MYOCARDIAL BLOOD FLOW AND OXYGEN CONSUMPTION DURING EXERCISE Charles R. Jorgensen, Frederick L. Gobel. Henry L. Taylor, and Yang Wang Department of Medicine and Laboratory of Physiological Hygiene University of Minnesota Medical School Minneapolis. Minnesotn 55455

Our concepts of what variables determine myocardial oxygen consumption ( M V ( , * )have evolved considerably over the last six to seven decades. Perhaps the earliest significant investigation of this problem was published in 1912 showing that oxygen use in an isovolumetrically contracting preparation was proportional to the product of pulse rate and left ventricular pulse pressure.’ For many years stroke work, the product of stroke volume and arterial pressure, was considered the primary factor, although it was recognized early that pressure work is more expensive than volume work and that pressure changes reflect changes in ventricular wall tension only if ventricular volume is not altered.’ Very comprehensive approaches have thought in terms of contractile element an entity based on the three component model of muscle and requiring several difficult measurements and some assumptions in its calculation. Our current understanding is relatively complete and is the result of the work of many investigators, primarily with in vitro preparations. A number of factors have been identified as determinants of myocardial oxygen consumption (TABLE l ) , but the major factors are: ( a ) the heart rate; ( b ) internal work, the stress or tension in the wall of the ventricle; ( c ) the contractile state of the heart; and ( d ) external work. The heart rate is listed first because it provides the summing factor for most of the other variables listed, which are determined on a per beat basis.“ Furthermore, in experiments comparing severe exercise and pacing to the same heart rate, it was suggested that the tachycardia alone was responsible for about one-third the increment in coronary blood flow that normally occurs during strenuous exercise.!’ The second factor, internal or pressure-generation work, accounts for about 50% of the oxygen consumption of the heart doing external work at a high level.’ The expression given for the wall stress is the familiar law of Laplace and indicates that the stress is a function of intraventricular pressure, intraventricular radius (volume), and ventricular wall thickness. Although this equation is for a sphere and the left ventricle is not spherical, it should be noted that expressions for more appropriate shapes (the prolate spheroid or the ellipsoid of revolution) have exactly the same form with the radius replaced by the semiminor axis and the one-half replaced by a dimensionless multiplier, which is a function of the semimajor and semiminor axes.l” The term “tension” has been used interchangeably with the term “stress” in the literature on cardiac rnechanics,l(’ but the two terms do have different physical meanings and there would appear to be merit in distinguishing between them in physiology also. 213

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Stress is the force per unit cross-sectional area of a materia1,'O and thus has units of dyneslcm'. Tension is a force that produces an extension lo and thus has units of dynes, although for hollow structures it has been defined as the force per unit length of circumference l1 and thus has units of dynes/cm and is equal to wall stress times wall thickness. A third equation has been used to calculate total force in dynes across the cross-sectional area of the heart muscle at the equatorll or against the entire surface area of the inner wall of the veqtricle.'* The distinction between these variables is pertinent in discussing MVo, in that the oxygen consumption when measured per 100 g left ventricular myocardium is related to the stress.13 Of interest in this regard are hypertrophied and dilated hearts. It has been suggested that a rise in stroke energy expenditure is causally related to myocardial hypertrophy.'* With hypertrophy, wall thickness is increased so that the wall stress,". l 5 and likewise the energy expenditure per unit mass of contractile tissue per beat,", lo. l i are TABLE1 DETERMINANTS OF OXYGEN CONSUMPTION OF THE HEART (9-64 ml per 100 g left ventricle per minute) Major Determinants 1. Heart rate 2. Internal work,intramyocardial stress or tension u=

PR/21t

T= P R / 2 TF= rPRa 3 . Contractile state 4. External work, load

x shortening

SW=PxSV

Others 5. Basal cardiac metabolism (nonbeating, nondepolarized) 6. Depolarization 7. Activation and relaxation 8. ? Maintenance of the active state

restored to or toward normal. I n contrast to wall stress, wall tension and total force would be increased in pressure-overloaded or dilated hearts, and it is not clear which of the latter two expressions would best relate to total left ventricular blood flow. Although we use the term "contractility" extensively in cardiac physiology, it remains a difficult concept to define and a hard variable to measure.'" Nevertheless, there has been a considerable amount of work indicating that changes in inotropic state are associated with substantial changes in MV,,,, and with what measurement techniques are available it has been suggested that the contractile state may account for up to 35% of MVo, along with such other variables as basal cardiac metabolism.7 In contrast to the thinking in the early. years of this century, external work is not the dominant factor determining M V o , but might account for only about 15% .?

Basal cardiac metabolism has been listed as a minor determinant even

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though it is recognized that measurements of the oxygen consum@ion of the arrested heart are as high as 20%-25% of measurements of the MV,,z in intact subjects at rest.'" However, presumably this "basal" metabolism remains constant with increased cardiac activity while the other variables mentioned will increase markedly.'" At this point it is worth remembering several features of cardiac physiology. The heart is an aerobic organ with little capacity to function anaerobically or to incur an oxygen debt. Furthermore, the oxygen saturation of coronary venous blood is very low as the heart is extracting from the blood most of the oxygen available. Therefore any increase in the heart's demands for oxygen must be met primarily by increasing myocardial blood flow ( M B F ) , so that among the various possible mechanisms for the regulation of blood flow in different regional circulations, it would appear that for the coronary circulation the metabolic theory is dominant.'!' Thus, measurements of myocardial blood flow closely parallel measurements of myocardial oxygen consumption although the normal human heart does have some capacity to increase the latter by increasing oxygen extraction by as much as 50%.20-22This is more of a factor in species such as the dog where there is a greater increase in hematocrit with A discussion of myocardial blood flow and oxygen consumption during exercise then comes down to a consideration of what changes occur in the primary determinants of myocardial oxygen consumption during exercise. This varies somewhat with such factors as age, type of exercise being performed (dynamic or static), the muscle groups involved, the body position, the state of physical training, and the presence or absence of disease. For purposes of simplicity we will consider primarily upright, dynamic, leg exercise in healthy, young individuals and will emphasize maximal performances of well-trained persons. Data from animals will also be reviewed where pertinent to certain issues. The heart rate might be expected to increase by 21/24 times resting values at maximal exercise.2n*2.1 This immediately suggests that marked increases in M B F will occur. To estimate the changes in left ventricular wall stress we have to consider the changes in systemic arterial pressure and ventricular volume. Acute changes in wall thickness would have to be small and inversely proportional to changes in ventricular volume since total left ventricular mass would not change acutely. Unfortunately most of the available data on arterial pressure during exercise was measured in the brachial or femoral arteries and hence over-estimates the pressure load on the heart as measured in the aorta because of the well-known phenomenon of peripheral amplification of the systolic blood pressure.'.' A recent study in our laboratory showed a linear relationship between aortic and brachial artery pressure with the aortic pressure being equal to 37 mmHg plus two-thirds of brachial artery pressure ( r = 0.83) .z5 In general the greatest increase in aortic systolic pressure from rest to maximal exercise was about 50%. It should be noted that these pressures were measured in the usual way with a catheter having both end and side holes being directed against the flow axis and therefore stagnation or impact pressure was being measured. Measurements made with the catheter tip pointing downstream so that static or distending pressure is being measured reveal that the aortic systolic pressure rises only slightly with increasing levels of exertion.20 The changes that occur in left ventricular volume with exercise have been

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debated for many years but a fairly clear picture is available at present. Direct measurements of left ventricular diameter or volume 2i-30 in animals indicate that the increase in stroke volume that occurs with mild work is accomplished by ejecting to a lower end systolic volume with end diastolic volume remaining the same. With maximal exercise there is in addition an increase in end diastolic volume, which might be estimated to be 15% as the heart utilizes the Frank-Starling mechanism to increase stroke volume. Studies in man in the upright position are limited to determinations of overall transverse diameter or volume of the heart determined from chest roentgenograms. These indicate that with the onset of upright exercise the overall heart volume initially increases about 10% then decreases somewhat towards resting size with increasing levels of submaximal exerci~e,~'and the transverse diameter decreases slightly from rest to mild exercise.32 Thus, what data is available for humans is compatible with the animal data. Since stroke volume is increasing by as much as 150% 30. 33 to 200% 34, 35 while the systolic ejection period is decreasing by 50%,20 the rate of ejection increases markedly during exercise. At maximal exertion such measures of contractility (dPldt) l P and isolength velocity have increased to 250% and 220% of control, r e s p e ~ t i v e l y . ~ ~ The changes in external cardiac work during exercise are implicit in the changes in arterial pressure and stroke volume mentioned above. Thus, with the exception of left ventricular end diastolic volume, all the major determinants of myocardial oxygen consumption change markedly with graded exercise, some of the variables linearly and some nonlinearly. Remembering the tight coupling between myocardial metabolic demand and myocardial blood flow we find it obvious that striking increases in coronary flow must occur during exercise. This sort of survey provides one with a qualitative answer, but to know the actual magnitude of the response and its relation to the degree of exercise requires actual measurement. Studies done during graded exercise in animals reveal increases in coronary blood flow of between 3 and 6 times resting values at heavy 23, 36-40 I n recent years there has been increasing interest in the transmural distribution of myocardial blood flow, and it has been shown that at rest endocardial flow exceeds epicardial flow by a ratio of between 1.1 and 1.3 to 1. With graded exercise there is a progressive decrease in this ratio so that at maximal exertion endocardial and epicardial flow are 40 Most of the data in the literature on myocardial flow in man is for mjld levels of exercise in the supine position. Many of the determinants of MVo, are difficult or impractical to measure in exercising man. Therefore several years ago we set out to determine if simpler measurements could give us some idea of energy demands of the heart over a wide range of exercise intensity. Data were obtained at two or three levels of exertion in ten normal young male volunteers. MBF was measured by the nitrous oxide saturation method, which yields flow in units of ml per 100 g left ventricle per minute in lieu of obtaining the absolute flow for the whole heart. Heart rate was obtained from the electrocardiogram and phasic blood pressure was measured with a catheter in the ascending aorta. Various hemodynamic variables were correlated with myocardial blood flow and oxygen consumption by regression techniques. It was found that the product of heart rate ( H R ) and systolic blood pressure (BP) considered as a single variable correlated best with myocardial oxygen consumption, the correlation coefficient being quite high at 0.90.20 (FIGURE1).

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This quantity is similar to what was termed the index of cardiac effort*l but may more simply be called the rate-pressure product (RPP) . When one includes in the product the systolic ejection period to obtain the tension-time index (=I) [better termed pressure-time per minute (PTM)] o r the triple product, the correlation actually becomes poorer, although the difference is not statistically significant. Similar measurements were carried out in a separate group of subjects after giving the beta-adrenergic blocking agent pro-

CAF

-

MVO7

5or

.

r.07 1KJ

150

190

230

270

r = .90 O I 110

I

150

I

I I 190

I

230

I

I

270

H R x PEAK SY S.Ao x lob2

FIGURE I. Relarionship of coronary blood flow (CBF) (left) or myocardial oxygen consumption ( M V o , ) (right) and the rate-pressure prduct (HR x PEAK SYS. AO X 10.'). The regression line is the heavy straight line, and the lighter curved lines indicate the 95% confidence zones for the slope of the regression line; r=correlation coefficient. pranolol in doses that decreased myocardial contractility and significantly lengthened the ejection period. The correlation coefficients between myocardial flow or oxygen consumption and the T T I became much worse, in contrast to the persistently good correlations with the RPP.*l We feel that the deficiencies of any index including the systolic ejection period have been clearly demonstrated. In contrast, the heart rate alone is almost as good an index of MVO2as the RPP (r = 0.88),20suggesting at first that including the blood pressure is un-

I

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necessary. This is deceptive, however, as it occurs because for this simple dynamic exercise the heart rate and blood pressure are strongly correlated ( r = 0.73). We have recently reanalyz,ed the data by performing a threevariable rather than two-variable linear regression, considering the heart rate and blood pressure as separate variables rather than combined into a product. This yields the regression equation MGoz = 0.24 HR

+ 0.16 BT - 29.9, r = 0.89.

Since the ranges of the two variables were similar (HR 99-173, mean 134 beats/min, BP 1 1 1-160 mmHg, mean 133 mmHg), the fact that the coefficients were sizable on both the heart rate and blood-pressure terms indicates both variables were important determinants of the MV,,. When one considers interventions where BP does not rise pari passu with HR, the necessity of including BP in the index becomes even more evident. In a third group of subjects studied in our laboratory, myocardial oxygen consumption was measured during static work alone or static plus dynamic exercise. The isometric exercise was chosen since it induces a more marked change in .blood pressure than dynamic exercise. Again the RPP correlated best with MV,, and the TTI was a much poorer index.22 Others have compared the responses to supine leg exercise and atrial pacing at rest supine. The slope of the regression of MV,, on HR was much lower during pacing than exercise, but the relationship between MV,, and the RPP fell along the same regression line as during exercise.42 Myocardial oxygen consumption on a per beat basis increases with exercise and decreases with pacing,?O hence the importancc of including some variable influencing MVo,/beat in an index. We conclude that the rate-pressure product is a good index of myocardial metabolic needs, and that even though ventricular v01ume,~3contractility, and external cardiac work do determine the absolute value of myocardial oxygen consumption, actually measuring them appears to be of lesser importance in studying relative values during exercise. The usefulness of this index for clinical purposes has been pointed 45 Although our work has all been done using centrally measured blood pressure, there is a direct relationship between aortic and brachial artery pressure,25 SO use of a peripheral pressure measurement will still yield a valid RPP but with a slightly different slope of the regression line with MV0,.22~.le The measurements done before and after propranolol administration raise one further point. After giving propranolol the repeat exercise load was altered to achieve the same heart rate, 129 beatdminute, as before propranolol and nearly twice the external work load was required, 112 versus 63 watts. Nevertheless, the systemic blood pressure was the same so that the RPP was the same, 150 before propranolol and 154 after. Correspondingly the myocardial oxygen consumption was the same, 20.8 versus 22.1 ml per 100 g left ventricle per minute, but this was achieved by a significantly lower myocardial blood flow and a significantly higher coronary arteriovenous difference.21 These data emphasize that the stress on the heart is not necessarily proportional to the degree of exertion and that there is a separation of the metabolic load for the body as a whole induced by a given intervention from the concomitant metabolic demands of the heart (FIGURE 2). Since physical training produces a significantly lower heart rate at any given level of submaximal exercise,24 it is apparent that the oxygen demands of the heart would likewise be lower.

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We have left then to consider the magnitude of myocardial blood flow at maximal exertion in the normal person and, in particular, in the championship level endurance athlete. At rest at a heart rate of 75 beats per minute and an aortic systolic blood pressure of 120 mmHg, MBF is 85 ml per 100 g left ventricle per minute.2n For a heart rate of 190 beats/minute and aortic systolic blood pressure of 170 mmHg at maximal exercise for both untrained subjects and athletes,", 2 8 * 33. li the MBF can be calculated from the regression equation to be 345 ml per 100 g left ventricle per minute, an increase of four times. However, the endurance athlete has the capacity to generate a much higher stroke volume, values up to 200 ml/beat being reported,l' achieved by a significantly increased heart volume 2'. ,*7-19 and an increase in contractility brought

Total Body Metabolic Load 0 02. Iiters/min

FIGURE2. Illustration of the variable relationship between total body metabolic load (vo2)and the cardiac metabolic load, expressed as either myocardial oxygen consumption ( M V o , ) or its hemodynamic correlate, the rate-pressure product. The dashed lines represent the upper limits of myocardial oxygen supply that might be seen in patients with varying severities of coronary artery disease. about by changes in the intrinsic physiology and biochemistry of cardiac muscle.5n With the increase in end-diastolic volume there will be hypertrophy to keep wall stress constant,l?. 1 s and even though only modest changes in wall thickness are demonstrable in the athlete,lR.l o left ventricular mass may be 50% greater than n0rma1.4~ Therefore our regression equation will underestimate the level of MBF at maximal exertion in the endurance athlete, even though there is some evidence indicating hearts of trained subjects are more efficient in converting chemical energy to external and it seems reasonable to suggest that an athlete working near or at maximal will have a MBF per unit mass 4-5 times the normal resting value and an even greater increase in total left ventricular flow. This corresponds to the magnitude of increase documented in animals alluded to earlier. This is within the capability of the

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Annals New York Academy of Sciences

human coronary circulation as it has been demonstrated in man that the MBF can go from 80 ml per 100 g left ventricle per minute at rest to 400 ml per 100 g left ventricle per minute during pharmacologically induced maximal coronary vasodilatation with dipyridamole.51 Coronary flows of this magnitude are probably reached and sustained during competition in distance running and other racing activities. The heart rate increases rapidly during the initial stages of a race and reaches approximately 180 beats per minute within half a minute.52 Estimates53 and actual measurements 5 4 of cardiorespiratory responses during competitive marathon running show levels of total body oxygen consumption between 68% and 100% of maximal at various stages of the race with heart rate, stroke volume, and cardiac output being maintained at greater than 90% maximal. This would imply that myocardial blood flow and oxygen consumption are also near maxima1 throughout the race. The question might be suggested: Is MBF a limiting factor to physical performance in the absence of disease? It appears to be established that the limitation to maximal total body oxygen consumption is not pulmonary or the metabolic capacity of the muscles, but cardiac-the maximal cardiac output and oxygen extraction, or the capacity to develop pressure against a particular total peripheral Subjects exercised to maximal capacity while breathing hypoxic gas mixtures develop the same heart rates and blood pressure suggesting coronary flow is not limiting since it must actually be increased given the decreased oxygen content of the blood.5fi Similarly during exhaustive exercise the heart rate, aortic pressure, and cardiac output are continuing to rise while there is shift of blood flow from the endocardia1 to the epicardial layers of the myocardium suggesting this redistribution is not a limiting factor:'" Since the capillary density of the hearts of trained animals increases, one would not expect limitations in flow at the microscopic level to be a limiting factor to the athlete's maximal ~apacity.~7 It appears the limitation must lie in the mechanics or pumping ability of the 5s as well as the maximal attainable heart rate. 5iv

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Myocardial blood flow and oxygen consumption during exercise.

MYOCARDIAL BLOOD FLOW AND OXYGEN CONSUMPTION DURING EXERCISE Charles R. Jorgensen, Frederick L. Gobel. Henry L. Taylor, and Yang Wang Department of Me...
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