Myocardial mechanics and energetics experimental iron-deficiency anemia
in
HERBERT J. LEVINE, MICHAEL J. WOLK, JOHN F. KEEFE, OSCAR H. L. BING, JERRY A. SNOW, AND JOSEPH V. MESSER New England Medical Center Hospital, Boston City Hospital, and Department of Medicine, TUBS University School of Medicine, Boston, Massachusetts 02111
HERBERT J., MICHAEL J. WOLK, JOHN F. KEEFE, L. BING, JERRY A. SNOW, AND JOSEPH V. MESSER. Myocardial mechanics and energetics in experimental irondeficiency anemia. Am. J. Physiol. 232(5): H470-H477, 1977 or Am. J. Physiol.: Heart Circ. Physiol. l(5): H470-H477, 1977. The effect of iron-deficiency anemia on myocardial mechanics and energetics was studied in 10 anesthetized beagle puppies. Nine littermates served as controls. Left ventricular/body weight ratio was increased 14.2% (P < 0.05) and cardiac index 36.5% (P < 0.02) in the anemic puppies. Heart rate, mean systolic pressure, myocardial lactate extraction coefficient, and lactic dehydrogenase isozymes were similar in both groups. Contractile state measured in vivo (pressure-velocity curves) and in isolated muscles (isotonic force-velocity curves) was virtually identical in the littermate groups. Despite markedly increased coronary blood flow in the anemic animals, oxygen consumption per unit weight of myocardium was the same in both groups. Contractile element efficiency averaged 18.3% in 10 adult mongrel dogs studied in a similar fashion and was 27.1% and 39.8% in the normal puppies and anemic puppies, respectively. The oxygen cost of internal or forcegenerating work was similar among the three groups of dogs. It is concluded that the volume load produced by iron-deficiency anemia was associated with a normal contractile state, normal unit myocardial oxygen consumption, no evidence of chronic anaerobiosis, and a high contractile element efficiency, perhaps as a consequence of increased diastolic fiber stretch. LEVINE, OSCAR H.
canine studies; force-velocity relations; coronary systemic hemodynamics; myocardial anaerobiosis
blood
flow;
IT HAS BEEN KNOWN FOR MANY YEARS that circulatory dynamics may be altered markedly in severe iron-deficiency anemia. Relatively few studies, however, have examined coronary hemodynamics and myocardial energetics in iron-deficient states. In 1963, Regan et al. (27) reported that myocardial oxygen consumption per unit weight of heart muscle was low in patients with chronic anemia from blood loss. A similar observation was made by Bhatia, Manchanda, and Roy (4) in humans with severe chronic anemia. Since the unit oxygen consumption of the heart is normal during a steady resting state in congestive heart failure and hypertrophy (1, 6, 20), these observations suggest unique energetics of iron-deficient myocardium and the possibility of chronic anaerobiosis.
Iron-containing enzymes are widely distributed in body tissues, particularly in the role of oxidative enzymes. Studies of the activity of iron-containing enzymes in experimental iron deficiency have revealed reduced succinic dehydrogenase activity in heart muscle (3) and depleted stores of cytochrome c in rat kidney and liver (2). These observations provide some rationale for altered oxidative metabolism in iron deficiency and a possible basis for systemic manifestations of this disease. The present study examines the effects of experimental iron-deficiency anemia on circulatory dynamics, myocardial mechanics, and myocardial energetics in the dog . METHODS
Upon weaning, 19 littermate beagle puppies were divided into two groups. One group (9 puppies) was fed a powdered dog diet (General Biochemicals, Chagrin Falls, Ohio) containing 10 mg iron/100 g diet (control group); the second group (10 puppies) was given a diet similar in every respect except that it contained 0.09 mg iron/100 g diet (anemic group). All studies were performed during the 5th mo of age. A third group of 10 normal adult mongrel dogs, weighing 15-22 kg, underwent similar studies and were compared with the two groups of puppies. All animals were anesthetized with pentobarbital sodium (25 mg/kg). Respiration with room air was controlled by a Harvard pump via a cuffed endotracheal tube. Left ventricular (LV) pressure was measured with a Statham SF-l catheter-tip micromanometer and its time derivative determined by a universal differentiator (model UD-20, Crane Bio-Medical Instruments, Inc., Elmont, N. Y.). Polyethylene catheters attached to Statham P23Db transducers were used to monitor aortic pressures. Similar catheters were employed to sample coronary sinus efIluent. A thermistor (Victory Engineering Corp., Union, N. J.) with a time constant of 0.12 s was advanced to the root of the aorta and the ejection fraction was measured by the thermal dilution technic after the injection of l-2 ml of iced saline into the left ventricle. Cardiac output was measured in duplicate by the indocyanine green dilution method with injection of the dye into the inferior vena cava and sampling from the thoracic aorta.
H470
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 14, 2019.
THE
HEART
IN
IRON-DEFICIENCY
H471
ANEMIA
After a right thoracotomy, an electromagnetic flowmeter probe (Carolina Medical Electronics, King, N. C.) was positioned snugly around the aorta just above the aortic valve. The time course of left ventricular pressure (dP/dt), aortic flow rate, and lead II of the scaler electrocardiogram were recorded on an Electronics for Medicine DR-8 photographic recorder at paper speeds of 200 mm/s. Isovolumic beats were produced by abrupt diastolic occlusion of the aorta just proximal to the flowmeter probe. Coronary blood flow was measured by the krypton-85 washout technic with injection of the isotope into the left ventricle and sampling from the coronary sinus. Transmyocardial oxygen content was measured by the manometric technic of Van Slyke and Neil1 (24). Plasma lactate was determined enzymatically by a method modified from that of Horn and Bruns (17). Tissue lactic dehydrogenase (LDH) isozymes were separated by electrophoresis at pH 8.8 with 0.05 M Tris-barbital buffer and cellulose acetate electrophoresis strips. Electrophoresis was carried out for 1 h at 4°C with a current of 1.5 mA (23). The percent M-type LDH was estimated by inspection of the stained strips with a binomial expansion curve. Trabeculae carneae muscles from the right ventricle were mounted between two spring clips and suspended in a muscle chamber containing Krebs-Henseleit solution, gassed with 95% oxygen and 5% CO*, and maintained at a temperature of 28°C. The lower clip was attached to a Statham G7B-0.75-350 force transducer and the upper clip to the arm of an isotonic muscle lever. Muscles were stretched to the peak of their active length-tension curve and stimulated at a rate of 12 times/min. After 1 h of stabilization, variably afterloaded isotonic contractions were recorded and forcevelocity curves contructed. Muscle length was measured with a Gaertner cathetometer and average cross-sectional area of muscle was calculated from the length and blotted wet weight of the muscle between the spring clips. Contractile element velocity (V,,) was normalized for length and expressed as muscle lengths per second; total force was corrected for cross-sectional area and expressed as grams per square millimeter. CaZculations. Cardiac index was obtained from the formula of Guyton as: cardiac output/O.112 (body wt, kg) 213.Stroke volume was obtained by dividing the cardiac output by the heart rate. End-diastolic volume (EDV) was derived from the equation: EDV = stroke volume 1 - K, where K is equal to the average proportional temperature change per beat calculated from the three to five thermodilution curves (18). The average area under the aortic flow curve per beat was equated to the stroke volume and instantaneous changes in ventricular volume (dV/&) were determined by electrical integration of the flow rate curve. The ventricle was assumed to be a sphere and myocardial tensile force (F) was calculated at lo-ms intervals from the equation: F - m2P, where P = ventricular pressure in dynes per square centimeter and r = endocardial radius of the ventricle in centimeters. “Peak” systolic stress (PSS) was estimated from the equation: PSS = r’P,,/2h,
where r’ equals the midwall radius of the ventricle at the moment one -third of the stroke volume was ejected, P,, equals mean systolic pressure in dynes per square centimeter, and h equals ventricular wall thickness in centimeters at the midwall radius r’. Contractile element velocity (V,,) was calculated as the instantaneous sum of the fiber-shortening rate (FSR) and the lengthening velocity of the series-elastic component (dZ/ dt).- During isovolumic contractions of the ventricle, FSR was zero and V,, equaled dZ/& and derived as (dp/ dt)lkP, where k = 24 cm-l (14, 18). In auxotonic contractions FSR was calculated as: flow rate/2r2. The maximum velocity of the contractile element at zero load (V,,,) was estimated from extrapolation of pressurevelocity curves of isovolumic beats (35). Contractile element work (CEW) was measured from auxotonic beats by integrating the time plot of contractile element power as previously described (7). Fibershortening work ‘(FSW) and force-generating work (FGW) were obtained in like fashion by integration of the power-time plots of the muscle fiber and serieselastic component, respectively. The CEW per beat was multiplied by heart rate to obtain CEW per minute, normalized for each 100 g of left ventricle and expressed as lo6 dyn-cm/min per 100 g LV. Contractile element efficiency was calculated as: CE efficiency = 0.003155 CEW/MVO,, where 0.003155 represents the product of 2/ 7~ and the units conversion factor (0.0102 kg-m/lo” dyncm) divided by 2.06 kg-m/ml, the mechanical equivalent of oxygen (7). Pressure-time per minute (PTM) and force-time per minute (FTM > were derived as the product of the heart rate a nd the direct1 ,y planimetered area under the pressure-time and force-time curves, respectively. The PTM was expressed as mmHg s/min and FTM as lo6 dyn s/min per 100 g LV. Left ventricular oxygen consumption (MVO,) was derived as the product of the myocardial arteriovenous oxygen difference in ml 0, per 100 ml and the coronary blood flow (CBF) in ml/l00 g LV per min. Coronary blood flow was calculated from the formula: CBF = log, 2 100/t,,, p, where A is the myocardium-blood partition coefficient for “5Kr (unity), t1,2 is the time in minutes during which there was been a 50% decrease in radioactivity measured in the coronary sinus emuent, and p equals the density of myocardium (assumed to be 1.05) (26). Experimental design. After anesthesia, blood samples were collected for the determination of serum iron, hemoglobin, pH, Pco2, Pop, and arterial lactate concentration. At least 15 min after the surgical procedure was completed, experimental studies were begun. In both control and anemic puppies, the following measurements were made: cardiac output (in duplicate), three to five thermal dilution curves, measurement of myocardial mechanics in auxotonic and isovolumic beats, coronary blood flow, and transmyocardial concentrations of oxygen and 1.actate. In order to examine a wide range of altered hemodynamics, the control and anem 1C puppies and the 10 adult dogs (total 29 animals) were gi ven intravenous norepinephrine (5-20 pg/min) to augment myocardial perl
l
l
A
l
l
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 14, 2019.
H472 formance or intravenous pentobarbital sufficient to produce hypotension. In this fashion, 59 differing observations were made (anemic group, 20; control puppies, 13; adult dogs, 25). At the end of the experiment, the dogs were sacrificed and right ventricular trabeculae carneae muscles were excised rapidly and suspended in a myograph for the determination of isotonic force-velocity curves. The left ventricle with the interventricular septum was dissected from the remaining chambers and valves and was weighed. Samples were obtained from all four chambers for the determination of lactic dehydrogenase isoenzymes. Data analysis was performed after conversion to digital form on an IBM 360/50 computer. The Student t test was used to evaluate paired and unpaired data with essentially similar variances. All results are expressed as mean t SE. When the variances of two unpaired populations were dissimilar, t’ was calculated as described by Snedecor and Cochran (29). RESULTS
In the resting state (Table 1) no significant differences were observed between the anemic puppies (A) or their littermate controls (C) in: arterial PO, (C, 80.3; A, 84.7 mmHg), arterial pH (C, 7.38; A, 7X), or PCO~ (C, 35.1; A, 35.1 mmHg). Although left ventricular weight was significantly higher in the control puppies (C, 34.1; A, 27.2 g; P < 0.02), body weight was less in the anemic puppies (C, 7.1; A, 4.9 kg) and the LV/body weight ratio was significantly higher in the anemic group (C, 478; A, 546 x 10e5; P < 0.05). As the LV/heart weight ratios were similar in the two groups of animals (C, 0.58; A, 0.60; P = NS), the relative increase in heart weight observed in the anemic animals may be considered generalized. As shown in Fig. 1, the anemic puppies had a significantly lower hemoglobin (C, 9.8; A, 5.3 g/100 ml; P < 0.001) and serum iron (C, 114; A, 30; P < 0.001) than their normal littermates. Hemodynamics. The anemic animals exhibited an elevated cardiac index (C, 1.62; A, 2.21 liters/min per m*; P < 0.02). Since resting heart rates were not significantly different (Fig. 2), this increase in output was mediated entirely by an increased stroke index. No differences were observed in mean systolic pressure. Left ventricular end-diastolic volume was slightly larger in the anemic puppies and the ratio of EDV/LV weight was 24% greater in the anemic group (P = 0.07), suggesting dilatation of these hearts. ContractiZe state. The contractile state of the intact heart, as assessed by the extrapolated V,,, of isovolumic pressure-velocity curves, was virtually identical in the control and anemic puppies (Fig. 2). This observation is supported by the results of studies from isolated trabeculae carneae muscles. In Fig. 3, the averages of 22 normalized force-velocity curves (10 control, 12 anemic) are shown. At each level of load, the values for contractile element velocity are almost superimposable for the two groups of animals and the extrapolated V,,, was not significantly different (C, 0.95; A, 0.98 muscle lengths/s; P = NS). Muscle lengths (C, 5.79; A, 5.56 mm;
LEVINE
P = NS) and cross-sectional P = NS) of these trabeculae two groups. Coronary hemodynamics 1. Resting
TABLE
-
AL.
areas (C, 1.61; A, 1.31 mm’; carneae were similar in the and myocardial
state values
energetics. ---
Controls Hemoglobin,
ET
n/l00 ml
(9)
P
Anemia (10)
.-__~___
9.8 + .4
)y:.:.>:.‘.’ .:::::. ~...~_~.~.‘,~.‘_‘.‘.~.~.~. ..,._ ..~_~_~.~.~.~_‘_‘_‘.‘.‘. .;:.~~:.:.~~:.:.‘.‘.,.,. ::. ~.~_~.~.~.‘.‘_:.:. :::::::::::.::::...:.::::: .:.:.:.:.:.:.:.:.:.:.:.~ : :.:.:,:.:.:.~:.:.:.:.:.:. :::.:f:~:::1:l:i:::1:I:i:i :.:.~:.:.:.:.:.:.:.:.~:. :i:i:i:i’::i:i:i:i:i:i:i:i ..:.:.:.:.:.:.:-~:.:.~:.: .:,~~:.:.:.:.:.:.:.:.:.:. .::.~::::.‘.~. ~ p
in
HERBERT J. LEVINE, MICHAEL J. WOLK, JOHN F. KEEFE, OSCAR H. L. BING, JERRY A. SNOW, AND JOSEPH V. MESSER New England Medical Center Hospital, Boston City Hospital, and Department of Medicine, TUBS University School of Medicine, Boston, Massachusetts 02111
HERBERT J., MICHAEL J. WOLK, JOHN F. KEEFE, L. BING, JERRY A. SNOW, AND JOSEPH V. MESSER. Myocardial mechanics and energetics in experimental irondeficiency anemia. Am. J. Physiol. 232(5): H470-H477, 1977 or Am. J. Physiol.: Heart Circ. Physiol. l(5): H470-H477, 1977. The effect of iron-deficiency anemia on myocardial mechanics and energetics was studied in 10 anesthetized beagle puppies. Nine littermates served as controls. Left ventricular/body weight ratio was increased 14.2% (P < 0.05) and cardiac index 36.5% (P < 0.02) in the anemic puppies. Heart rate, mean systolic pressure, myocardial lactate extraction coefficient, and lactic dehydrogenase isozymes were similar in both groups. Contractile state measured in vivo (pressure-velocity curves) and in isolated muscles (isotonic force-velocity curves) was virtually identical in the littermate groups. Despite markedly increased coronary blood flow in the anemic animals, oxygen consumption per unit weight of myocardium was the same in both groups. Contractile element efficiency averaged 18.3% in 10 adult mongrel dogs studied in a similar fashion and was 27.1% and 39.8% in the normal puppies and anemic puppies, respectively. The oxygen cost of internal or forcegenerating work was similar among the three groups of dogs. It is concluded that the volume load produced by iron-deficiency anemia was associated with a normal contractile state, normal unit myocardial oxygen consumption, no evidence of chronic anaerobiosis, and a high contractile element efficiency, perhaps as a consequence of increased diastolic fiber stretch. LEVINE, OSCAR H.
canine studies; force-velocity relations; coronary systemic hemodynamics; myocardial anaerobiosis
blood
flow;
IT HAS BEEN KNOWN FOR MANY YEARS that circulatory dynamics may be altered markedly in severe iron-deficiency anemia. Relatively few studies, however, have examined coronary hemodynamics and myocardial energetics in iron-deficient states. In 1963, Regan et al. (27) reported that myocardial oxygen consumption per unit weight of heart muscle was low in patients with chronic anemia from blood loss. A similar observation was made by Bhatia, Manchanda, and Roy (4) in humans with severe chronic anemia. Since the unit oxygen consumption of the heart is normal during a steady resting state in congestive heart failure and hypertrophy (1, 6, 20), these observations suggest unique energetics of iron-deficient myocardium and the possibility of chronic anaerobiosis.
Iron-containing enzymes are widely distributed in body tissues, particularly in the role of oxidative enzymes. Studies of the activity of iron-containing enzymes in experimental iron deficiency have revealed reduced succinic dehydrogenase activity in heart muscle (3) and depleted stores of cytochrome c in rat kidney and liver (2). These observations provide some rationale for altered oxidative metabolism in iron deficiency and a possible basis for systemic manifestations of this disease. The present study examines the effects of experimental iron-deficiency anemia on circulatory dynamics, myocardial mechanics, and myocardial energetics in the dog . METHODS
Upon weaning, 19 littermate beagle puppies were divided into two groups. One group (9 puppies) was fed a powdered dog diet (General Biochemicals, Chagrin Falls, Ohio) containing 10 mg iron/100 g diet (control group); the second group (10 puppies) was given a diet similar in every respect except that it contained 0.09 mg iron/100 g diet (anemic group). All studies were performed during the 5th mo of age. A third group of 10 normal adult mongrel dogs, weighing 15-22 kg, underwent similar studies and were compared with the two groups of puppies. All animals were anesthetized with pentobarbital sodium (25 mg/kg). Respiration with room air was controlled by a Harvard pump via a cuffed endotracheal tube. Left ventricular (LV) pressure was measured with a Statham SF-l catheter-tip micromanometer and its time derivative determined by a universal differentiator (model UD-20, Crane Bio-Medical Instruments, Inc., Elmont, N. Y.). Polyethylene catheters attached to Statham P23Db transducers were used to monitor aortic pressures. Similar catheters were employed to sample coronary sinus efIluent. A thermistor (Victory Engineering Corp., Union, N. J.) with a time constant of 0.12 s was advanced to the root of the aorta and the ejection fraction was measured by the thermal dilution technic after the injection of l-2 ml of iced saline into the left ventricle. Cardiac output was measured in duplicate by the indocyanine green dilution method with injection of the dye into the inferior vena cava and sampling from the thoracic aorta.
H470
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 14, 2019.
THE
HEART
IN
IRON-DEFICIENCY
H471
ANEMIA
After a right thoracotomy, an electromagnetic flowmeter probe (Carolina Medical Electronics, King, N. C.) was positioned snugly around the aorta just above the aortic valve. The time course of left ventricular pressure (dP/dt), aortic flow rate, and lead II of the scaler electrocardiogram were recorded on an Electronics for Medicine DR-8 photographic recorder at paper speeds of 200 mm/s. Isovolumic beats were produced by abrupt diastolic occlusion of the aorta just proximal to the flowmeter probe. Coronary blood flow was measured by the krypton-85 washout technic with injection of the isotope into the left ventricle and sampling from the coronary sinus. Transmyocardial oxygen content was measured by the manometric technic of Van Slyke and Neil1 (24). Plasma lactate was determined enzymatically by a method modified from that of Horn and Bruns (17). Tissue lactic dehydrogenase (LDH) isozymes were separated by electrophoresis at pH 8.8 with 0.05 M Tris-barbital buffer and cellulose acetate electrophoresis strips. Electrophoresis was carried out for 1 h at 4°C with a current of 1.5 mA (23). The percent M-type LDH was estimated by inspection of the stained strips with a binomial expansion curve. Trabeculae carneae muscles from the right ventricle were mounted between two spring clips and suspended in a muscle chamber containing Krebs-Henseleit solution, gassed with 95% oxygen and 5% CO*, and maintained at a temperature of 28°C. The lower clip was attached to a Statham G7B-0.75-350 force transducer and the upper clip to the arm of an isotonic muscle lever. Muscles were stretched to the peak of their active length-tension curve and stimulated at a rate of 12 times/min. After 1 h of stabilization, variably afterloaded isotonic contractions were recorded and forcevelocity curves contructed. Muscle length was measured with a Gaertner cathetometer and average cross-sectional area of muscle was calculated from the length and blotted wet weight of the muscle between the spring clips. Contractile element velocity (V,,) was normalized for length and expressed as muscle lengths per second; total force was corrected for cross-sectional area and expressed as grams per square millimeter. CaZculations. Cardiac index was obtained from the formula of Guyton as: cardiac output/O.112 (body wt, kg) 213.Stroke volume was obtained by dividing the cardiac output by the heart rate. End-diastolic volume (EDV) was derived from the equation: EDV = stroke volume 1 - K, where K is equal to the average proportional temperature change per beat calculated from the three to five thermodilution curves (18). The average area under the aortic flow curve per beat was equated to the stroke volume and instantaneous changes in ventricular volume (dV/&) were determined by electrical integration of the flow rate curve. The ventricle was assumed to be a sphere and myocardial tensile force (F) was calculated at lo-ms intervals from the equation: F - m2P, where P = ventricular pressure in dynes per square centimeter and r = endocardial radius of the ventricle in centimeters. “Peak” systolic stress (PSS) was estimated from the equation: PSS = r’P,,/2h,
where r’ equals the midwall radius of the ventricle at the moment one -third of the stroke volume was ejected, P,, equals mean systolic pressure in dynes per square centimeter, and h equals ventricular wall thickness in centimeters at the midwall radius r’. Contractile element velocity (V,,) was calculated as the instantaneous sum of the fiber-shortening rate (FSR) and the lengthening velocity of the series-elastic component (dZ/ dt).- During isovolumic contractions of the ventricle, FSR was zero and V,, equaled dZ/& and derived as (dp/ dt)lkP, where k = 24 cm-l (14, 18). In auxotonic contractions FSR was calculated as: flow rate/2r2. The maximum velocity of the contractile element at zero load (V,,,) was estimated from extrapolation of pressurevelocity curves of isovolumic beats (35). Contractile element work (CEW) was measured from auxotonic beats by integrating the time plot of contractile element power as previously described (7). Fibershortening work ‘(FSW) and force-generating work (FGW) were obtained in like fashion by integration of the power-time plots of the muscle fiber and serieselastic component, respectively. The CEW per beat was multiplied by heart rate to obtain CEW per minute, normalized for each 100 g of left ventricle and expressed as lo6 dyn-cm/min per 100 g LV. Contractile element efficiency was calculated as: CE efficiency = 0.003155 CEW/MVO,, where 0.003155 represents the product of 2/ 7~ and the units conversion factor (0.0102 kg-m/lo” dyncm) divided by 2.06 kg-m/ml, the mechanical equivalent of oxygen (7). Pressure-time per minute (PTM) and force-time per minute (FTM > were derived as the product of the heart rate a nd the direct1 ,y planimetered area under the pressure-time and force-time curves, respectively. The PTM was expressed as mmHg s/min and FTM as lo6 dyn s/min per 100 g LV. Left ventricular oxygen consumption (MVO,) was derived as the product of the myocardial arteriovenous oxygen difference in ml 0, per 100 ml and the coronary blood flow (CBF) in ml/l00 g LV per min. Coronary blood flow was calculated from the formula: CBF = log, 2 100/t,,, p, where A is the myocardium-blood partition coefficient for “5Kr (unity), t1,2 is the time in minutes during which there was been a 50% decrease in radioactivity measured in the coronary sinus emuent, and p equals the density of myocardium (assumed to be 1.05) (26). Experimental design. After anesthesia, blood samples were collected for the determination of serum iron, hemoglobin, pH, Pco2, Pop, and arterial lactate concentration. At least 15 min after the surgical procedure was completed, experimental studies were begun. In both control and anemic puppies, the following measurements were made: cardiac output (in duplicate), three to five thermal dilution curves, measurement of myocardial mechanics in auxotonic and isovolumic beats, coronary blood flow, and transmyocardial concentrations of oxygen and 1.actate. In order to examine a wide range of altered hemodynamics, the control and anem 1C puppies and the 10 adult dogs (total 29 animals) were gi ven intravenous norepinephrine (5-20 pg/min) to augment myocardial perl
l
l
A
l
l
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (128.059.222.107) on January 14, 2019.
H472 formance or intravenous pentobarbital sufficient to produce hypotension. In this fashion, 59 differing observations were made (anemic group, 20; control puppies, 13; adult dogs, 25). At the end of the experiment, the dogs were sacrificed and right ventricular trabeculae carneae muscles were excised rapidly and suspended in a myograph for the determination of isotonic force-velocity curves. The left ventricle with the interventricular septum was dissected from the remaining chambers and valves and was weighed. Samples were obtained from all four chambers for the determination of lactic dehydrogenase isoenzymes. Data analysis was performed after conversion to digital form on an IBM 360/50 computer. The Student t test was used to evaluate paired and unpaired data with essentially similar variances. All results are expressed as mean t SE. When the variances of two unpaired populations were dissimilar, t’ was calculated as described by Snedecor and Cochran (29). RESULTS
In the resting state (Table 1) no significant differences were observed between the anemic puppies (A) or their littermate controls (C) in: arterial PO, (C, 80.3; A, 84.7 mmHg), arterial pH (C, 7.38; A, 7X), or PCO~ (C, 35.1; A, 35.1 mmHg). Although left ventricular weight was significantly higher in the control puppies (C, 34.1; A, 27.2 g; P < 0.02), body weight was less in the anemic puppies (C, 7.1; A, 4.9 kg) and the LV/body weight ratio was significantly higher in the anemic group (C, 478; A, 546 x 10e5; P < 0.05). As the LV/heart weight ratios were similar in the two groups of animals (C, 0.58; A, 0.60; P = NS), the relative increase in heart weight observed in the anemic animals may be considered generalized. As shown in Fig. 1, the anemic puppies had a significantly lower hemoglobin (C, 9.8; A, 5.3 g/100 ml; P < 0.001) and serum iron (C, 114; A, 30; P < 0.001) than their normal littermates. Hemodynamics. The anemic animals exhibited an elevated cardiac index (C, 1.62; A, 2.21 liters/min per m*; P < 0.02). Since resting heart rates were not significantly different (Fig. 2), this increase in output was mediated entirely by an increased stroke index. No differences were observed in mean systolic pressure. Left ventricular end-diastolic volume was slightly larger in the anemic puppies and the ratio of EDV/LV weight was 24% greater in the anemic group (P = 0.07), suggesting dilatation of these hearts. ContractiZe state. The contractile state of the intact heart, as assessed by the extrapolated V,,, of isovolumic pressure-velocity curves, was virtually identical in the control and anemic puppies (Fig. 2). This observation is supported by the results of studies from isolated trabeculae carneae muscles. In Fig. 3, the averages of 22 normalized force-velocity curves (10 control, 12 anemic) are shown. At each level of load, the values for contractile element velocity are almost superimposable for the two groups of animals and the extrapolated V,,, was not significantly different (C, 0.95; A, 0.98 muscle lengths/s; P = NS). Muscle lengths (C, 5.79; A, 5.56 mm;
LEVINE
P = NS) and cross-sectional P = NS) of these trabeculae two groups. Coronary hemodynamics 1. Resting
TABLE
-
AL.
areas (C, 1.61; A, 1.31 mm’; carneae were similar in the and myocardial
state values
energetics. ---
Controls Hemoglobin,
ET
n/l00 ml
(9)
P
Anemia (10)
.-__~___
9.8 + .4
)y:.:.>:.‘.’ .:::::. ~...~_~.~.‘,~.‘_‘.‘.~.~.~. ..,._ ..~_~_~.~.~.~_‘_‘_‘.‘.‘. .;:.~~:.:.~~:.:.‘.‘.,.,. ::. ~.~_~.~.~.‘.‘_:.:. :::::::::::.::::...:.::::: .:.:.:.:.:.:.:.:.:.:.:.~ : :.:.:,:.:.:.~:.:.:.:.:.:. :::.:f:~:::1:l:i:::1:I:i:i :.:.~:.:.:.:.:.:.:.:.~:. :i:i:i:i’::i:i:i:i:i:i:i:i ..:.:.:.:.:.:.:-~:.:.~:.: .:,~~:.:.:.:.:.:.:.:.:.:. .::.~::::.‘.~. ~ p
