EXPERIMENTAL
The
AND
Effects
ASRAR
MOLECULAR
of Atherosclerosis
B. MALIK,~
Department
PATHOLOGY
25, 293-300
on the Hypertrophied
IRSHAD H. CHAUDRY,TOMIO
ABE,
of Physiology, Albany Medical College, Department of Surgery, Yale University New Haven, Connecticut Received
January
16, 1976,
( 19%)
and
in revised
Albany, School 06510 form
Rabbit
Heart’
AND ALEXANDER
S. GF.HA
New York of Medicine,
April
26,
12208,
and
1976
We studied the effects of high cholesterol diet and atherosclerosis on the development of left ventricular hypertrophy (LVH) in rabbits. The suprarenal aorta was banded in rabbits on a normal diet and in rabbits on a 4% cholesterol diet. A group of sham-operated rabbits was fed a normal diet, and another group of sham-operated rabbits was fed a 4% cholesterol diet. All four groups were sacrificed after approximately 6 months, when hypertrophy in the banded rabbits had stabilized. The LVand RV-to-body weight ratios were determined. LV to body weight increased from a value in controls of 0.78 -C 0.052 to 1.02 +- 0.085 gm/kgm (P < 0.05) in the banded group on a normal diet and to 1.03 f 0.031 gm/kgm (P < 0.05) in the sham-operated group on a cholesterol diet. The increase in the LV-to-body weight ratio to 1.21 f 0.072 gm/kgm was largest (P < 0.05) in the banded group on the high cholesterol diet. RV to body weight did not change in any group. The development of LVH in atherosclerotic rabbits was associated with an increase in arterial pressure. Myocardial ischemia could not be responsible for LVH since hypertrophy was confirmed only in the left ventricle even in the presence of right ventricular myocardial ischemia. Atherosclerosis increased the degree of LVH induced by aortic banding in an additive manner. Therefore, the findings Indicate that LVH in the atherosclerotic rabbit was due to increased arterial pressure induced by the atherosclerosis and that atherosclerosis further increased the degree of hypertrophy induced by aortic banding by increasing the arterial pressure proximal to the band.
INTRODUCTION Cardiac hypertrophy has been produced in animals by a variety of methods ( Badeer, 1971; Fanburg, 1970), including pressure and volume overloading (Malik et al., 1973). Meerson has suggested that myocardial ischemia can also induce cardiac hypertrophy (Meerson, 1974). There is no clinical evidence that coronary artery occlusive disease and the resulting myocardial ischemia results in hypertrophy (Fanburg, 1970; Norman and Coers, 1960). HOWever, it is a difficult question to evaluate in patients, since associated conditions such as hypertension, diabetes, and renal disease can also induce hypertrophy (Badeer, 1971; Fanburg, 1970). The relationship between atherosclerosis and cardiac hypertrophy is not clear. These two lesions commonly coexist (Keys, 1970), and it is of significance to understand how atherosclerosis affects the degree of hypertrophy. 1 Supported by the Eastern New York Heart Association and NIH Grant HL-13088. 3 Address reprint requests to: Dr. A. B. Malik, Department of Physiology, Albany Gollege, Albany, New York 12208.
293 Copyright All rights
1976 by Academic Press, Inc. o8 reproduction in any form reserved.
Medical
294
MALIK
ET AL.
Therefore, in the present study we have determined whether experimental atherosclerosis associated with coronary atherosclerosis can itself induce cardiac hypertrophy. Second, we have studied the effects of atherosclerosis on cardiac hypertrophy induced by banding the aorta to determine how coexistence of the two affects the degree of hypertrophy. METHODS A total of 41 adult white New Zealand rabbits of both sexes, weighing between 2.5 and 3.0 kgm was divided into the following four experimental groups: Group A: control, 9 animals; a sham midline abdominal operation; fed standard rabbit diet. Group B: 10 animals; the abdominal aorta was bauded 1 cm above the renal arteries; fed standard rabbit diet. Group C: 11 animals; a sham midline abdominal operation; diet included 4% cholesterol. Group D: 11 animals; the abdominal aorta was banded 1 cm above renal arteries; diet included 4% cholesterol. The animals were anesthetized with intraperitoneally administered sodium pentobarbital, 30 mgm/kgm for al1 surgica1 procedures. For the banding procedure, the descending aorta was exposed 1 cm above the renal artery. An umbilical tape (3 mm wide) was placed around the aorta and adjusted until the aortic diameter was reduced to one-half the original diameter and was sutured in this position. After 6 to 7 months, the animals in each group were anesthetized with intraperitoneally administered sodium pentobarbital, 30 mgm/kgm and connected to a Harvard Respirator via a tracheostomy. A midabdominal incision was performed to measure the arterial pressure by aortic puncture with a 20-gauge needIe proximal and dista1 to the banding. These measurements were made using a Hewlett-Packard 7700 recorder. Animals were then sacrificed with a KC1 injection and the aorta, liver, kidneys, lungs, and heart were examined. The hearts were removed and fixed in 10% formaldehyde solution. After 10 days fixation, the epicardial fat and the large vessels were carefully removed and the hearts were separated into right ventricle (RV) and left ventricle (LV) according to the method described previously (O’Kane et al., 1973). The weight of each ventricle was determined on a Mettler H-51 balance. In another four groups of rabbits, tissue samples weighing approximately 150 mgm were removed from the left and right ventricle free walls in open chest, ventiIated rabbits. Tissue Iactate and pyruvate concentrations were determined ( Bergmeyer, 1965). Significance between mean values was determined using the Student’s t test. RESULTS Natural History As shown in Table I, in Group A, nine rabbits survived more than 6 months and two rabbits died with an infection soon after the sham operation. In Group C, two rabbits died, probably as a result of atherosclerosis, 5 to 6 months after
ATHEROSCLEROSIS
AND CARDIAC TABLE
The Natural
295
I
History of the Rabbits in the Four Groups N
Group A (sham)
HYPERTROPHY
Number of deaths
Cause of death
Time after operation
9
2
Infection
2-10 days
10
2
Left venkicular
11
2
Atherosclerosis
5-6 mont,hs
11
5
Left ventricular failure (N = 2) Atherosclerosis (N = 3)
5-10 days 54 months
Group B (banded) Group C (sham, cholest,erol)
failure
7-10 days
Group D (banded, cholesferol)
the operation. These two animals showed severe atheromatous lesions in the wall of the aorta and coronary arteries, as well as fat infiltrates in lungs, liver, and heart. Death was ascribed to the severe coronary artery lesions. In both banded Groups B and D, two rabbits died 5 to 10 days after the banding with left ventricular failure, as evidenced by the fluid in the chest and pulmonary edema upon autopsy. Three rabbits in Group D that died 5 to 6 months after the banding procedure showed severe atherosclerotic lesions in the segmentsboth proximal and distal to the band and severe coronary artery lesions. Hewdynamics,
Autopsy Findings, Lactate and Pyruvate Concentrations
The peak systolic pressure gradient across the band was 33 * 5 mm Hg (mean 2 SEM) with a range of 21 to 47 mm Hg on the standard diet and 51 f 4 mm Hg with a range of 35 to 65 mm Hg on the high cholesterol diet (Table I). Therefore, atherosclerosis produced a significantly greater increase in the pressure gradient (P < 0.05) across the aortic band. Mean arterial pressures were elevated in the banded Group B (P < 0.05) and in the atherosclerotic Group C (P < 0.05) (Table II). Mean arterial pressure was further elevated in the banded, atherosclerotic Group D (P < 0.01) ( Table II ) . Grossly, the aorta was patent at the site of stenosis in all banded rabbits. The inner diameter of the aorta at the band was reduced to approximately one-half the original diameter, and there was no evidence of dilatation proximal or distal to the stenosis. Both ,groups of animals on the high cholesterol diet for 6 to 7 months had atherosclerotic plaques in the aorta. Atherosclerosis of the mesentery arteries was evident in both atheroclerotic groups; however, renal artery atherosclerosis was observed only in the unbanded atherosclerotic group. Coronary atherosclerosis of left and right coronary arteries was evident in both groups, and the degree of the lesion in the two groups did not appear to be different. In Group D, the degree of atherosclerosis was much ,greater in the aorta proximal to the band than distal to the band.
296
MALIK
ET AL,
ATHEROSCLEROSIS
AND CARDIAC
HYPERTROPHY
297
298
MALIK
ET
AL.
Lactate and pyruvate concentrations in the right and left ventricles and lactate-to-pyruvate ratios are indicated in Table III. Lactate levels and lactate/ pyruvate ratios were not significantly elevated in the banded group. Lactate concentrations were significantly increased (P < 0.05) in right and left ventricles in the cholesterol-fed group and the banded, cholesterol-fed group (Table III); the 1actateJpyruvate ratios were significantly elevated only in the banded cholesterol-fed group ( Table III ). Ventricular
Weights
Banding the abdominal aorta produced a selective increase (P < 0.05) in LV weight as evidenced by an increase in the LV-to-body weight ratio. The atherosclerosis produced a similar increase in the LV-to-body weight ratio (P < 0.05), but not in the RV-to-body weight ratio (Table II). A combination of banding and atherosclerosis produced a greater increase (P < 0.01) in the LV-to-body weight ratio and no change in the RV-to-body weight ratio. The LV-to-RV weight ratio increased (P < 0.05) in both banded and atherosclerotic groups and increased more significantly (P < 0.01) in the banded, atherosclerotic group ( Table II ) . DISCUSSION Atherosclerosis in rabbits has been produced by a number of investigators ( Wellman and Volk, 1970). Experimentally induced atherosclerosis offers the advantage of not having complicating factors encountered in patients, such as diabetes and renal disease. Therefore, it is possible to determine the independent effects of atherosclerosis and aortic stenosis on the development of hypertrophy. There is little information from experimental animals as to whether atherosclerosis and the resulting myocardial ischemia can induce cardiac hypertrophy, as suggested by Meerson ( Meerson, 1974). Moreover, it is not clear what effect atherosclerosis has on the degree of cardiac hypertrophy induced by aortic stenosis. This is a relevant question since atherosclerosis and cardiac hypertrophy commonly coexist in patients (Keys, 1970). In the present study, stable cardiac hypertrophy without any evidence of failure developed by banding the suprarenal abdominal aorta. Congestive heart failure developed in only four of the banded rabbits, and these were not included in the data. In the surviving banded rabbits, the LV-to-body weight ratio increased to 1.02 * 0.085 gm/kgm from a value in control rabbits of 0.78 * 0.052. The banded rabbits did not develop a significant degree of right ventricular hypertrophy. In the control sham-operated rabbits fed a high cholesterol diet, the LV-to-body weight ratio was also higher than control sham-operated rabbits on a normal diet. There was also no evidence of right ventricular hypertrophy in this group. Arterial pressure was significantly elevated in the atherosclerotic rabbits. The mechanism of increase in arterial pressure in the atherosclerotic group is not clear, but it may be due to the increase in the vascular resistance resulting from the atherosclerosis-induced decrease in vascular caliber of not only the larger arteries but also the smaller resistance vessels. Small decreases in vessel radii (r) at any site can result in large increases in resistance (R) and therefore pressure, since according to Poiseuille’s law, R a l/r*. In the banded cholesterol-fed group, the development of atherosclerosis increased the degree
ATHEROSCLEROSIS
AND
CARDIAC
HYPERTROPHY
299
of left ventricular hypertrophy induced by banding. The effect on left ventricular weight was an additive one, rather than potentiatory. In the banded rabbits on the high cholesterol diet, the mean arterial pressure proximal to the band was greater than the pressure in banded rabbits on a normal diet. The peak systolic pressure gradient across the band increased to 51 t 4 mm Hg from a mean value of 33 + 5 mm Hg in banded rabbits on a normal diet. The greater pressure gradient may be due to the localization of an atherosclerotic lesion proximal to the band, as in previous studies (Mestel et al., lQ64), and a further increase in resistance against which the heart pumps. Therefore, there was a further increase in the left ventricular afterload in the group in which atherosclerosis was associated with aortic stenosis, resulting in a greater degree of left ventricular hypertrophy. Left ventricular hypertrophy likely developed in the rabbits fed cholesterol because of the increase in afterload as evidenced by an increase in arterial pressure, rather than myocardial ischemia. If myocardial ischemia had been a significant factor in the development of hypertrophy, it would have also resulted in a significant degree of right ventricular hypertrophy; however, this did not occur in the present study. MyocardiaI ischemia is excluded as a cause of left ventricular hypertrophy, since myocardial ischemia as evidenced by increases in lactate concentrations occurred in both left and right ventricles in the atherosclerotic groups. Significant right ventricular hypertrophy was not observed despite the evidence that right ventricular ischemia was comparable to left ventricular ischemia. In the banded, cholesterol-fed group, the right and left ventricular lactate-to-pyruvate concentrations were not elevated from the control group, yet there was no evidence of right ventricular hypertrophy and there was a significant degree of left ventricular hypertrophy. Therefore, the results suggest that coronary atherosclerosis and myocardial ischemia per se do not result in hypertrophy, but that hypertrophy is secondary to increases in afterload due to the atherosclerosis-induced increase in systemic vascular resistance (Malik et al., 1973). Interstitial fat accumulation may also account for the increase in the LV-to-body weight ratio during atherosclerosis; however, this is unlikely to be a major factor since RV-to-body weight did not increase significantly in either group of animals on the high cholesterol diet. In conclusion, these findings are not consistent with Meerson’s hypothesis (Meerson, 1974) that atherosclerosis and resulting myocardial ischemia per se induces cardiac hypertrophy. The present findings suggest that cardiac hypertrophy occurring ‘during atherosclerosis is secondary to the increase in the afterload induced by atherosclerosis. In addition, the results indicate that when atherosclerosis and aortic stenosis coexist, there is a greater degree of left ventricular hypertrophy which is equal to the hypertrophy induced independently by the atherosclerosis and by aortic stenosis. This additive effect is due to the greater increase in afterload when atherosclerosis coexists with aortic stenosis. REFERENCES BADEER, H. S. ( 1971). Myocardial blood flow and oxygen uptake in clinical and experimental cardiomegaly. Amer. Heart J. 8, 205-216. BERGMEYER, H. U. (1965). “Methods in Enzymatic Analysis.” Academic Press, New York. FANBURG, B. L. (1970). Experimental cardiac hypertrophy. N. Engl. J. Med. 282, 723-731. KEYS, A. ( 1970). Coronary heart disease in seven countries. Circulation (Suppl. 1) 41, l-211.
300
MALIK
ET
AL.
A. B., ABE, T., O’KANE, H., and GEHA, A. S. (1973). Cardiac function, coronary flow and oxygen consumption in stable left ventricular hypertrophy. Amer. J. Physiol. 225, 186191. MEERSON, F. Z. ( 1974). Development of modern components of the mechanism of cardiac hypertrophy. Circ. Res. (Suppl. 2) 35, 58-63. MESTEL, A. L., SPAIN, D. M., and TURNER, H. A. ( 1964). Atheroma absence distal to subtotal aorta occlusion. Arch. Pathol. 78, 84-92. NORMAN, T. D., and COERS, C. R. (1960). Cardiac hypertrophy after coronary artery ligation in rats. Arch. Puthol. 69, 181-184. O’KANJI, H., GEHA, A. S., KLEIGER, R. E., ABE, T., SALEYMEH, M. R., and MALIK, A. B. (1973). Stable left ventricular hypertrophy in the dog: Experimental production, time course, and natural history. .l. Thorac. Cardiovasc. Surg. 65, 264-271. WELLMAN, K. F., and VOLK, B. W. ( 1970). Experimental atherosclerosis in normal and subdiabetic rabbits. Arch. Pathol. 90, 206-212. MALIK,
The
AND
Effects
ASRAR
MOLECULAR
of Atherosclerosis
B. MALIK,~
Department
PATHOLOGY
25, 293-300
on the Hypertrophied
IRSHAD H. CHAUDRY,TOMIO
ABE,
of Physiology, Albany Medical College, Department of Surgery, Yale University New Haven, Connecticut Received
January
16, 1976,
( 19%)
and
in revised
Albany, School 06510 form
Rabbit
Heart’
AND ALEXANDER
S. GF.HA
New York of Medicine,
April
26,
12208,
and
1976
We studied the effects of high cholesterol diet and atherosclerosis on the development of left ventricular hypertrophy (LVH) in rabbits. The suprarenal aorta was banded in rabbits on a normal diet and in rabbits on a 4% cholesterol diet. A group of sham-operated rabbits was fed a normal diet, and another group of sham-operated rabbits was fed a 4% cholesterol diet. All four groups were sacrificed after approximately 6 months, when hypertrophy in the banded rabbits had stabilized. The LVand RV-to-body weight ratios were determined. LV to body weight increased from a value in controls of 0.78 -C 0.052 to 1.02 +- 0.085 gm/kgm (P < 0.05) in the banded group on a normal diet and to 1.03 f 0.031 gm/kgm (P < 0.05) in the sham-operated group on a cholesterol diet. The increase in the LV-to-body weight ratio to 1.21 f 0.072 gm/kgm was largest (P < 0.05) in the banded group on the high cholesterol diet. RV to body weight did not change in any group. The development of LVH in atherosclerotic rabbits was associated with an increase in arterial pressure. Myocardial ischemia could not be responsible for LVH since hypertrophy was confirmed only in the left ventricle even in the presence of right ventricular myocardial ischemia. Atherosclerosis increased the degree of LVH induced by aortic banding in an additive manner. Therefore, the findings Indicate that LVH in the atherosclerotic rabbit was due to increased arterial pressure induced by the atherosclerosis and that atherosclerosis further increased the degree of hypertrophy induced by aortic banding by increasing the arterial pressure proximal to the band.
INTRODUCTION Cardiac hypertrophy has been produced in animals by a variety of methods ( Badeer, 1971; Fanburg, 1970), including pressure and volume overloading (Malik et al., 1973). Meerson has suggested that myocardial ischemia can also induce cardiac hypertrophy (Meerson, 1974). There is no clinical evidence that coronary artery occlusive disease and the resulting myocardial ischemia results in hypertrophy (Fanburg, 1970; Norman and Coers, 1960). HOWever, it is a difficult question to evaluate in patients, since associated conditions such as hypertension, diabetes, and renal disease can also induce hypertrophy (Badeer, 1971; Fanburg, 1970). The relationship between atherosclerosis and cardiac hypertrophy is not clear. These two lesions commonly coexist (Keys, 1970), and it is of significance to understand how atherosclerosis affects the degree of hypertrophy. 1 Supported by the Eastern New York Heart Association and NIH Grant HL-13088. 3 Address reprint requests to: Dr. A. B. Malik, Department of Physiology, Albany Gollege, Albany, New York 12208.
293 Copyright All rights
1976 by Academic Press, Inc. o8 reproduction in any form reserved.
Medical
294
MALIK
ET AL.
Therefore, in the present study we have determined whether experimental atherosclerosis associated with coronary atherosclerosis can itself induce cardiac hypertrophy. Second, we have studied the effects of atherosclerosis on cardiac hypertrophy induced by banding the aorta to determine how coexistence of the two affects the degree of hypertrophy. METHODS A total of 41 adult white New Zealand rabbits of both sexes, weighing between 2.5 and 3.0 kgm was divided into the following four experimental groups: Group A: control, 9 animals; a sham midline abdominal operation; fed standard rabbit diet. Group B: 10 animals; the abdominal aorta was bauded 1 cm above the renal arteries; fed standard rabbit diet. Group C: 11 animals; a sham midline abdominal operation; diet included 4% cholesterol. Group D: 11 animals; the abdominal aorta was banded 1 cm above renal arteries; diet included 4% cholesterol. The animals were anesthetized with intraperitoneally administered sodium pentobarbital, 30 mgm/kgm for al1 surgica1 procedures. For the banding procedure, the descending aorta was exposed 1 cm above the renal artery. An umbilical tape (3 mm wide) was placed around the aorta and adjusted until the aortic diameter was reduced to one-half the original diameter and was sutured in this position. After 6 to 7 months, the animals in each group were anesthetized with intraperitoneally administered sodium pentobarbital, 30 mgm/kgm and connected to a Harvard Respirator via a tracheostomy. A midabdominal incision was performed to measure the arterial pressure by aortic puncture with a 20-gauge needIe proximal and dista1 to the banding. These measurements were made using a Hewlett-Packard 7700 recorder. Animals were then sacrificed with a KC1 injection and the aorta, liver, kidneys, lungs, and heart were examined. The hearts were removed and fixed in 10% formaldehyde solution. After 10 days fixation, the epicardial fat and the large vessels were carefully removed and the hearts were separated into right ventricle (RV) and left ventricle (LV) according to the method described previously (O’Kane et al., 1973). The weight of each ventricle was determined on a Mettler H-51 balance. In another four groups of rabbits, tissue samples weighing approximately 150 mgm were removed from the left and right ventricle free walls in open chest, ventiIated rabbits. Tissue Iactate and pyruvate concentrations were determined ( Bergmeyer, 1965). Significance between mean values was determined using the Student’s t test. RESULTS Natural History As shown in Table I, in Group A, nine rabbits survived more than 6 months and two rabbits died with an infection soon after the sham operation. In Group C, two rabbits died, probably as a result of atherosclerosis, 5 to 6 months after
ATHEROSCLEROSIS
AND CARDIAC TABLE
The Natural
295
I
History of the Rabbits in the Four Groups N
Group A (sham)
HYPERTROPHY
Number of deaths
Cause of death
Time after operation
9
2
Infection
2-10 days
10
2
Left venkicular
11
2
Atherosclerosis
5-6 mont,hs
11
5
Left ventricular failure (N = 2) Atherosclerosis (N = 3)
5-10 days 54 months
Group B (banded) Group C (sham, cholest,erol)
failure
7-10 days
Group D (banded, cholesferol)
the operation. These two animals showed severe atheromatous lesions in the wall of the aorta and coronary arteries, as well as fat infiltrates in lungs, liver, and heart. Death was ascribed to the severe coronary artery lesions. In both banded Groups B and D, two rabbits died 5 to 10 days after the banding with left ventricular failure, as evidenced by the fluid in the chest and pulmonary edema upon autopsy. Three rabbits in Group D that died 5 to 6 months after the banding procedure showed severe atherosclerotic lesions in the segmentsboth proximal and distal to the band and severe coronary artery lesions. Hewdynamics,
Autopsy Findings, Lactate and Pyruvate Concentrations
The peak systolic pressure gradient across the band was 33 * 5 mm Hg (mean 2 SEM) with a range of 21 to 47 mm Hg on the standard diet and 51 f 4 mm Hg with a range of 35 to 65 mm Hg on the high cholesterol diet (Table I). Therefore, atherosclerosis produced a significantly greater increase in the pressure gradient (P < 0.05) across the aortic band. Mean arterial pressures were elevated in the banded Group B (P < 0.05) and in the atherosclerotic Group C (P < 0.05) (Table II). Mean arterial pressure was further elevated in the banded, atherosclerotic Group D (P < 0.01) ( Table II ) . Grossly, the aorta was patent at the site of stenosis in all banded rabbits. The inner diameter of the aorta at the band was reduced to approximately one-half the original diameter, and there was no evidence of dilatation proximal or distal to the stenosis. Both ,groups of animals on the high cholesterol diet for 6 to 7 months had atherosclerotic plaques in the aorta. Atherosclerosis of the mesentery arteries was evident in both atheroclerotic groups; however, renal artery atherosclerosis was observed only in the unbanded atherosclerotic group. Coronary atherosclerosis of left and right coronary arteries was evident in both groups, and the degree of the lesion in the two groups did not appear to be different. In Group D, the degree of atherosclerosis was much ,greater in the aorta proximal to the band than distal to the band.
296
MALIK
ET AL,
ATHEROSCLEROSIS
AND CARDIAC
HYPERTROPHY
297
298
MALIK
ET
AL.
Lactate and pyruvate concentrations in the right and left ventricles and lactate-to-pyruvate ratios are indicated in Table III. Lactate levels and lactate/ pyruvate ratios were not significantly elevated in the banded group. Lactate concentrations were significantly increased (P < 0.05) in right and left ventricles in the cholesterol-fed group and the banded, cholesterol-fed group (Table III); the 1actateJpyruvate ratios were significantly elevated only in the banded cholesterol-fed group ( Table III ). Ventricular
Weights
Banding the abdominal aorta produced a selective increase (P < 0.05) in LV weight as evidenced by an increase in the LV-to-body weight ratio. The atherosclerosis produced a similar increase in the LV-to-body weight ratio (P < 0.05), but not in the RV-to-body weight ratio (Table II). A combination of banding and atherosclerosis produced a greater increase (P < 0.01) in the LV-to-body weight ratio and no change in the RV-to-body weight ratio. The LV-to-RV weight ratio increased (P < 0.05) in both banded and atherosclerotic groups and increased more significantly (P < 0.01) in the banded, atherosclerotic group ( Table II ) . DISCUSSION Atherosclerosis in rabbits has been produced by a number of investigators ( Wellman and Volk, 1970). Experimentally induced atherosclerosis offers the advantage of not having complicating factors encountered in patients, such as diabetes and renal disease. Therefore, it is possible to determine the independent effects of atherosclerosis and aortic stenosis on the development of hypertrophy. There is little information from experimental animals as to whether atherosclerosis and the resulting myocardial ischemia can induce cardiac hypertrophy, as suggested by Meerson ( Meerson, 1974). Moreover, it is not clear what effect atherosclerosis has on the degree of cardiac hypertrophy induced by aortic stenosis. This is a relevant question since atherosclerosis and cardiac hypertrophy commonly coexist in patients (Keys, 1970). In the present study, stable cardiac hypertrophy without any evidence of failure developed by banding the suprarenal abdominal aorta. Congestive heart failure developed in only four of the banded rabbits, and these were not included in the data. In the surviving banded rabbits, the LV-to-body weight ratio increased to 1.02 * 0.085 gm/kgm from a value in control rabbits of 0.78 * 0.052. The banded rabbits did not develop a significant degree of right ventricular hypertrophy. In the control sham-operated rabbits fed a high cholesterol diet, the LV-to-body weight ratio was also higher than control sham-operated rabbits on a normal diet. There was also no evidence of right ventricular hypertrophy in this group. Arterial pressure was significantly elevated in the atherosclerotic rabbits. The mechanism of increase in arterial pressure in the atherosclerotic group is not clear, but it may be due to the increase in the vascular resistance resulting from the atherosclerosis-induced decrease in vascular caliber of not only the larger arteries but also the smaller resistance vessels. Small decreases in vessel radii (r) at any site can result in large increases in resistance (R) and therefore pressure, since according to Poiseuille’s law, R a l/r*. In the banded cholesterol-fed group, the development of atherosclerosis increased the degree
ATHEROSCLEROSIS
AND
CARDIAC
HYPERTROPHY
299
of left ventricular hypertrophy induced by banding. The effect on left ventricular weight was an additive one, rather than potentiatory. In the banded rabbits on the high cholesterol diet, the mean arterial pressure proximal to the band was greater than the pressure in banded rabbits on a normal diet. The peak systolic pressure gradient across the band increased to 51 t 4 mm Hg from a mean value of 33 + 5 mm Hg in banded rabbits on a normal diet. The greater pressure gradient may be due to the localization of an atherosclerotic lesion proximal to the band, as in previous studies (Mestel et al., lQ64), and a further increase in resistance against which the heart pumps. Therefore, there was a further increase in the left ventricular afterload in the group in which atherosclerosis was associated with aortic stenosis, resulting in a greater degree of left ventricular hypertrophy. Left ventricular hypertrophy likely developed in the rabbits fed cholesterol because of the increase in afterload as evidenced by an increase in arterial pressure, rather than myocardial ischemia. If myocardial ischemia had been a significant factor in the development of hypertrophy, it would have also resulted in a significant degree of right ventricular hypertrophy; however, this did not occur in the present study. MyocardiaI ischemia is excluded as a cause of left ventricular hypertrophy, since myocardial ischemia as evidenced by increases in lactate concentrations occurred in both left and right ventricles in the atherosclerotic groups. Significant right ventricular hypertrophy was not observed despite the evidence that right ventricular ischemia was comparable to left ventricular ischemia. In the banded, cholesterol-fed group, the right and left ventricular lactate-to-pyruvate concentrations were not elevated from the control group, yet there was no evidence of right ventricular hypertrophy and there was a significant degree of left ventricular hypertrophy. Therefore, the results suggest that coronary atherosclerosis and myocardial ischemia per se do not result in hypertrophy, but that hypertrophy is secondary to increases in afterload due to the atherosclerosis-induced increase in systemic vascular resistance (Malik et al., 1973). Interstitial fat accumulation may also account for the increase in the LV-to-body weight ratio during atherosclerosis; however, this is unlikely to be a major factor since RV-to-body weight did not increase significantly in either group of animals on the high cholesterol diet. In conclusion, these findings are not consistent with Meerson’s hypothesis (Meerson, 1974) that atherosclerosis and resulting myocardial ischemia per se induces cardiac hypertrophy. The present findings suggest that cardiac hypertrophy occurring ‘during atherosclerosis is secondary to the increase in the afterload induced by atherosclerosis. In addition, the results indicate that when atherosclerosis and aortic stenosis coexist, there is a greater degree of left ventricular hypertrophy which is equal to the hypertrophy induced independently by the atherosclerosis and by aortic stenosis. This additive effect is due to the greater increase in afterload when atherosclerosis coexists with aortic stenosis. REFERENCES BADEER, H. S. ( 1971). Myocardial blood flow and oxygen uptake in clinical and experimental cardiomegaly. Amer. Heart J. 8, 205-216. BERGMEYER, H. U. (1965). “Methods in Enzymatic Analysis.” Academic Press, New York. FANBURG, B. L. (1970). Experimental cardiac hypertrophy. N. Engl. J. Med. 282, 723-731. KEYS, A. ( 1970). Coronary heart disease in seven countries. Circulation (Suppl. 1) 41, l-211.
300
MALIK
ET
AL.
A. B., ABE, T., O’KANE, H., and GEHA, A. S. (1973). Cardiac function, coronary flow and oxygen consumption in stable left ventricular hypertrophy. Amer. J. Physiol. 225, 186191. MEERSON, F. Z. ( 1974). Development of modern components of the mechanism of cardiac hypertrophy. Circ. Res. (Suppl. 2) 35, 58-63. MESTEL, A. L., SPAIN, D. M., and TURNER, H. A. ( 1964). Atheroma absence distal to subtotal aorta occlusion. Arch. Pathol. 78, 84-92. NORMAN, T. D., and COERS, C. R. (1960). Cardiac hypertrophy after coronary artery ligation in rats. Arch. Puthol. 69, 181-184. O’KANJI, H., GEHA, A. S., KLEIGER, R. E., ABE, T., SALEYMEH, M. R., and MALIK, A. B. (1973). Stable left ventricular hypertrophy in the dog: Experimental production, time course, and natural history. .l. Thorac. Cardiovasc. Surg. 65, 264-271. WELLMAN, K. F., and VOLK, B. W. ( 1970). Experimental atherosclerosis in normal and subdiabetic rabbits. Arch. Pathol. 90, 206-212. MALIK,
