J. H. G. M. Van Beek

Fractal Branchings: The Basis of Myocardial Flow Heterogeneities?

The distribution of myocardial blood flows was found by Yipintsoi et al1 to be surprisingly broad, broader than could be expected from variation in the microsphere technique itself in their studies of anesthetized dog hearts. This was observed by others2,3 and was expanded by observations in awake baboons by King et al.,4 who found that the shape of the distribution of regional myocardial blood flows in about 0.2-g pieces was maintained over long periods of time, as estimated by repeated injections of tracer labeled microspheres. In these studies, the microsphere technique variation gave about 8 percent noise, but the heterogeneity of flows had a standard deviation that was about 35 percent of the mean flow, that is, the relative dispersion (RD) or coefficient of variation was 35 percent. The regional flow in a given piece remained almost constant at each of six observation times, spread over many hours, that is, the broad heterogeneity of myocardial blood flows was stable. More detailed analyses of these data by King and Bassingthwaighte5 showed that the temporal fluctuation in regional flows was quite modest compared with the spatial variation. Temporal fluctuations were such that, while flow in a given region showed some apparently random variation with time, local flow in regions with flow less than 50 percent of the mean flow never increased enough to reach the mean. Similarly, regions with flow greater than 150 percent of the mean never diminished to the mean flow. Thus, myocardial regional flows maintained their relative position in the distribution of flows throughout the heart. These observations gave rise to methodologic and physiological questions. Methodologic questions are: Since there are only four to six observations over time in each of these individual pieces, what could one say about the frequency of temporal fluctuations? Were they rhythmic or not? Which regions of the heart had higher flows vs. lower flows? Were there consistent endocardial and epicardial gradients? The physiological questions are: What are the implications of having regions that are of consistently high flow or consistently low flow? Is the metabolic rate more in high-flow regions than in low-flow regions? Do high-flow regions have a plethora of flow and relatively low oxygen extraction? Are low-flow regions on the verge of becoming ischemic under stress? If the myocardium is stressed and lactate production occurs, is the lactate mainly from low-flow regions whose metabolic demands have now exceeded the supply of substrate and oxygen? Do low-flow regions recruit more under stress than high-flow regions? The basic question relating to those just posed is one on which many investigators have sought definite information, namely, What is the relationship between metabolism and flow regionally in the heart? Since the organ is essentially monofunctional, and the tissue is reasonably uniform throughout the left ventricular myocardium, this in turn raises the question of why metabolism might be different in one region than another. But before attempting to answer these methodologic and physiological questions, we had to face a relatively simple methodologic question: What is the appropriate estimate of heterogeneity?

Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

To investigate the dynamic control of cardiac ATP synthesis, we simultaneously determined the time course of mitochondrial oxygen consumption with the time course of changes in high-energy phosphates following steps in cardiac energy demand. Isolated isovolumically contracting rabbit hearts were perfused with Tyrodes solution at 28 degrees C (n = 7) or at 37 degrees C (n = 7). Coronary arterial and venous oxygen tensions were monitored with fast-responding oxygen electrodes. A cyclic pacing protocol in which we applied 64 step changes between two different heart rates was used. This enabled nuclear magnetic resonance measurement of the phosphate metabolites with a time resolution of approximately 2 seconds. Oxygen consumption changed after heart-rate steps with time constants of 14 +/- 1 (mean +/- SEM) seconds at 28 degrees C and 11 +/- 1 seconds at 37 degrees C, which are already corrected for diffusion and vascular transport delays. Doubling of the heart rate resulted in a significant decrease in phosphocreatine (PCr) content (11% at 28 degrees C, 8% at 37 degrees C), which was matched by an increase in inorganic phosphate (P(i)) content, although oxygen supply was shown to be nonlimiting. The time constants for the change of both P(i) and PCr content, approximately 5 seconds at 28 degrees C and 2.5 seconds at 37 degrees C, are significantly smaller than the respective time constants for oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of temperature on the response time of mitochondrial oxygen consumption in isolated rabbit heart.

1. In this study we determined the temperature dependence of the mean response time of cardiac mitochondrial oxygen consumption following steps in metabolic demand. Metabolic demand was altered by stepwise changes in heart rate or in left ventricular volume at 20 and 28 degrees C. 2. Ten isolated rabbit hearts were perfused with Tyrode solution at constant oxygen tension and constant arterial flow. A balloon was inserted in the left ventricle and developed pressure was measured. Coronary venous oxygen tension was measured continuously with a Clark‐type oxygen electrode. 3. The mean response time of mitochondrial oxygen consumption is defined as the first statistical moment of the impulse response function. This mean response time of mitochondrial oxygen consumption, following the change in metabolic demand, is calculated from the measured mean response time for the change in coronary venous oxygen tension by subtracting the transport time resulting from diffusion and convective transport in the blood vessels. The transport time is obtained from a model for oxygen transport developed previously. Experimental data, necessary for the model calculation, were obtained from measurement of the coronary venous oxygen tension transients following stepwise changes either in arterial oxygen tension or perfusion flow. 4. The calculated mean response times of mitochondrial oxygen consumption were 26.9 +/‐ 3.0 s (mean +/‐ S.E.M.) at 20 degrees C and 14.9 +/‐ 1.0 s at 28 degrees C. The mean response times of mitochondrial oxygen consumption did not differ significantly for steps in heart rate and in left ventricular volume and between upward and downward steps. 5. We suggest that intracellular calcium concentration is not the sole regulator of mitochondrial oxygen consumption in the isolated rabbit heart, since steps in heart rate and in left ventricular volume showed the same time course of oxygen uptake. 6. The mean response time of mitochondrial oxygen consumption obtained in the isolated rabbit heart at 20 degrees C did not differ significantly from the mean response time of mitochondrial oxygen consumption of isolated rabbit papillary muscle. After combining our data with previously published data on empty beating hearts at 37 degrees C, a Q10, which is the factor by which the mean response time of mitochondrial oxygen consumption increases per 10 degrees C decrease in temperature, of 2.1 was calculated.

Oxygen uptake in saline-perfused rabbit heart is decreased to a similar extent during reductions in flow and in arterial oxygen concentration

In experiments reported in the literature, oxygen uptake in saline-perfused heart decreased after small reductions in arterial O2 concentration (CaO2) at constant perfusion flow. This may have resulted from the decrease in O2 supply, but may also have been due to decreased O2 demand caused by reduced perfusion pressure following hypoxic vasodilation (garden hose effect). We tested both possibilities in 8 isolated rabbit hearts, perfused with Tyrode solution at 37°C, perfusion pressure 94±4 mm Hg (mean ±SD). Vasodilation with 10 μM adenosine in the perfusate prevented changes in perfusion pressure during hypoxia. Oxygen uptake decreased significantly by 5.8±2.1% for a 10% decrease inCaO2 at constant flow, and by 4.4±1.8% per 10% decrease in flow at constantCaO2. In both cases a 10% reduction in oxygen supply was applied and the decrease in oxygen uptake was not significantly different. The decrease in perfusion pressure during flow reduction did therefore not cause a detectable decrease in oxygen consumption via the garden hose effect in addition to the decrease caused by reduced oxygen supply. The data show that oxygen uptake in saline-perfused rabbit heart, at 37°C, is limited by O2 supply.

Acidosis slows the response of oxidative phosphorylation to metabolic demand in isolated rabbit heart

The purpose of this study was to investigate the effect of acidosis on the mean response time of mitochondrial oxygen consumption to steps in heart rate and in left ventricular balloon volume. The mean response time may be viewed as the average delay between a change in adenosine triphosphate (ATP) hydrolysis and oxygen consumption. The mean response time is calculated by subtracting the transport time, required for diffusion of oxygen and for convective transport through the coronary vessels, from the response time measured in the coronary venous effluent. Eight isolated rabbit hearts were perfused according to Langendorff using Tyrode solution at 28°C. Arterial perfusate pH was lowered from 7.30±0.03 (mean±SD) to 6.59±0.02 by increasing the CO2 tension. At pH 7.3 the mean response time was 12.6±1.6 s, independent of the time after isolation of the heart. During acidosis, applied 40–75 min after isolation of the heart, the mean response time was 21.4±0.7 s and increased to 32.6±4.3 s during acidosis, 85–120 min after isolation. Thus the retardation of the metabolic response by acidosis might depend on the condition of the heart. A decrease of mitochondrial ATP synthetic capacity during acidosis may contribute to the retardation of the metabolic response. Since determination of the mean response time at 37°C is not yet feasible, the experiments were done at 28°C. Extrapolation of our findings to 37°C appears premature.

Response of vertebral and carotid blood flow to isocapnic changes in end-tidal oxygen tension

The response of the vertebral and carotid blood flow to isocapnic hypoxia was measured in 9 cats anaesthetized with chloralose-urethane using perivascular electromagnetic flow probes. The carotid flow was already significantly increased when going from hyperoxia (PETO2 55 kPa) to normoxia. For the vertebral blood flow a significant increase compared to hyperoxia was observed at a moderate level of hypoxia (PETO2 9 kPa). The time course of the response of the blood flow to isocapnic step-like changes in PETO2 was fitted with a first order model. The mean time constant (+/- SD) for steps into hypoxia for the carotid flow was 35 +/- 38 sec(8 cats) and for the vertebral flow, 44 +/- 37 sec (5 cats). The mean time constant (+/- SD) for steps out of hypoxia was significantly smaller and found to be 23 +/- 22 sec (8 cats) and 19 +/- 18 sec (4 cats), respectively. We argue that a major part of the changes in vertebral and carotid blood flow to steps into hypoxia goes to brain tissue.

Diffusional shunting of oxygen in saline-perfused isolated rabbit heart is negligible.

Diffusional shunting of oxygen in the saline-perfused heart was studied by comparing the time course of the coronary venous concentrations of oxygen and an intravascular indicator following a simultaneous step-like change in their arterial concentrations. To this end 7 rabbit hearts were perfused according to Langendorff with Tyrode solution at a perfusion flow rate of 3.8±1.4 ml·min−1·g−1 (wet weight) at 37°C. In the reference situation arterial (PaO2) and venous oxygen tensions (PvO2) were about 610 and 290 mmHg, respectively. Step changes inPaO2 were made to a 60 mmHg lower level and back. Simultaneously the arterial concentration of albumin-bound indocyanine green, an intravascular indicator, was changed. No deflection inPvO2 was detected before the venous dye concentration changed. The venous dye concentration crossed 5% of its step amplitude 4 s after the arterial change, on average 2.3 s beforePvO2 crossed its 5% level. We conclude that shunt diffusion of oxygen from arterioles to venules and from arterial to venous ends of the capillary bed is negligible in saline-perfused hearts and thus cannot explain the high value ofPvO2 in these preparations.