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Abnormal coronary hemodynamics and myocardial energetics in patients with chronic heart failure caused by ischemic heart disease and dilated cardiomyopathy
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Abnormal coronary hemodynamics and myocardial energetics in patients with chronic heart failure caused by ischemic heart disease and dilated cardiomyopathy Coronary sinus blood flow, transmyocardial oxygen extraction, myocardial oxygen conaumption, and transmyocardial lactate extraction were determined, along with systemic hemodynamics, in 34 patients with chronic stable angina without heart failure (group 1), in 66 patients with heart failure associated with coronary artery disease (group 2), and in 28 patients with heart failure caused by dilated cardiomyopathy without coronary artery disease (group 3). Compared with group 1 patients, in patients with heart failure in groups 2 and 3, resting coronary sinus blood flow was 30% and 24% higher, respectively (p < 0.05), myocardial oxygen consumption was 25% higher (p < 0.01), and coronary sinus oxygen content was 33% lower (p < 0.01). The rate-pressure product was not different between the three groups. In eight patients with heart failure (five in group 2 and three in group 3), myocardial lactate production was observed without angina. Thus in patients with chronic heart failure resulting from either chronic coronary artery disease or dilated cardiomyopathy, resting coronary blood flow and myocardial oxygen consumption tend to increase probably because of an increase in myocardial oxygen requirements. Silent myocardial iachemla may also occur in both the prelence and absence of coronary artery disease in patients with chronic heart failure. The abnormal coronary hemodynamica and myocardial metabolic function may play a role in causing progreasive deterioration in cardiac function in dilated cardiomyopathy. (AN HSAaT J 1988;115:809.)
T e r e s a De Marco, M.D., K a n u Chatterjee, M.B., F.R.C.P., J e a n - L u c i e n Rouleau, M.D., a n d William W. P a r m l e y , M.D.
A reduction in contractile and p u m p function, along with an increase in ventricular end systolic and end diastolic volumes, is the consistent functional derangement in dilated cardiomyopathy and chronic heart failure. Decreased systemic flow, along with elevated systemic and pulmonary venous pressures and enhanced peripheral vascular tone, are also frequent hemodynamic abnormalities. I Although resting cardiac output m a y be less than normal in m a n y of these patients, the distribution of cardiac output, particularly to the vital organs, is not uniform. In general, changes in organ flow are influenced by the metabolic demand. In patients with dilated cardiomyopathy and chronic heart failure
From the Cardiovascular Division, Department of Medicine, and the Cardiovascular Research Institute,University of California. Supported in part by grants from the Don and Susan Schleicher Fund, the George and Camilla Smith Fund, and the Benny Binion Fund. Received for publication Oct. 27, 1987; accepted Dec. 1, 1987. Reprint requests: Kanu Chatterjee, M.B., Cardiovascular Research Institute, University of California,Box 0124, R o o m 1186M, San Francisco, C A 94143.
San Francisco, Calif.
caused by coronary artery disease, myocardial functional and hemodynamic derangements m a y produce diverse effects on myocardial oxygen requirements and therefore on coronary blood flow.2 This study compared resting systemic and coronary hemodynamics and myocardial energetics of patients with chronic heart failure caused by dilated cardiomyopathy and coronary artery disease with those of patients without heart failure and functional characteristics of dilated cardiomyopathy. METHODS Patient population. Thirty-four patients with chronic stable angina but without heart failure or dilated hearts and 94 patients with symptoms and signs of severe, chronic heart failure with cardiomegaly formed the patient population. Patients with chronic stable angina but without heart failure served as our control group (group 1). The control group consisted of 26 men and 8
women with a mean age of 62 years (range 48 to 81 years), who were in either New York Heart Association functional class II or III for angina pectoris. These patients did not have cardiomegaly or evidence of pulmonary venous hypertension on a chest x-ray film. 809
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Table I. Systemic hemodynamies (mean _+ SD) Control (N=34) H R (bpm) MAP (ram Hg) RAP (ram Hg) PAP (ram Hg) PAD (ram Hg) P C W P (ram Hg) CI (L/min/m 2 SVI (ml/m 2) SWI (gm/m/m 2 SVR (dyne - sec • cm -s) PVR (dyne • sec • cm -5)
70 99 6 18 13 10 3.0 43 51 1440 120
Heart failure with coronary artery disease (N=66)
+ 12 _+ 13 -+ 3 _+ 5 _+ 4 _+ 4 _+ 0.6 _+ 10 --_ 14 + 450 _+ 60
85 89 12 40 29 26 2.2 27 24 1610 290
Heart failure caused by dilated cardiomyopathy (N=28)
+ 15 -+ 15 _+ 6 ± 9 _+ 7 + 7* + 0.4 + 8 _+ 11" _+ 510 _+ 160
85 81 11 36 26 24 2.3 27 22 1470 210
± 15 _+ 10 _+ 7 _+ 8 _+ 6 _+ 7t + 0.6 ± 8 + 9t + 540 ± 130
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 NS <0.01
cI = cardiac index; HR ffi heart rate; MAP = mean arterial pressure; PAD = pulmonary artery diastolic pressure; PAP ffimean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP ffi right atrial pressure; RPP = rate-pressure product; SVI = stroke volume index; SVR ffi systemic vascular resistance; SWI = stroke work index; p value represents a comparison of ischemic and nonischemic dilated cardiomyopathy vs control. *N = 62. tN = 25.
Table
II. C o r o n a r y h e m o d y n a m i c a n d m y o c a r d i a l m e t a b o l i c d a t a ( m e a n _+ SD)
Control (N=34) Mvo2 (ml O2/min) CSBF (ml/min) ART 02C (vol%) Cso2C (vol%) A-Cso2 (vol%) ART LAC (mg/dl) CS LAC (mg/dl) LAC E X T (%)
8.7 74.0 18.3 6.0 12.2 9.8 6.5 33.0
_+ 4.2* _+ 37.0 + 2.3* _+ 1.5" ± 1.8" ± 5.5 _+ 3.5 _+ 14.0
Heart failure with coronary artery disease (N=66) 11.9 103 16.3 4.0 12.2 9.2 6.4 30.0
+ 6.4t + 57.0 _+ 2.8 ± 1.3 _+ 2.2 -+ 4.2§ _+ 3.6§ _ 23§
Heart failure caused by dilated cardiomyopathy (N=28) 11.9 97.0 16.7 4.3 12.5 8.8 5.4 31.0
_+ 4.75 _+ 44.0 _+ 2.65 _+ 1.85 _+ 2.5 ± 5.0 _+ 2.8 _+ 44.0
<0.01 <0.05 <0.01 <0.01 NS NS NS NS
myocardial oxygen extraction; ART LAC = arterial lactate; ART O2C = arterial oxygen content; CSBF = coronary sinus blood flow; CS LAC = coronary sinus lactate; LAC EXT ffi lactate extraction; Mvo2 = myocardial oxygen consumption; p represents a comparison of ischemic and nonischemic dilated cardiomyopathy vs control. *N = 33. IN = 63. SN = 24. §N = 65. A-Cso 2 =
P a t i e n t s w i t h h e a r t f a i l u r e were s u b c l a s s i f i e d w i t h r e s p e c t t o etiology. O n e g r o u p c o n s i s t e d o f 66 p a t i e n t s w h o h a d c o r o n a r y a r t e r y d i s e a s e ( g r o u p 2). I n t h i s g r o u p , t h e r e were 52 m e n a n d 14 w o m e n , w i t h a m e a n age o f 53 y e a r s ( r a n g e 42 t o 80 years). T h i r t y - f o u r p a t i e n t s were in N e w Y o r k H e a r t A s s o c i a t i o n f u n c t i o n a l class I I I a n d 32 were i n class IV. T h e l e f t v e n t r i c u l a r e j e c t i o n f r a c t i o n o n twod i m e n s i o n a l e c h o c a r d i o g r a p h y or r a d i o n u c l i d e s c i n t i g r a p h y r a n g e d f r o m 10% t o 4 4 % . T h e o t h e r g r o u p of p a t i e n t s w i t h h e a r t f a i l u r e c o n s i s t e d o f 28 p a t i e n t s w i t h d i l a t e d cardiomyopathy who did not have coronary artery disease ( g r o u p 3). I n t h i s g r o u p , 22 were m e n a n d 6 were w o m e n , w i t h a m e a n age o f 57 y e a r s ( r a n g e 24 t o 77 years). T w e l v e p a t i e n t s were i n N e w Y o r k A s s o c i a t i o n class I I I a n d 16 were in class I V h e a r t failure. All p a t i e n t s i n g r o u p 3 had an ejection fraction <40%. The patients with chronic
h e a r t f a i l u r e w i t h or w i t h o u t a s s o c i a t e d c o r o n a r y a r t e r y d i s e a s e h a d c a r d i o m e g a l y a n d e v i d e n c e for p u l m o n a r y v e n o u s or a r t e r i a l h y p e r t e n s i o n o n a c h e s t r a d i o g r a p h . Study Protocol. P a t i e n t s were s t u d i e d in t h e c a r d i a c care u n i t . A p p r o v a l f r o m t h e i n s t i t u t i o n a l r e v i e w b o a r d was o b t a i n e d . E a c h p a t i e n t p r o v i d e d w r i t t e n , i n f o r m e d c o n s e n t . T h e p a t i e n t s were s t u d i e d in a r e s t i n g , n o n s e dated state. Calcium channel blockers and beta blockers were w i t h h e l d a t l e a s t 24 h o u r s a n d n i t r a t e s a t l e a s t 12 h o u r s b e f o r e s t u d y in p a t i e n t s w i t h c h r o n i c s t a b l e a n g i n a ( g r o u p 1). T h e p a t i e n t s w i t h h e a r t f a i l u r e ( g r o u p s 2 a n d 3) h a d v a s o d i l a t o r s d i s c o n t i n u e d a t l e a s t 24 h o u r s b e f o r e s t u d y . T h e s e p a t i e n t s were m a i n t a i n e d o n s t a b l e d o s e s of d i g o x i n a n d d i u r e t i c s a n d r e c e i v e d a m a i n t e n a n c e d o s e of 2 gin/day of sodium diet during the study. Right atrial, pulmonary artery, and pulmonary capillary
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Fig. 1. Coronary hemodym~mics and myocardial metabolic parameters. Rate-pressure product was not different between the three groups. Myocardial oxygen consumption and coronary sinus blood flow were higher, whereas coronary sinus oxygen content was lower in patients with heart failure (groups 2 and 3) compared with control subjects. Arterial oxygen content was lower in patients with heart failure caused by coronary artery disease compared with control subjects (group 1). Values are given as mean ± standard error of the mean.
wedge pressures were measured with a triple-lumen balloon flotation thermodilution catheter. Cardiac output was determined in triplicate by the thermodilution technique with the same catheter. Arterial pressure was recorded directly by cannulation of a radial artery. A double thermistor coronary sinus catheter (Webster Labs Inc, Baldwin Park, Calif.) was introduced percutaneously into the coronary sinus to measure coronary sinus blood flow by the constant infusion thermodilution technique and obtain coronary sinus venous samples, s,4 T o minimize coronary sinus reflux, the catheter was advanced under fluoroscopic guidance into the midcoronary sinus, and its position was ensured with a small bolus injection of contrast medium. Significant reflux was further excluded by monitoring changes in coronary sinus blood temperature during an injection of 10 ml of iced saline solution into the right atrium before and at the conclusion of the study. ~ T w o sets of resting systemic and coronary hemodynamic measurements were recorded, and arterial and coronary sinus blood samples were drawn.
Calculations. The derived systemic and coronary hemodynamic parameters were calculated as follows: ratepressure product (RPP, bpm, m m H g x 10 -s) = H R (bpm) x S B P (ram Hg), where H R = heart rate and S B P = systolic blood pressure; cardiac index (CI, L/rain/ m 2) = CO/body surface area, where C O = cardiac output; stroke work index (SWI, ml/m 2) = ( M S P - P C W P ) × SVI x 0.0136, where M S P = m e a n systolic arterialpressure and P C W P = pulmonary capillary wedge pressure; systemic vascular resistance (SVR, dyne • sec • c m -s) = ( M A P - R A P ) / C O × 80, where R A P = right atrial pressure; pulmonary vascular resistance (PVR, dyne-sec-cm -6) ffi( P A P - P C W P / C O ) × 80, where P A P = m e a n pulmonary artery pressure; coronary sinus blood flow (CSBF, ml/min) = [Tb - Ti/Tb - T m ] 1 × 1.08 × 46 ml/min, where T b = temperature of blood, Ti = temperature of injectate, and T m = temperature of mixture of blood and indicator; 1.08 is a constant accounting for specific heat and density of both blood and indicator, and 46 ml/min is the injection rate of the
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Group2 (a)
Group3
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Group 3 (b)
Fig. 2. Myocardial lactate data. a, Mean lactate extraction was not different among the three groups of patients. Values are given as mean + standard error of the mean. b, Each bar represents the lactate extraction of an individual patient. Five different patients in the group with heart failure caused by coronary artery disease (group 2) and three different patients in the group with dilated cardiomyopathy (group 3) exhibited net lactate production at rest.
indicator (5% dextrose and water) through the Harvard constant infusion pump. Oxygen saturations were measured with a Corning 175 automated blood and pH analyzer. Lactate concentrations were measured by enzymatic spectrofluorometric technique. 6 Normal lactate levels are 5 to 18 mg/dl. The derived metabolic variables were calculated as follows: oxygen content (col%) = oxygen saturation × hemoglobin × 1.34; myocardial oxygen consumption (Mvo~), ml/ rain) ffi (arterial - coronary sinus oxygen content) × coronary sinus blood flow x 10-3; myocardial lactate extraction (%) = arterial - coronary sinus/arterial lactate × 100. Statistical analysis. One-way analysis of variance techniques was used for data analysis. Posthoc tests were performed with Scheff~'s method for multiple contrast. A p value <0.05 was considered significant. RESULTS Systemic hemodynamics. Table I summarizes the systemic hemodynamic profiles of the three groups of patients. The resting hemodynamic profiles in patients with heart failure caused by ischemic heart disease (group 2) and dilated cardiomyopathy (group 3) were similar. However, as expected, cardiac index, volume, and stroke work indexes were lower, and systemic and pulmonary venous pressures were higher in group 2 and 3 patients than in group 1 patients without heart failure. This indicates severely compromised ventricular function in patients with heart failure. Patients with heart failure (groups 2 and 3) had a higher heart rate and lower systolic, arterial blood pressure compared with the control group without heart failure. Systemic vascular resistance was not significantly different among the three groups. Coronary hemodynamics and myocardial metabolism. The coronary hemodynamic and myocardial
metabolic values in the patients in the three groups are summarized in Table II and depicted graphically
in Figs. 1 and 2. Coronary sinus blood flow and myocardial oxygen consumption were higher, whereas the coronary sinus oxygen content was lower in both group 2 and 3 patients with heart failure compared with control subjects. The arterial oxygen content tended to be lower in patients with heart failure compared with the control group. However, the rate-pressure product and myocardial oxygen extraction were not different between the three groups of patients. The average myocardial lactate extraction was not different among the three groups. However, five (8%) individual patients with chronic heart failure caused by ischemic heart disease and three (11%) patients with dilated cardiomyopathy had net lactate production at rest in the absence of angina. The patients who had myocardial lactate production had higher left ventricular filling pressures compared with other patients with heart failure who did not produce lactate (mean pulmonary capillary wedge pressures 33 + 3 vs 24 + 7; p <.005). DISCUSSION
The results of the present investigation demonstrate that chronic severe heart failure caused by either ischemic heart disease or dilated cardiomyopathy may have abnormal coronary hemodynamics and myocardial metabolic function. Evaluation of systemic hemodynamics demonstrated marked elevation of p,]lmonary capillary wedge pressure and reduced stroke volume, stroke work, and cardiac indexes. Among patients with heart failure the systemic hemodynamics were similar in both the group with and the group without coronary artery disease. An augmented coronary blood flow in heart failure is likely to result from increased myocardial
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oxygen requirements rather than from a primary decrease in coronary vascular resistance. When coronary blood flow is in excess of myocardial metabolic demand, coronary sinus venous oxygen content tends to increase and myocardial oxygen extraction to decrease.2 In this study in patients with heart failure caused by dilated cardiomyopathy or ischemic heart disease, coronary sinus venous oxygen saturation was lower than in patients without heart failure. This strongly suggests that myocardial oxygen requirements are greater in these patients even at rest. Indeed, calculated myocardial oxygen consumption was significantly higher in group 2 and 3 patients (Fig. 1) with heart failure. However, the potential mechanisms for the increase in myocardial oxygen requirements and consumption in patients with dilated cardiomyopathy are not entirely clear. The rate-pressure product, a commonly used index of myocardial oxygen demand, was not higher in patients with dilated cardiomyopathy compared with control subjects. Contractility is another major determinant of myocardial oxygen demand. The overall contractile function however, is generally depressed in patients with dilated cardiomyopathy, which should decrease myocardial oxygen consumption.2 However, reflex increase in contractility caused by enhanced sympathetic activity can potentially increase myocardial oxygen requirements. Another important determinant for an increase in myocardial oxygen demand is an increase in left ventricular wall stress. In patients with dilated cardiomyopathy, end systolic and end diastolic volumes are considerably greater than in normal patients; although left ventricular mass may increase, wall thickness usually remains unchanged or only increases slightly. Thus despite lower systolic pressure, left ventricular wall stress may significantly increase in patients with dilated cardiomyopathy. Increased mass may also contribute to an increase in coronary sinus blood flow. Left ventricular volume, mass, or wall thickness were not quantitatively assessed in this study. Thus the differences in wall stress in patients with dilated cardiomyopathy and control subjects could not be precisely determined. However, patients with heart failure had obvious left ventricular enlargement and depressed left ventricular systolic function. Thus it is very likely that wall stress was greater in our patients with heart failure than that in control subjects, which might have contributed to an increase in coronary blood flow and myocardial oxygen consumption. Strauer 7 also observed that in many patients with dilated cardiomyopathy, myocardial oxygen con-
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sumption is higher. In this study, patients with high wall stress associated with low left ventricular massto-volume ratio had higher myocardial oxygen consumption and coronary blood flow per 100 g m compared with control subjects and patients with low wall stress associated with a high mass-tovolume ratio.7 In some studies, myocardial blood flow per 100 g m of left ventricular mass has been found to be less than normal in patients with dilated cardiomyopathy. 8-12In this study, we did not calculate left ventricular mass and myocardial flow per 100 g m of the left ventricle. However, because the left ventricular mass is usually increased in dilated cardiomyopathy, it is possible that such relatively decreased flow for the left ventricular mass was also present in our patients despite increased global coronary sinus blood flow. In this study in patients with dilated cardiomyopathy, coronary hemodynarnics and myocardial metabolic function were similar to those with chronic heart failure caused by coronary artery disease. It is not surprising since the resting coronary blood flow is usually not restricted even in the presence of severe obstructive lesions. With increasing metabolic demand, coronary blood flow increases as the distal coronary vascular resistance falls. A n increase in myocardial oxygen requirements are usually met by the concomitant increase in coronary blood flow. However, inhomogeneity of coronary blood flow and regional myocardial ischemia can occur in patients with coronary artery disease. Whether abnormalities of regional coronary hemodynamics were present in patients with heart failure caused by coronary artery disease could not be determined in this study. Despite increased myocardial oxygen consumption, myocardial lactate extraction remained in the normal range in most patients in the heart failure groups and was not different from the control group. However, in five patients (8%) with chronic heart failure caused by ischemic heart disease and in three patients (11%) with dilated cardiomyopathy, myocardial lactate production occurred. None of the patients with stable angina, but without heart failure had lactate production. It has been shown in m a n y studies of patients with coronary artery disease that myocardial lactate production is a specific although not sensitive indicator of myocardial ischemia. Myocardial lactate production has been correlated with other manifestations of myocardial ischemia, such as ischemic S T segment changes in the E C G and wall motion abnormalities. 13-21 Marked activation of the anaerobic glycolytic pathway can rarely be associated with myocardial lactate production in the absence of ischemia or hypoxia. In animal
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models, bicarbonate, insulin, and glucose infusions can cause lactate production, particularly when myocardial work is increased c o n c o m i t a n t l y . 22"24 However, such mechanisms were not present in these patients. Thus myocardial lactate production was, in all probability, caused by myocardial ischemia. The patients who exhibited lactate production did not complain of anginal pain, which suggests that myocardial ischemia was silent. The potential mechanisms for myocardial ischemia were not explored in this study. Because myocardial oxygen consumption was higher, it is possible that the increase in coronary blood flow was inadequate to meet the higher metabolic demand. Pulmonary capillarywedge pressure was markedly elevated and arterial pressure was relativelylower; thus the transmyocardial pressure gradient was lower in patients with heart failure,which has the potential to induce subendocardial ischemia.23"26Inadequate coronary vasodilatoryreserve and decreased diastolic fillingtime caused by tachycardia may also compromise myocardial perfusion. It is apparent that without further studies the mechanisms for myocardial ischemia will remain conjectural. Of interest is the finding that the patients who exhibited restingmyocardial lactateproduction had some hemodynamic evidence of worse ventricular function than the other patients with dilated cardiomyopathy who did not produce lactate.These eight patients had higher leftventricularfillingpressures (33 + 3 mm Hg compared with 24 _+ 6 mm Hg in patients with normal lactate metabolism (p < 0.OO5). It should be emphasized, however, that the finding of resting myocardial lactate production in our eight patients does not imply that these patients are continually producing lactate and hence are subject to constant myocardial ischemia. Myocardial ischemia with lactate production may be an intermittent phenomenon in these patients. In this study, only resting coronary hemodynamics were determined. Thus changes in coronary reserve and myocardial metabolic function during stress in patients with heart failure remain unknown. During exercise, however, myocardial oxygen consumption increases and deterioration of metabolic function is more likely to occur. Therefore it is expected that the incidence of myocardial ischemia will be higher during exercise compared with the observed incidence at rest in this study. The limitations of this study also need to be considered. It needs to be appreciated that the potential for significant "coronary sinus reflux" exists in all patients with elevated right atrial pres-
American Heart Journal
sure. 5 In these circumstances, estimated coronary sinus flow by the thermodilution technique is overestimated. To avoid coronary sinus reflux, the catheter was positioned in the midcoronary sinus. Significant reflux was further excluded by monitoring changes in coronary sinus blood temperature during the injection of cold saline solution into the right atrium. When the catheter is positioned in the mid-coronary sinus, the estimated coronary sinus flow is more representative of great cardiac vein flow and therefore underestimates the global coronary blood flow. Thus it is likely that the estimated coronary sinus flow and myocardial oxygen consumption were lower than expected in our patients. The patients in groups 1 and 2 in the study had obstructive coronary artery disease with nonuniform distribution and severity, and therefore it can be argued that the coronary blood flow might have been restricted to variable extents in these patients. However, resting coronary blood flow is not usually compromised even in the presence of severe coronary artery stenosis. Thus it is unlikely that the presence of coronary artery disease of different severity in these patients influences the results at any physiologic significance. In conclusion, the results of this study suggest that resting myocardial oxygen consumption is usually higher in patients with chronic heart failure caused by dilated cardiomyopathy or ischemic heart disease and that silent myocardial ischemia can occur even at rest in some of these patients. These abnormal myocardial energetics may potentially accelerate the downhill course in dilated cardiomyopathy. We thank Beverly Atherton, Deidre Curran, Maggie Liu, and Debra Lau for their technical assistance, Gunnard Modin for statistical assistance, the coronary care unit nurses, housestaff, and cardiology fellows who participated in the care of the study patients, and Kathleen Hecker and Cynthia Lotane for their editorial assistance.
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1. Parmley WW. Cardiac failure. In: Rosen MR, Hoffman BF, eds. Cardiac therapy. Boston: Martinus Nijhoff Publishers, 1983:21. 2. Braunwald E. Control of myocardial oxygen consumption. Physiologic and clinical considerations. Am J Cardiol 1971; 27:416. 3. Ganz W, Tanura K, Marals HS, Donoso R, Yoshido S, Swan HS. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181. 4. Pepine CJ, Mehta J, Webster Jr WW, Nedrols WW. In vivo validation of the thermodilution method to determine regional left ventricular blood flow in patients with coronary disease. Circulation 1978;58:795. 5. Mathey DG, Chatterjee K, Tyberg JV, Lekven J, Brundage B, Parmley WW. Coronary sinus reflux: a source of error in
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the measurement of thermodilution coronary sinus flow. Circulation 1978;57:778. Loomis ME. An enzymatic fluorometric method for the determination of lactic acid in serum. J Lab Clin Med 1961; 57:966. Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 1979;44:730. Blain JM, Schafer H, Siegal AL. Studies on myocardial metabolism. Am J Med 1962;20:820. Wendt VE, Stock TB, Hayden RO, Bruce TA, Gudbjarnason S, Bing RJ. The hemodynamics and cardiac metabolism in cardiomyopathies. Med Clin North Am 1962;46:1445. Henry PD, Eckberg D, Gault JH, Ross J. Depressed inotropic state and reduced myocardial oxygen consumption in the human heart. Am J Cardiol 1973;31:300. Weiss MB, Ellis K, Sciacca RR, Johnson LL, Schmidt DH, Cannot PJ. Myocardial blood flow in congestive and hypertrophic cardiomyopathy. Relationship to peak wall stress and mean velocity of circumferential fiber shortening. Circulation 1976;54:484. Pasternac A, Noble J, Streulens Y, Elie R, Henschke C, Bourassa MG. Pathophysiology of chest pain in patients with cardiomyopathies and normal coronary arteries. Circulation 1982;65:778. Shea TM, Watson RM, Piotrowski SF, Dermksian G, Case RB. Anaerobic myocardial metabolism. Am J Physiol 1962; 203:463. Case RB, Nasser MG, Crampton RS. Biochemical aspects of early myocardial ischemia. Am J Cardiol 1969;24:766. Cohen LS, Elliott WC, Klein MD, Gorlin R. Coronary heart disease: clinical, cinearteriographic and metabolic considerations. Am J Cardiol 1955;17:153.
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16. Neill WA. Myocadial hypoxia and anaerobic metabolism in coronary heart disease. Am J Cardiol 1968;22:507. 17. Parker JO, Chiang MA, West RO, Case RB. Sequential alterations in myocardial lactate metabolism, ST segments and left ventricular function during angina induced by atrial pacing. Circulation 1969;40:113. 18. Conti CR, Pitt B, Gundel WB, Friesinger GC, Ross RS. Myocardial blood flow in pacing-induced angina. Circulation 1970;42:815. 19. Opie LH, Owen P, Thomas M, Sanson R. Coronary sinus lactate measurements in assessment of myocardial ischemia. Am J Cardiol 1973;32:295. 20. Neill WA, Kremkau E. Criteria for detecting ischemic myocardial hypoxia from lactate and pyruvate dam during atrial pacing in humans. J Lab Clin Med 1974;83:428. 21. Markham Jr LV, Winniford MD, Firth BG, et al. Symptomatic electrocardiographic, metabolic, and hemodynamic alterations during pacing-induced myocardial ischemia. Am J Cardiol 1983;51:1589. 22. Huckabee WE. Relationship of pyruvate and lactate during anaerobic metabolism. V: coronary adequacy. Am J Physiol 1961;200:1169. 23. Kobayashi K, Nealy JR. Control of maximum rates of glycolysis in rat cardiac muscle. Circ Res 1979;44:166. 24. Sudgen PH, Smith DM. The effects of glucose uptake and lactate release in perfused working rat heart preparations. Biochem J 1982;206:473. 25. Hoffman JIE. Determinants and prediction of transmural myocardial perfusion. Circulation 1978;58:381. 26. Unverferth DV, Magorien RD, Lewis RP, Leier CV. The role of subendocardial ischemia in perpetrating myocardial failure in patients with nonischemic congestive cardiomyopathy. AM HZARTJ 1983;105:176.
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Abnormal coronary hemodynamics and myocardial energetics in patients with chronic heart failure caused by ischemic heart disease and dilated cardiomyopathy Coronary sinus blood flow, transmyocardial oxygen extraction, myocardial oxygen conaumption, and transmyocardial lactate extraction were determined, along with systemic hemodynamics, in 34 patients with chronic stable angina without heart failure (group 1), in 66 patients with heart failure associated with coronary artery disease (group 2), and in 28 patients with heart failure caused by dilated cardiomyopathy without coronary artery disease (group 3). Compared with group 1 patients, in patients with heart failure in groups 2 and 3, resting coronary sinus blood flow was 30% and 24% higher, respectively (p < 0.05), myocardial oxygen consumption was 25% higher (p < 0.01), and coronary sinus oxygen content was 33% lower (p < 0.01). The rate-pressure product was not different between the three groups. In eight patients with heart failure (five in group 2 and three in group 3), myocardial lactate production was observed without angina. Thus in patients with chronic heart failure resulting from either chronic coronary artery disease or dilated cardiomyopathy, resting coronary blood flow and myocardial oxygen consumption tend to increase probably because of an increase in myocardial oxygen requirements. Silent myocardial iachemla may also occur in both the prelence and absence of coronary artery disease in patients with chronic heart failure. The abnormal coronary hemodynamica and myocardial metabolic function may play a role in causing progreasive deterioration in cardiac function in dilated cardiomyopathy. (AN HSAaT J 1988;115:809.)
T e r e s a De Marco, M.D., K a n u Chatterjee, M.B., F.R.C.P., J e a n - L u c i e n Rouleau, M.D., a n d William W. P a r m l e y , M.D.
A reduction in contractile and p u m p function, along with an increase in ventricular end systolic and end diastolic volumes, is the consistent functional derangement in dilated cardiomyopathy and chronic heart failure. Decreased systemic flow, along with elevated systemic and pulmonary venous pressures and enhanced peripheral vascular tone, are also frequent hemodynamic abnormalities. I Although resting cardiac output m a y be less than normal in m a n y of these patients, the distribution of cardiac output, particularly to the vital organs, is not uniform. In general, changes in organ flow are influenced by the metabolic demand. In patients with dilated cardiomyopathy and chronic heart failure
From the Cardiovascular Division, Department of Medicine, and the Cardiovascular Research Institute,University of California. Supported in part by grants from the Don and Susan Schleicher Fund, the George and Camilla Smith Fund, and the Benny Binion Fund. Received for publication Oct. 27, 1987; accepted Dec. 1, 1987. Reprint requests: Kanu Chatterjee, M.B., Cardiovascular Research Institute, University of California,Box 0124, R o o m 1186M, San Francisco, C A 94143.
San Francisco, Calif.
caused by coronary artery disease, myocardial functional and hemodynamic derangements m a y produce diverse effects on myocardial oxygen requirements and therefore on coronary blood flow.2 This study compared resting systemic and coronary hemodynamics and myocardial energetics of patients with chronic heart failure caused by dilated cardiomyopathy and coronary artery disease with those of patients without heart failure and functional characteristics of dilated cardiomyopathy. METHODS Patient population. Thirty-four patients with chronic stable angina but without heart failure or dilated hearts and 94 patients with symptoms and signs of severe, chronic heart failure with cardiomegaly formed the patient population. Patients with chronic stable angina but without heart failure served as our control group (group 1). The control group consisted of 26 men and 8
women with a mean age of 62 years (range 48 to 81 years), who were in either New York Heart Association functional class II or III for angina pectoris. These patients did not have cardiomegaly or evidence of pulmonary venous hypertension on a chest x-ray film. 809
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Table I. Systemic hemodynamies (mean _+ SD) Control (N=34) H R (bpm) MAP (ram Hg) RAP (ram Hg) PAP (ram Hg) PAD (ram Hg) P C W P (ram Hg) CI (L/min/m 2 SVI (ml/m 2) SWI (gm/m/m 2 SVR (dyne - sec • cm -s) PVR (dyne • sec • cm -5)
70 99 6 18 13 10 3.0 43 51 1440 120
Heart failure with coronary artery disease (N=66)
+ 12 _+ 13 -+ 3 _+ 5 _+ 4 _+ 4 _+ 0.6 _+ 10 --_ 14 + 450 _+ 60
85 89 12 40 29 26 2.2 27 24 1610 290
Heart failure caused by dilated cardiomyopathy (N=28)
+ 15 -+ 15 _+ 6 ± 9 _+ 7 + 7* + 0.4 + 8 _+ 11" _+ 510 _+ 160
85 81 11 36 26 24 2.3 27 22 1470 210
± 15 _+ 10 _+ 7 _+ 8 _+ 6 _+ 7t + 0.6 ± 8 + 9t + 540 ± 130
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 NS <0.01
cI = cardiac index; HR ffi heart rate; MAP = mean arterial pressure; PAD = pulmonary artery diastolic pressure; PAP ffimean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP ffi right atrial pressure; RPP = rate-pressure product; SVI = stroke volume index; SVR ffi systemic vascular resistance; SWI = stroke work index; p value represents a comparison of ischemic and nonischemic dilated cardiomyopathy vs control. *N = 62. tN = 25.
Table
II. C o r o n a r y h e m o d y n a m i c a n d m y o c a r d i a l m e t a b o l i c d a t a ( m e a n _+ SD)
Control (N=34) Mvo2 (ml O2/min) CSBF (ml/min) ART 02C (vol%) Cso2C (vol%) A-Cso2 (vol%) ART LAC (mg/dl) CS LAC (mg/dl) LAC E X T (%)
8.7 74.0 18.3 6.0 12.2 9.8 6.5 33.0
_+ 4.2* _+ 37.0 + 2.3* _+ 1.5" ± 1.8" ± 5.5 _+ 3.5 _+ 14.0
Heart failure with coronary artery disease (N=66) 11.9 103 16.3 4.0 12.2 9.2 6.4 30.0
+ 6.4t + 57.0 _+ 2.8 ± 1.3 _+ 2.2 -+ 4.2§ _+ 3.6§ _ 23§
Heart failure caused by dilated cardiomyopathy (N=28) 11.9 97.0 16.7 4.3 12.5 8.8 5.4 31.0
_+ 4.75 _+ 44.0 _+ 2.65 _+ 1.85 _+ 2.5 ± 5.0 _+ 2.8 _+ 44.0
<0.01 <0.05 <0.01 <0.01 NS NS NS NS
myocardial oxygen extraction; ART LAC = arterial lactate; ART O2C = arterial oxygen content; CSBF = coronary sinus blood flow; CS LAC = coronary sinus lactate; LAC EXT ffi lactate extraction; Mvo2 = myocardial oxygen consumption; p represents a comparison of ischemic and nonischemic dilated cardiomyopathy vs control. *N = 33. IN = 63. SN = 24. §N = 65. A-Cso 2 =
P a t i e n t s w i t h h e a r t f a i l u r e were s u b c l a s s i f i e d w i t h r e s p e c t t o etiology. O n e g r o u p c o n s i s t e d o f 66 p a t i e n t s w h o h a d c o r o n a r y a r t e r y d i s e a s e ( g r o u p 2). I n t h i s g r o u p , t h e r e were 52 m e n a n d 14 w o m e n , w i t h a m e a n age o f 53 y e a r s ( r a n g e 42 t o 80 years). T h i r t y - f o u r p a t i e n t s were in N e w Y o r k H e a r t A s s o c i a t i o n f u n c t i o n a l class I I I a n d 32 were i n class IV. T h e l e f t v e n t r i c u l a r e j e c t i o n f r a c t i o n o n twod i m e n s i o n a l e c h o c a r d i o g r a p h y or r a d i o n u c l i d e s c i n t i g r a p h y r a n g e d f r o m 10% t o 4 4 % . T h e o t h e r g r o u p of p a t i e n t s w i t h h e a r t f a i l u r e c o n s i s t e d o f 28 p a t i e n t s w i t h d i l a t e d cardiomyopathy who did not have coronary artery disease ( g r o u p 3). I n t h i s g r o u p , 22 were m e n a n d 6 were w o m e n , w i t h a m e a n age o f 57 y e a r s ( r a n g e 24 t o 77 years). T w e l v e p a t i e n t s were i n N e w Y o r k A s s o c i a t i o n class I I I a n d 16 were in class I V h e a r t failure. All p a t i e n t s i n g r o u p 3 had an ejection fraction <40%. The patients with chronic
h e a r t f a i l u r e w i t h or w i t h o u t a s s o c i a t e d c o r o n a r y a r t e r y d i s e a s e h a d c a r d i o m e g a l y a n d e v i d e n c e for p u l m o n a r y v e n o u s or a r t e r i a l h y p e r t e n s i o n o n a c h e s t r a d i o g r a p h . Study Protocol. P a t i e n t s were s t u d i e d in t h e c a r d i a c care u n i t . A p p r o v a l f r o m t h e i n s t i t u t i o n a l r e v i e w b o a r d was o b t a i n e d . E a c h p a t i e n t p r o v i d e d w r i t t e n , i n f o r m e d c o n s e n t . T h e p a t i e n t s were s t u d i e d in a r e s t i n g , n o n s e dated state. Calcium channel blockers and beta blockers were w i t h h e l d a t l e a s t 24 h o u r s a n d n i t r a t e s a t l e a s t 12 h o u r s b e f o r e s t u d y in p a t i e n t s w i t h c h r o n i c s t a b l e a n g i n a ( g r o u p 1). T h e p a t i e n t s w i t h h e a r t f a i l u r e ( g r o u p s 2 a n d 3) h a d v a s o d i l a t o r s d i s c o n t i n u e d a t l e a s t 24 h o u r s b e f o r e s t u d y . T h e s e p a t i e n t s were m a i n t a i n e d o n s t a b l e d o s e s of d i g o x i n a n d d i u r e t i c s a n d r e c e i v e d a m a i n t e n a n c e d o s e of 2 gin/day of sodium diet during the study. Right atrial, pulmonary artery, and pulmonary capillary
Myocardial energetics in CHF
vo,.m 11s Number 4
811
J': 0
~=
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0
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~
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.
:
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:fill j :lain I -allil Group 1
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li Group 3
o
Group 1
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Group 3
Fig. 1. Coronary hemodym~mics and myocardial metabolic parameters. Rate-pressure product was not different between the three groups. Myocardial oxygen consumption and coronary sinus blood flow were higher, whereas coronary sinus oxygen content was lower in patients with heart failure (groups 2 and 3) compared with control subjects. Arterial oxygen content was lower in patients with heart failure caused by coronary artery disease compared with control subjects (group 1). Values are given as mean ± standard error of the mean.
wedge pressures were measured with a triple-lumen balloon flotation thermodilution catheter. Cardiac output was determined in triplicate by the thermodilution technique with the same catheter. Arterial pressure was recorded directly by cannulation of a radial artery. A double thermistor coronary sinus catheter (Webster Labs Inc, Baldwin Park, Calif.) was introduced percutaneously into the coronary sinus to measure coronary sinus blood flow by the constant infusion thermodilution technique and obtain coronary sinus venous samples, s,4 T o minimize coronary sinus reflux, the catheter was advanced under fluoroscopic guidance into the midcoronary sinus, and its position was ensured with a small bolus injection of contrast medium. Significant reflux was further excluded by monitoring changes in coronary sinus blood temperature during an injection of 10 ml of iced saline solution into the right atrium before and at the conclusion of the study. ~ T w o sets of resting systemic and coronary hemodynamic measurements were recorded, and arterial and coronary sinus blood samples were drawn.
Calculations. The derived systemic and coronary hemodynamic parameters were calculated as follows: ratepressure product (RPP, bpm, m m H g x 10 -s) = H R (bpm) x S B P (ram Hg), where H R = heart rate and S B P = systolic blood pressure; cardiac index (CI, L/rain/ m 2) = CO/body surface area, where C O = cardiac output; stroke work index (SWI, ml/m 2) = ( M S P - P C W P ) × SVI x 0.0136, where M S P = m e a n systolic arterialpressure and P C W P = pulmonary capillary wedge pressure; systemic vascular resistance (SVR, dyne • sec • c m -s) = ( M A P - R A P ) / C O × 80, where R A P = right atrial pressure; pulmonary vascular resistance (PVR, dyne-sec-cm -6) ffi( P A P - P C W P / C O ) × 80, where P A P = m e a n pulmonary artery pressure; coronary sinus blood flow (CSBF, ml/min) = [Tb - Ti/Tb - T m ] 1 × 1.08 × 46 ml/min, where T b = temperature of blood, Ti = temperature of injectate, and T m = temperature of mixture of blood and indicator; 1.08 is a constant accounting for specific heat and density of both blood and indicator, and 46 ml/min is the injection rate of the
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American
~40
50.
tu 20
-50'
I
|o
Group 1
Group2 (a)
Group3
l
HeartJournal
-100' Group 2
Group 3 (b)
Fig. 2. Myocardial lactate data. a, Mean lactate extraction was not different among the three groups of patients. Values are given as mean + standard error of the mean. b, Each bar represents the lactate extraction of an individual patient. Five different patients in the group with heart failure caused by coronary artery disease (group 2) and three different patients in the group with dilated cardiomyopathy (group 3) exhibited net lactate production at rest.
indicator (5% dextrose and water) through the Harvard constant infusion pump. Oxygen saturations were measured with a Corning 175 automated blood and pH analyzer. Lactate concentrations were measured by enzymatic spectrofluorometric technique. 6 Normal lactate levels are 5 to 18 mg/dl. The derived metabolic variables were calculated as follows: oxygen content (col%) = oxygen saturation × hemoglobin × 1.34; myocardial oxygen consumption (Mvo~), ml/ rain) ffi (arterial - coronary sinus oxygen content) × coronary sinus blood flow x 10-3; myocardial lactate extraction (%) = arterial - coronary sinus/arterial lactate × 100. Statistical analysis. One-way analysis of variance techniques was used for data analysis. Posthoc tests were performed with Scheff~'s method for multiple contrast. A p value <0.05 was considered significant. RESULTS Systemic hemodynamics. Table I summarizes the systemic hemodynamic profiles of the three groups of patients. The resting hemodynamic profiles in patients with heart failure caused by ischemic heart disease (group 2) and dilated cardiomyopathy (group 3) were similar. However, as expected, cardiac index, volume, and stroke work indexes were lower, and systemic and pulmonary venous pressures were higher in group 2 and 3 patients than in group 1 patients without heart failure. This indicates severely compromised ventricular function in patients with heart failure. Patients with heart failure (groups 2 and 3) had a higher heart rate and lower systolic, arterial blood pressure compared with the control group without heart failure. Systemic vascular resistance was not significantly different among the three groups. Coronary hemodynamics and myocardial metabolism. The coronary hemodynamic and myocardial
metabolic values in the patients in the three groups are summarized in Table II and depicted graphically
in Figs. 1 and 2. Coronary sinus blood flow and myocardial oxygen consumption were higher, whereas the coronary sinus oxygen content was lower in both group 2 and 3 patients with heart failure compared with control subjects. The arterial oxygen content tended to be lower in patients with heart failure compared with the control group. However, the rate-pressure product and myocardial oxygen extraction were not different between the three groups of patients. The average myocardial lactate extraction was not different among the three groups. However, five (8%) individual patients with chronic heart failure caused by ischemic heart disease and three (11%) patients with dilated cardiomyopathy had net lactate production at rest in the absence of angina. The patients who had myocardial lactate production had higher left ventricular filling pressures compared with other patients with heart failure who did not produce lactate (mean pulmonary capillary wedge pressures 33 + 3 vs 24 + 7; p <.005). DISCUSSION
The results of the present investigation demonstrate that chronic severe heart failure caused by either ischemic heart disease or dilated cardiomyopathy may have abnormal coronary hemodynamics and myocardial metabolic function. Evaluation of systemic hemodynamics demonstrated marked elevation of p,]lmonary capillary wedge pressure and reduced stroke volume, stroke work, and cardiac indexes. Among patients with heart failure the systemic hemodynamics were similar in both the group with and the group without coronary artery disease. An augmented coronary blood flow in heart failure is likely to result from increased myocardial
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oxygen requirements rather than from a primary decrease in coronary vascular resistance. When coronary blood flow is in excess of myocardial metabolic demand, coronary sinus venous oxygen content tends to increase and myocardial oxygen extraction to decrease.2 In this study in patients with heart failure caused by dilated cardiomyopathy or ischemic heart disease, coronary sinus venous oxygen saturation was lower than in patients without heart failure. This strongly suggests that myocardial oxygen requirements are greater in these patients even at rest. Indeed, calculated myocardial oxygen consumption was significantly higher in group 2 and 3 patients (Fig. 1) with heart failure. However, the potential mechanisms for the increase in myocardial oxygen requirements and consumption in patients with dilated cardiomyopathy are not entirely clear. The rate-pressure product, a commonly used index of myocardial oxygen demand, was not higher in patients with dilated cardiomyopathy compared with control subjects. Contractility is another major determinant of myocardial oxygen demand. The overall contractile function however, is generally depressed in patients with dilated cardiomyopathy, which should decrease myocardial oxygen consumption.2 However, reflex increase in contractility caused by enhanced sympathetic activity can potentially increase myocardial oxygen requirements. Another important determinant for an increase in myocardial oxygen demand is an increase in left ventricular wall stress. In patients with dilated cardiomyopathy, end systolic and end diastolic volumes are considerably greater than in normal patients; although left ventricular mass may increase, wall thickness usually remains unchanged or only increases slightly. Thus despite lower systolic pressure, left ventricular wall stress may significantly increase in patients with dilated cardiomyopathy. Increased mass may also contribute to an increase in coronary sinus blood flow. Left ventricular volume, mass, or wall thickness were not quantitatively assessed in this study. Thus the differences in wall stress in patients with dilated cardiomyopathy and control subjects could not be precisely determined. However, patients with heart failure had obvious left ventricular enlargement and depressed left ventricular systolic function. Thus it is very likely that wall stress was greater in our patients with heart failure than that in control subjects, which might have contributed to an increase in coronary blood flow and myocardial oxygen consumption. Strauer 7 also observed that in many patients with dilated cardiomyopathy, myocardial oxygen con-
Myocardial energetics in CHF
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sumption is higher. In this study, patients with high wall stress associated with low left ventricular massto-volume ratio had higher myocardial oxygen consumption and coronary blood flow per 100 g m compared with control subjects and patients with low wall stress associated with a high mass-tovolume ratio.7 In some studies, myocardial blood flow per 100 g m of left ventricular mass has been found to be less than normal in patients with dilated cardiomyopathy. 8-12In this study, we did not calculate left ventricular mass and myocardial flow per 100 g m of the left ventricle. However, because the left ventricular mass is usually increased in dilated cardiomyopathy, it is possible that such relatively decreased flow for the left ventricular mass was also present in our patients despite increased global coronary sinus blood flow. In this study in patients with dilated cardiomyopathy, coronary hemodynarnics and myocardial metabolic function were similar to those with chronic heart failure caused by coronary artery disease. It is not surprising since the resting coronary blood flow is usually not restricted even in the presence of severe obstructive lesions. With increasing metabolic demand, coronary blood flow increases as the distal coronary vascular resistance falls. A n increase in myocardial oxygen requirements are usually met by the concomitant increase in coronary blood flow. However, inhomogeneity of coronary blood flow and regional myocardial ischemia can occur in patients with coronary artery disease. Whether abnormalities of regional coronary hemodynamics were present in patients with heart failure caused by coronary artery disease could not be determined in this study. Despite increased myocardial oxygen consumption, myocardial lactate extraction remained in the normal range in most patients in the heart failure groups and was not different from the control group. However, in five patients (8%) with chronic heart failure caused by ischemic heart disease and in three patients (11%) with dilated cardiomyopathy, myocardial lactate production occurred. None of the patients with stable angina, but without heart failure had lactate production. It has been shown in m a n y studies of patients with coronary artery disease that myocardial lactate production is a specific although not sensitive indicator of myocardial ischemia. Myocardial lactate production has been correlated with other manifestations of myocardial ischemia, such as ischemic S T segment changes in the E C G and wall motion abnormalities. 13-21 Marked activation of the anaerobic glycolytic pathway can rarely be associated with myocardial lactate production in the absence of ischemia or hypoxia. In animal
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De Marco et al.
models, bicarbonate, insulin, and glucose infusions can cause lactate production, particularly when myocardial work is increased c o n c o m i t a n t l y . 22"24 However, such mechanisms were not present in these patients. Thus myocardial lactate production was, in all probability, caused by myocardial ischemia. The patients who exhibited lactate production did not complain of anginal pain, which suggests that myocardial ischemia was silent. The potential mechanisms for myocardial ischemia were not explored in this study. Because myocardial oxygen consumption was higher, it is possible that the increase in coronary blood flow was inadequate to meet the higher metabolic demand. Pulmonary capillarywedge pressure was markedly elevated and arterial pressure was relativelylower; thus the transmyocardial pressure gradient was lower in patients with heart failure,which has the potential to induce subendocardial ischemia.23"26Inadequate coronary vasodilatoryreserve and decreased diastolic fillingtime caused by tachycardia may also compromise myocardial perfusion. It is apparent that without further studies the mechanisms for myocardial ischemia will remain conjectural. Of interest is the finding that the patients who exhibited restingmyocardial lactateproduction had some hemodynamic evidence of worse ventricular function than the other patients with dilated cardiomyopathy who did not produce lactate.These eight patients had higher leftventricularfillingpressures (33 + 3 mm Hg compared with 24 _+ 6 mm Hg in patients with normal lactate metabolism (p < 0.OO5). It should be emphasized, however, that the finding of resting myocardial lactate production in our eight patients does not imply that these patients are continually producing lactate and hence are subject to constant myocardial ischemia. Myocardial ischemia with lactate production may be an intermittent phenomenon in these patients. In this study, only resting coronary hemodynamics were determined. Thus changes in coronary reserve and myocardial metabolic function during stress in patients with heart failure remain unknown. During exercise, however, myocardial oxygen consumption increases and deterioration of metabolic function is more likely to occur. Therefore it is expected that the incidence of myocardial ischemia will be higher during exercise compared with the observed incidence at rest in this study. The limitations of this study also need to be considered. It needs to be appreciated that the potential for significant "coronary sinus reflux" exists in all patients with elevated right atrial pres-
American Heart Journal
sure. 5 In these circumstances, estimated coronary sinus flow by the thermodilution technique is overestimated. To avoid coronary sinus reflux, the catheter was positioned in the midcoronary sinus. Significant reflux was further excluded by monitoring changes in coronary sinus blood temperature during the injection of cold saline solution into the right atrium. When the catheter is positioned in the mid-coronary sinus, the estimated coronary sinus flow is more representative of great cardiac vein flow and therefore underestimates the global coronary blood flow. Thus it is likely that the estimated coronary sinus flow and myocardial oxygen consumption were lower than expected in our patients. The patients in groups 1 and 2 in the study had obstructive coronary artery disease with nonuniform distribution and severity, and therefore it can be argued that the coronary blood flow might have been restricted to variable extents in these patients. However, resting coronary blood flow is not usually compromised even in the presence of severe coronary artery stenosis. Thus it is unlikely that the presence of coronary artery disease of different severity in these patients influences the results at any physiologic significance. In conclusion, the results of this study suggest that resting myocardial oxygen consumption is usually higher in patients with chronic heart failure caused by dilated cardiomyopathy or ischemic heart disease and that silent myocardial ischemia can occur even at rest in some of these patients. These abnormal myocardial energetics may potentially accelerate the downhill course in dilated cardiomyopathy. We thank Beverly Atherton, Deidre Curran, Maggie Liu, and Debra Lau for their technical assistance, Gunnard Modin for statistical assistance, the coronary care unit nurses, housestaff, and cardiology fellows who participated in the care of the study patients, and Kathleen Hecker and Cynthia Lotane for their editorial assistance.
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1. Parmley WW. Cardiac failure. In: Rosen MR, Hoffman BF, eds. Cardiac therapy. Boston: Martinus Nijhoff Publishers, 1983:21. 2. Braunwald E. Control of myocardial oxygen consumption. Physiologic and clinical considerations. Am J Cardiol 1971; 27:416. 3. Ganz W, Tanura K, Marals HS, Donoso R, Yoshido S, Swan HS. Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 1971;44:181. 4. Pepine CJ, Mehta J, Webster Jr WW, Nedrols WW. In vivo validation of the thermodilution method to determine regional left ventricular blood flow in patients with coronary disease. Circulation 1978;58:795. 5. Mathey DG, Chatterjee K, Tyberg JV, Lekven J, Brundage B, Parmley WW. Coronary sinus reflux: a source of error in
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6. 7. 8. 9. 10. 11.
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the measurement of thermodilution coronary sinus flow. Circulation 1978;57:778. Loomis ME. An enzymatic fluorometric method for the determination of lactic acid in serum. J Lab Clin Med 1961; 57:966. Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 1979;44:730. Blain JM, Schafer H, Siegal AL. Studies on myocardial metabolism. Am J Med 1962;20:820. Wendt VE, Stock TB, Hayden RO, Bruce TA, Gudbjarnason S, Bing RJ. The hemodynamics and cardiac metabolism in cardiomyopathies. Med Clin North Am 1962;46:1445. Henry PD, Eckberg D, Gault JH, Ross J. Depressed inotropic state and reduced myocardial oxygen consumption in the human heart. Am J Cardiol 1973;31:300. Weiss MB, Ellis K, Sciacca RR, Johnson LL, Schmidt DH, Cannot PJ. Myocardial blood flow in congestive and hypertrophic cardiomyopathy. Relationship to peak wall stress and mean velocity of circumferential fiber shortening. Circulation 1976;54:484. Pasternac A, Noble J, Streulens Y, Elie R, Henschke C, Bourassa MG. Pathophysiology of chest pain in patients with cardiomyopathies and normal coronary arteries. Circulation 1982;65:778. Shea TM, Watson RM, Piotrowski SF, Dermksian G, Case RB. Anaerobic myocardial metabolism. Am J Physiol 1962; 203:463. Case RB, Nasser MG, Crampton RS. Biochemical aspects of early myocardial ischemia. Am J Cardiol 1969;24:766. Cohen LS, Elliott WC, Klein MD, Gorlin R. Coronary heart disease: clinical, cinearteriographic and metabolic considerations. Am J Cardiol 1955;17:153.
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16. Neill WA. Myocadial hypoxia and anaerobic metabolism in coronary heart disease. Am J Cardiol 1968;22:507. 17. Parker JO, Chiang MA, West RO, Case RB. Sequential alterations in myocardial lactate metabolism, ST segments and left ventricular function during angina induced by atrial pacing. Circulation 1969;40:113. 18. Conti CR, Pitt B, Gundel WB, Friesinger GC, Ross RS. Myocardial blood flow in pacing-induced angina. Circulation 1970;42:815. 19. Opie LH, Owen P, Thomas M, Sanson R. Coronary sinus lactate measurements in assessment of myocardial ischemia. Am J Cardiol 1973;32:295. 20. Neill WA, Kremkau E. Criteria for detecting ischemic myocardial hypoxia from lactate and pyruvate dam during atrial pacing in humans. J Lab Clin Med 1974;83:428. 21. Markham Jr LV, Winniford MD, Firth BG, et al. Symptomatic electrocardiographic, metabolic, and hemodynamic alterations during pacing-induced myocardial ischemia. Am J Cardiol 1983;51:1589. 22. Huckabee WE. Relationship of pyruvate and lactate during anaerobic metabolism. V: coronary adequacy. Am J Physiol 1961;200:1169. 23. Kobayashi K, Nealy JR. Control of maximum rates of glycolysis in rat cardiac muscle. Circ Res 1979;44:166. 24. Sudgen PH, Smith DM. The effects of glucose uptake and lactate release in perfused working rat heart preparations. Biochem J 1982;206:473. 25. Hoffman JIE. Determinants and prediction of transmural myocardial perfusion. Circulation 1978;58:381. 26. Unverferth DV, Magorien RD, Lewis RP, Leier CV. The role of subendocardial ischemia in perpetrating myocardial failure in patients with nonischemic congestive cardiomyopathy. AM HZARTJ 1983;105:176.