arterial signals mainly depend on the pressure dependency of the arteriolar compartment. Changes in the parameters of capillary and venular compartments hardly affected the arterial phasic signals. Furthermore, it can be concluded that the interpretation of results obtained by application of linear system theory is highly questionable and could easily lead to misleading conclusions on the magnitude of coronary compliance.

Theoretical analysis of coronary blood flow and tissue oxygen pressure-control

Coronary blood flow is tightly coupled to the myocardial oxygen consumption. We have presented a control model based on the assumption that the tissue oxygen pressure is the controlled variable. The coronary blood flow in itself is not a controlled variable but merely the result of a different control system: the tissue oxygen pressure. From our control equation there is no relation between the slope of the autoregulation curve and the gain of the tissue PO2 control system. The slope is independent of the level of oxygen consumption.

Heart rate affects the dependency of myocardial oxygen consumption on flow in goats

SummaryThe effect of flow steps in coronary arterial flow (Qa) on myocardial oxygen consumption (MVo2) was investigated at different heart rates (HR) to further elucidate the dependency of myocardial oxygen consumption on perfusion. In six anesthetized goats the left main coronary artery and the great cardiac vein were cannulated. The hearts were paced alternately at 60 and 130 beats per min. Flow steps were applied at both HR during control and maximal vasodilation by adenosine. MVo2, in steady state before and after the flow step, was calculated by multiplication of Qa and arterio-venous oxygen content difference (Ficks law). Heart rate affected the MVo2 dependency on flow during control as well as during maximal vasodilation. With vascular tone present, the MVo2 dependency on flow (ΔMVo2/ΔQa), in µl O2/ml, was 16.0 ± 3.6 at HR 60 and 21.7 ± 3.9 at HR 130. During maximal vasodilation, these values were 9.5 ± 2.9 and 17.0 ± 5.3 at HR 60 and 130, respectively. The higher MVo2 dependency on flow at high HR may be explained via a dependency of MVo2 on microvascular pressure. The pressure change in the microvessels induced by a flow step is probably larger at high HR than at low HR because of increased venous resistance at high HR, due to increased compression by the heart contraction.

Local Control of Coronary Flow

The heart needs coronary flow for its oxygen supply. Myocardial oxygen usage can vary over a wide range. In the potassium arrested heart 02 consumption is as low as 21 ul 02/s/100 g (14) whereas in dogs during severe exercise it may increase to 1 ml 02/s/100 g (27, 13). Coronary flow adapts to the level of oxygen usage required. This adaptation is not strictly proportional because oxygen extraction from the coronary blood is not constant. It is generally suggested that oxygen extraction by the myocardium is maximal and therefore the only way for the heart to receive more 02 would be to increase flow. This is (in general) not true as we will see below. It seems more likely that over a significant range of 02 consumption the coronary venous oxygen pressure is related to the control signal responsible for coronary flow regulation (11, 10).

Comparison of different oxygen exchange models.

A functional distribution of coronary volume can be estimated from the response of arterio-venous O2 content difference (AVO2) to a flow step. However, the results depend on the assumed O2 exchange model. The previously used model consisted of a single mixed compartment with O2 exchange in series with an unmixed compartment without O2 exchange (reference model). The purpose of this study is to provide an estimate of the errors made in the volume estimations by not taking into account factors as flow heterogeneity, different mixing sites or Krogh-like O2 exchange. The approach is indirect: the response of the AVO2 to a flow step has been calculated with alternative O2 exchange models in which the factors mentioned are incorporated. These transients are fitted with the reference model. The resulting estimated volumes are different from the volumes assumed in the alternative models. Large differences are obtained with some of the alternative models, e.g. the model with Krogh characteristics. However, these models seem unrealistic because capillary pO2 is higher than venous pO2. Only small differences in volume are obtained with the more realistic models. Therefore, these results indicate that the coronary volumes are approximated well by the estimations obtained with the reference model. These volume estimations were 9.9 and 3.8 ml 100 g−1 for the O2 exchange vessels and the distal venous volume, respectively.

Oxygen exchange between blood and tissue in the myocardium

Oxygen transport to the myocytes has been recognized as a factor of utmost importance to cardiac metabolism and control of blood flow for many decades. On a macroscopic scale, the problem seems simple since supply and demand are normally matched, as discussed in Chapter 9. However, as discussed in Chapters 1 and 3, both flow and oxygen pressures may vary widely in the myocardium at the microscopic level and in tissue units of milligrams and grams.

Static and dynamic analysis of local control of coronary flow

Coronary flow is controlled by the myocardium at the tissue level. This local control can be characterized by two manifestations: the adaptation of blood flow to the level of oxygen consumption and the relative independence of blood flow from coronary arterial pressure. The former manifestation is referred to as flow adaptation to metabolism, the latter one as autoregulation. Alternative terms for flow adaptation to metabolism found in the literature are metabolic regulation and functional hyperemia. However, autoregulation may also be mediated by metabolic processes and therefore metabolic regulation is an ambiguous term. Hyperemia means ‘increased blood flow’ and consequently hyperemia implies the definition of a standard control value of flow. The term flow adaptation to metabolism, or simply flow adaptation, expresses the ability of the coronary system to adapt flow to metabolic needs of the heart, and is the term further used here.