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Left ventricular changes resulting from chronic aortic regurgitation in dogs
Left Ventricular Changes Resulting from Chronic Aortic Regurgitation in Dogs ROBERT L. FELDMAN, MD, WILMER W. NICHOLS, PhD, LINDA V. THOMPSON, AS, DALE M. PALEY, BS, RICHARD GOLDMAN, PhD, C. RICHARD CONTI, MD, and CARL J. PEPINE, MD
Chronic aortic regurgitation (AR) was induced by aortic valve perforation using catheterization techniques in 7 closed-chest puppies. Approximately 2 years after the creation of AR in these puppies, their growth was similar to that in littermate controls. A gradually progressive degree of left ventricular (LV) dilation and hypertrophy occurred as LV end-diastolic volume (average 116%) and
mass (average 114 % ) increased in animals with AR compared with that in the littermate controls. The technique described to induce AR did not interfere with the normal growth and development of the animals, and permitted study of the functional characteristics of the resulting LV dilation and hypertrophy without added effects of thoracotomy and pericardiotomy. (Am J Cardiol 1984;54:8g0-892)
Many animal models of aortic regurgitation (AR) have been developed,z-zz but they differ considerably from humans who have a deformed, leaky valve from childhood or young adulthood. Results of these animal studies may have limited usefulness in predicting or clarifying the hemodynamic consequences of chronic AR in adult patients. Additionally, the magnitude of left ventricular (LV) dilation that occurred in adult dogs with acquired AR was usually only modest.1,6,9We thus modified previous techniques7,zl to develop a more suitable model to investigate effects of chronic AR. Our goals were (1) to create AR in young animals so that the left ventricle was exposed to a volume load during the growth and development period, (2) to create a defect sufficient to cause a large, dilated left ventricle but not acute heart failure, (3) to be able to increase severity of AR by repeated procedures if compensatory changes minimized its hemodynamic importance as the animal grew, (4) to avoid possible effects of thoracotomy and pericardiotomy, and (5) to permit normal growth.
Methods Catheterization procedures: Fourteen littermate foxhound puppies (12 to 16 weeks old) were randomly assigned to AR or control groups. Puppies in the AR group were anesthetized with an equal mixture of fentynal and phenobarbital, allowed to breath spontaneously and positioned on their right side. Antibiotic prophylaxis and sterile techniques were used. The right carotid artery was isolated and arteriotomy was performed. Image intensification of 4.5 inches was used to guide and position all catheters. An 8Fr NIH catheter was introduced and manipulated into the left ventricle while pressure was monitored. Ventriculography was performed (Renografin-76) using cine technique at 30 frames/s. An 8Fr end-hole guiding catheter was advanced to the ascending aorta. Repeated contrast media injections (1 to 2 m]) were used to position the catheter tip in the noncoronary sinus of Valsalva against the valve leaflet. Slight but constant pressure was applied to the catheter to fix its tip. A modified Bing stylet (needle was straightened and tip shortened to 1 cm and resharpened) was introduced into the catheter. To perforate the leaflet, we slowly advanced the stylet and needle tip several millimeters beyond the end of the catheter, advanced the guiding catheter over the stylet through the hole, and then withdrew the stylet as the guiding catheter was fLxed. Contrast injection confirmed intracavitary position. A large flexible metal basket (from a retrieval catheter set, Dotter Retriever, Cook Catheter Co.) was inserted through the guiding catheter into the left ventricle. The guiding catheter and open basket were withdrawn to enlarge the hole. An 8Fr N I H catheter was advanced to the ascending aorta. Aortography was performed at 30 or 60 frames/s. The carotid artery was repaired and the skin closed.
From the Veterans Administration Medical Center, and Division of Cardiology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida. This study was supported in part by the Medical Research Service of the Veterans Administration, Washington, D.C., and the American Heart Association, Florida Affiliate, St. Petersburg, Florida. Manuscript received April 16, 1984; revised manuscript received May 31, 1984, accepted June 5, 1984. Address for reprints: Robed L. Feldman, MD, Box J-277, Division of Cardiology, College of Medicine, University of Florida, Gainesville, Florida 32610. 890
October 1,1984
THE AMERICAN JOURNAL OF CARDIOLOGY
All puppies were allowed to mature. To serially follow progression of LV changes, we repeated catheterizations using the same techniques and anesthetic. Catheterization of animals with AR was repeated between 2 and 4 months (average 3 months) after creation of AR. Catheterization was again repeated after AR was present for 8 to 11 months (average 9 months, average age 13 months) and 19 to 29 months (average 24 months, average age 28 months)• In control animals, catheterization was performed during the last 2
Volume 54
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evaluations. Calculations and statisticalanalyses: The magnitude of A R was subjectivelygraded 1+ to 4-{-.12 L V volume and mass were calculated (mean ~- standard deviation).13,14 Control and A R values were compared using unpaired t tests. Serialvalues were compared using an analysisof variance.A p value <0.05 was considered significant.
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Results Heart block, infection, local hematoma or neurologic deficit did not develop in any dog. During attempted creation of AR, 3 puppies died. Postmortem examination showed the stylet had perforated the ascending aorta with subsequent bleeding into the thoracic cavity (1 puppy) or pericardium (2 puppies). The remaining 11 (7 dogs with AR and 4 control dogs) tolerated all procedures well; all are normally active and have been trained to run on a treadmill. All dogs with AR have persistent angiographic AR (2+ in 5, 3+ in 1 and 4+ in 1). During the 3 repeat catheterizations, grading of AR did not change. No control dogs had angiographic evidence for AR. Longitudinal evaluation of body weight and anglographic data are summarized in Table I. LV end-diastolic and end-systolic volumes, wall thickness and mass have increased in the dogs with AR (all p <0.01 compared with values at 4 months). This increase was first rapid, then seemed to stabilize, and during the last year has continued to increase. Ratio of LV mass to body weight decreased slightly through age 13 months and then increased at age 28 months (p <0.05 values at 28 months compared with values at 13 months). LV function as assessed by ejection fraction responses during rest has not changed (all differences not significant
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Discussion We have modified previous techniques to induce chronic AR and have applied them in a puppy model. The technique is not technically difficult and requires only equipment usually available in a catheterization
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At average ages of 13 and 28 months in the control dogs, LV volumes and mass were all less than in littermates with AR (all p <0.05). Values between 13 and 28 months had remained similar in the control dogs (p = NS). LV wall thickness was greater in the group with AR only at 28 months (p <0.05). Ratio of LV mass to body weight was larger in puppies with AR at 13 and 28 months (both p <0.05). Only LV ejection fraction has remained similar in control dogs and littermates with AR. Thus, the large changes in LV volume and mass in puppies with AR seems mostly secondary to AR with only a small portion secondary to normal LV growth over the 2-year follow-up.
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laboratory. Growth and development of the puppies with AR and in littermate controls were similar. This model should be applicable for evaluating circulatory changes to chronic AR. We suggest that even greater changes in LV volume and mass could be obtained if multiple aortic leaflets were perforated at either 1 or 2 settings or if the dogs were observed for a longer time. Acknowledgment: We thank R. Tom Sollaway for technical assistance and Alice Cullu for editorial assistance. References 1. Belenkle I, Rademaker A. Acute and chronic changes after aortic valve damage in the intact dog. Am J Physiel 1981;241:H95-H103. 2. Falseltl HL, Carroll RJ, Cramer JA. Total and regional myocardial blood flow in aortic regurgitation. Am Heart J 1979;97:485-493. 3. Feldman RL, Nichols WW, Peploe CJ, Contl CR. Influence of aortic insufficiency on the hamodynamicsignificance of a coronaryartery narrowing. Circulation 1979;60:259-268. 4. Grlggs DM Jr, ~ CC. Coronaryhamodynamicsand regional myocardial metabolism in experimental aortic insufficiency. J Clin Invest 1974;53:
1599-1606. 5. Herrmann GR. Experimental heart disease. II. The effect of experimental aortic regurgitation on the heart weights: with a consideration of some factors concerned in cardiac hypertrophy and a summary of the manifestations of experimental heart disease. Am Heart J 1926;1:485-507. 8. Karp RB, Roe BB. Effect of aortic insufficiency on phasic flow patterns in the coronary artery. Ann Surg 1966;164:959-966. 7. Sprleg DA, Rowe GG. A device for productionof aortic insufficiency in intact experimental animals. J Appl Physiol 1970;29:538-540. 8. Taylor RR, Hopkins BE, Left ventricular response to experimentally Induced chronic aortic regurgitation. Cardlovasc Res 1972;6:404-414. 9. Wegrla R, Muelhelms G, Golub JR, Jreiesaty R, Nekano J. Effect of aortic insufficiency on arterial blood pressure, coronary blood flow and cardiac oxygen consumption. J Clln Invest 1958;33:471-475. 10. Welch GH Jr, Braunwald E, Sarnoff SJ. Hemodynamlc effects of quantitatively varied experimental aortic regurgitation. Circ Res 1957;5:546551. 11. CrozaUer B, Calllel D, Chevrler JL, Haft PY. Nonsympathatic increased inotropic state early after aortic insufficiency. Am J Physlol 1982;242: H973-H979. 12. Sellers RD, Levy MJ, Amplalz K, Ullehel CW. Left retrograde cardioangiography in acquired cardiac disease. TeChnic, indications and interpretations In 700 cases. Am J Cardiol 1964; 14:437-447. 13. Sandier H, Dodge HT. The use of single plane angiocardiograms for the calculation of left ventricular volume in man. Am Heart J 1968;75:325334. 14. Rackley CE, Dodge liT, Coble YD, Hay RE. A method for determining left vantricular mass in man. Circulation 1964;29:666-671.
Chronic aortic regurgitation (AR) was induced by aortic valve perforation using catheterization techniques in 7 closed-chest puppies. Approximately 2 years after the creation of AR in these puppies, their growth was similar to that in littermate controls. A gradually progressive degree of left ventricular (LV) dilation and hypertrophy occurred as LV end-diastolic volume (average 116%) and
mass (average 114 % ) increased in animals with AR compared with that in the littermate controls. The technique described to induce AR did not interfere with the normal growth and development of the animals, and permitted study of the functional characteristics of the resulting LV dilation and hypertrophy without added effects of thoracotomy and pericardiotomy. (Am J Cardiol 1984;54:8g0-892)
Many animal models of aortic regurgitation (AR) have been developed,z-zz but they differ considerably from humans who have a deformed, leaky valve from childhood or young adulthood. Results of these animal studies may have limited usefulness in predicting or clarifying the hemodynamic consequences of chronic AR in adult patients. Additionally, the magnitude of left ventricular (LV) dilation that occurred in adult dogs with acquired AR was usually only modest.1,6,9We thus modified previous techniques7,zl to develop a more suitable model to investigate effects of chronic AR. Our goals were (1) to create AR in young animals so that the left ventricle was exposed to a volume load during the growth and development period, (2) to create a defect sufficient to cause a large, dilated left ventricle but not acute heart failure, (3) to be able to increase severity of AR by repeated procedures if compensatory changes minimized its hemodynamic importance as the animal grew, (4) to avoid possible effects of thoracotomy and pericardiotomy, and (5) to permit normal growth.
Methods Catheterization procedures: Fourteen littermate foxhound puppies (12 to 16 weeks old) were randomly assigned to AR or control groups. Puppies in the AR group were anesthetized with an equal mixture of fentynal and phenobarbital, allowed to breath spontaneously and positioned on their right side. Antibiotic prophylaxis and sterile techniques were used. The right carotid artery was isolated and arteriotomy was performed. Image intensification of 4.5 inches was used to guide and position all catheters. An 8Fr NIH catheter was introduced and manipulated into the left ventricle while pressure was monitored. Ventriculography was performed (Renografin-76) using cine technique at 30 frames/s. An 8Fr end-hole guiding catheter was advanced to the ascending aorta. Repeated contrast media injections (1 to 2 m]) were used to position the catheter tip in the noncoronary sinus of Valsalva against the valve leaflet. Slight but constant pressure was applied to the catheter to fix its tip. A modified Bing stylet (needle was straightened and tip shortened to 1 cm and resharpened) was introduced into the catheter. To perforate the leaflet, we slowly advanced the stylet and needle tip several millimeters beyond the end of the catheter, advanced the guiding catheter over the stylet through the hole, and then withdrew the stylet as the guiding catheter was fLxed. Contrast injection confirmed intracavitary position. A large flexible metal basket (from a retrieval catheter set, Dotter Retriever, Cook Catheter Co.) was inserted through the guiding catheter into the left ventricle. The guiding catheter and open basket were withdrawn to enlarge the hole. An 8Fr N I H catheter was advanced to the ascending aorta. Aortography was performed at 30 or 60 frames/s. The carotid artery was repaired and the skin closed.
From the Veterans Administration Medical Center, and Division of Cardiology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida. This study was supported in part by the Medical Research Service of the Veterans Administration, Washington, D.C., and the American Heart Association, Florida Affiliate, St. Petersburg, Florida. Manuscript received April 16, 1984; revised manuscript received May 31, 1984, accepted June 5, 1984. Address for reprints: Robed L. Feldman, MD, Box J-277, Division of Cardiology, College of Medicine, University of Florida, Gainesville, Florida 32610. 890
October 1,1984
THE AMERICAN JOURNAL OF CARDIOLOGY
All puppies were allowed to mature. To serially follow progression of LV changes, we repeated catheterizations using the same techniques and anesthetic. Catheterization of animals with AR was repeated between 2 and 4 months (average 3 months) after creation of AR. Catheterization was again repeated after AR was present for 8 to 11 months (average 9 months, average age 13 months) and 19 to 29 months (average 24 months, average age 28 months)• In control animals, catheterization was performed during the last 2
Volume 54
ell
~-X-X-Xl
°.
0 0 1
evaluations. Calculations and statisticalanalyses: The magnitude of A R was subjectivelygraded 1+ to 4-{-.12 L V volume and mass were calculated (mean ~- standard deviation).13,14 Control and A R values were compared using unpaired t tests. Serialvalues were compared using an analysisof variance.A p value <0.05 was considered significant.
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Results Heart block, infection, local hematoma or neurologic deficit did not develop in any dog. During attempted creation of AR, 3 puppies died. Postmortem examination showed the stylet had perforated the ascending aorta with subsequent bleeding into the thoracic cavity (1 puppy) or pericardium (2 puppies). The remaining 11 (7 dogs with AR and 4 control dogs) tolerated all procedures well; all are normally active and have been trained to run on a treadmill. All dogs with AR have persistent angiographic AR (2+ in 5, 3+ in 1 and 4+ in 1). During the 3 repeat catheterizations, grading of AR did not change. No control dogs had angiographic evidence for AR. Longitudinal evaluation of body weight and anglographic data are summarized in Table I. LV end-diastolic and end-systolic volumes, wall thickness and mass have increased in the dogs with AR (all p <0.01 compared with values at 4 months). This increase was first rapid, then seemed to stabilize, and during the last year has continued to increase. Ratio of LV mass to body weight decreased slightly through age 13 months and then increased at age 28 months (p <0.05 values at 28 months compared with values at 13 months). LV function as assessed by ejection fraction responses during rest has not changed (all differences not significant
o
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Discussion We have modified previous techniques to induce chronic AR and have applied them in a puppy model. The technique is not technically difficult and requires only equipment usually available in a catheterization
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At average ages of 13 and 28 months in the control dogs, LV volumes and mass were all less than in littermates with AR (all p <0.05). Values between 13 and 28 months had remained similar in the control dogs (p = NS). LV wall thickness was greater in the group with AR only at 28 months (p <0.05). Ratio of LV mass to body weight was larger in puppies with AR at 13 and 28 months (both p <0.05). Only LV ejection fraction has remained similar in control dogs and littermates with AR. Thus, the large changes in LV volume and mass in puppies with AR seems mostly secondary to AR with only a small portion secondary to normal LV growth over the 2-year follow-up.
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CHRONICAORTIC REGURGITATION
laboratory. Growth and development of the puppies with AR and in littermate controls were similar. This model should be applicable for evaluating circulatory changes to chronic AR. We suggest that even greater changes in LV volume and mass could be obtained if multiple aortic leaflets were perforated at either 1 or 2 settings or if the dogs were observed for a longer time. Acknowledgment: We thank R. Tom Sollaway for technical assistance and Alice Cullu for editorial assistance. References 1. Belenkle I, Rademaker A. Acute and chronic changes after aortic valve damage in the intact dog. Am J Physiel 1981;241:H95-H103. 2. Falseltl HL, Carroll RJ, Cramer JA. Total and regional myocardial blood flow in aortic regurgitation. Am Heart J 1979;97:485-493. 3. Feldman RL, Nichols WW, Peploe CJ, Contl CR. Influence of aortic insufficiency on the hamodynamicsignificance of a coronaryartery narrowing. Circulation 1979;60:259-268. 4. Grlggs DM Jr, ~ CC. Coronaryhamodynamicsand regional myocardial metabolism in experimental aortic insufficiency. J Clin Invest 1974;53:
1599-1606. 5. Herrmann GR. Experimental heart disease. II. The effect of experimental aortic regurgitation on the heart weights: with a consideration of some factors concerned in cardiac hypertrophy and a summary of the manifestations of experimental heart disease. Am Heart J 1926;1:485-507. 8. Karp RB, Roe BB. Effect of aortic insufficiency on phasic flow patterns in the coronary artery. Ann Surg 1966;164:959-966. 7. Sprleg DA, Rowe GG. A device for productionof aortic insufficiency in intact experimental animals. J Appl Physiol 1970;29:538-540. 8. Taylor RR, Hopkins BE, Left ventricular response to experimentally Induced chronic aortic regurgitation. Cardlovasc Res 1972;6:404-414. 9. Wegrla R, Muelhelms G, Golub JR, Jreiesaty R, Nekano J. Effect of aortic insufficiency on arterial blood pressure, coronary blood flow and cardiac oxygen consumption. J Clln Invest 1958;33:471-475. 10. Welch GH Jr, Braunwald E, Sarnoff SJ. Hemodynamlc effects of quantitatively varied experimental aortic regurgitation. Circ Res 1957;5:546551. 11. CrozaUer B, Calllel D, Chevrler JL, Haft PY. Nonsympathatic increased inotropic state early after aortic insufficiency. Am J Physlol 1982;242: H973-H979. 12. Sellers RD, Levy MJ, Amplalz K, Ullehel CW. Left retrograde cardioangiography in acquired cardiac disease. TeChnic, indications and interpretations In 700 cases. Am J Cardiol 1964; 14:437-447. 13. Sandier H, Dodge HT. The use of single plane angiocardiograms for the calculation of left ventricular volume in man. Am Heart J 1968;75:325334. 14. Rackley CE, Dodge liT, Coble YD, Hay RE. A method for determining left vantricular mass in man. Circulation 1964;29:666-671.