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Concurrent left and right ventricular hypertrophy in dog models of right ventricular overload
J THORAC CARDIOVASC SURG 84:543-547, 1982
Concurrent left and right ventricular hypertrophy in dog models of right ventricular overload In two pressure and volume overload models of canine right ventricular hypertrophy, we have demonstrated significant hypertrophy of both the left and the right ventricles. The extent of hypertrophy was correlated positively to the extent of the increase in plasma epinephrine in both volume and pressure overload models. Attenuation or ablation of plasma epinephrine through the administration of propranolol, a {3-adrenergic blocker, or by denervation of the adrenal medulla prevented the hypertrophy process. No hemodynamic parameter was altered consistently in a parallel manner to hypertrophy. This is the first report of concurrent right and left ventricular hypertrophy in response to pressure or volume overload of the right ventricle. These studies further implicate epinephrine as a major trophic hormone of the heart.
Douglas F. Larson, M.S. (by invitation), J. R. Womble, Ph.D. (by invitation), J. G. Copeland, M.D. (by invitation), and Diane Haddock Russell, Ph.D. (by invitation), Tucson, Ariz. Sponsored by Norman E. Shumway, M.D., Stanford, Calif.
Selective right and left ventricular hypertrophy generated by pressure or volume overload to the right or left ventricle has been thought to be related to the alteration of hemodynamic parameters such as peak systolic or end-diastolic pressure.' However, chronic pulmonary disease in man (cor pulmonale), which results in chronic right ventricular overload and hypertrophy, also is associated with left ventricular hypertrophy":" but is not associated with known hemodynamic alterations in the left ventricle."?" Further, studies of pulmonary artery banding in animals result in similar morphologic and biochemical changes in both the right and left ventricles, although, again, as in cor pulmonale, no altered hemodynamic parameters of the left ventricle have been detected.F"!" Evidence is accumulating that a chronic elevation in plasma epinephrine concentration is a major contributing event in myocardial hypertrophy. We 2 lT- 22 reported
previously that. the plasma epinephrine concentration remained markedly elevated during left ventricular hypertrophy in dogs in response to aortic constriction. Ablation of the endocrine source of epinephrine through denervation of the adrenal medulla resulted in atrophy of the left ventricle in the presence of continued cardiac overload. 23 Further, the exogenous administration of epinephrine or other ~-adrenergic agonists resulted in both right and left ventricular hypertrophy. 24-27 In this paper, we report that after 30 days of volume or pressure overload to the right ventricle, both right and left ventricular hypertrophy occurred. The extent 0 hypertrophy was correlated positively with the elevation in plasma epinephrine and was not consistently related to alterations in hemodynamic parameters such as ventricular end-diastolic pressure. Methods
From the Departments of Surgery and Pharmacology, University of Arizona Health Sciences Center, Tucson, Ariz. Read at the Sixty-second Annual Meeting of The American Association for Thoracic Surgery, Phoenix, Ariz., May 3-5,1982. Address for reprints: Diane H. Russell, Ph.D., Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Ariz. 85724.
A total of 55 adult mongrel dogs, male or female, 12 to 25 kg, preconditioned to kennel environment and free of microfilaria, were used in these studies. A Swan-Ganz thermodilution catheter (7 Fr., No. 93132-7F, Edwards Laboratories, Inc., Santa Ana, Calif.) was inserted through a permanently implanted external jugular Cordis Introducer (8 Fr., No. 501-608, Cordis Corp., Miami, Fla.) to position the distal tip of the
© 1982 The C. V. Mosby Co.
543
0022-5223/82/100543+05$00.50/0
The Journal of
544 Larson et al.
Thoracic and Cardiovascular Surgery
Table I. Ventricular dry weight/body weight ratios following right ventricular overload Dry weight/body weight (mg/kg) ratio (mean ± SEM) Right ventricle
Control (n = 25) Silica (n = 10) Silica plus propranolol (n = 5) Monocrotaline (n = 5) Shunt (n = 10)
300 374 341 434 407
± 8 ± 15* ± 15 ± 3* ± 18*
Septum
269 304 285 298 295
± 6 ± 18t ± 44 ± 17 ± 18
Left ventricle
566 628 631 691 675
± 19 ± 31 ± 16 ± 43t ± 33t
Total
1135 1306 1257 1423 1376
± 28 ± 54t ± 18 ± 48* ± 60*
'Data differ from controls (p < 0.(01). tData differ from controls (p < 0.01).
Table II. Plasma epinephrine and norepinephrine levels Norepinephrine (pg/ml)
Control (n = 25) Silica infusion (n = 10) Silica plus propranolol (n = 5) Monocrotaline (n = 5) Graft-shunt (n = 10)
105 302 154 322 495
± 8 ± 53* ± 16t ± 7\' ± 110*
278 ± 35 399 ± 103 171 ± 92 322 ± 53 476 ± 96t
Legend: Data are expressed as the mean ± SEM. Each value represents a minimum of five different dog plasma samples collected prior to termination and measured in duplicate. -
'Data differ from controls (p < 0.(01). f Data differ from controls (p < 0.05).
catheter in the pulmonary artery. All hemodynamic measurements and blood samples were obtained with the Swan-Ganz catheter. Mixed venous plasma catecholamine concentrations were analyzed with the Cat-A-Kit (Upjohn Diagnostics, Kalamazoo, Mich.). The hemodynamic and catecholamine sampling studies were accomplished in a dimly illuminated, quiet room with the dogs standing in a Pavlov harness apparatus. The dogs were maintained on a 7 A.M. to 7 P.M. photoperiod and fed standard dog chow and water ad libitum. At the completion of the designated study period, plasma samples were collected for catecholamine determinations, and the animals were put to death by intravenous pentobarbital; the hearts were removed and dissected free of the atria, valves, and great vessels. The right and left ventricles were dissected from the septum, and wet tissue weights were obtained. Tissues were dried for 48 hours at 50° C and - 20 psi, and dry tissue weight/body weight ratios were calculated and expressed as milligrams per kilogram. A progressive right ventricular pressure overload was produced in 15 dogs for a 7 day study by daily intravenous injections of silica particles (diatomaceous
earth, grade 1, Sigma Chemical Co., St. Louis, Mo.) in a concentration of 12.5 mg/kg suspended in 50 ml of 0.9% sodium chloride with 2 units/ml of sodium heparin (The Upjohn Company, Kalamazoo, Mich.). Five dogs in this group also were administered propranolol hydrochloride, 15 mg/kg/day, orally (Ayerst Laboratories, New York, N. Y.). Another model of progressive right ventricular pressure overload (studied for 30 days) was induced by injection of the plant alkaloid monocrotaline in 3 intraperitoneal doses of 10 mg/kg on consecutive days, a total dose of 30 mg/kg per dog. Monocrotaline has been demonstrated to produce right ventricular hypertrophy in rodents because of toxininduced pulmonary artery fibrosis.f" Volume overload of the right ventricle was accomplished by surgically implanting a pulmonary artery outflow tract-to-right atrial shunt graft (16 mm inner diameter by 8 em; Microvel double velour, No. 081608, Meadox Medicals, Inc., Oakland, N. J.). Simultaneous shunt to cardiac output ratios were measured (Statham electromagnetic blood flow meter, Model 2204, Statham Instruments, Inc., Oxnard, Calif.) during the initial shunt placement and at the completion of the 30 day study. Control blood sampling and hemodynamic measurements were conducted 4 to 5 days after placement of the Cordis Introducer and Swan-Ganz catheter prior to sacrifice with pentobarbital. Statistical analysis. Data are expressed as the mean ± SEM. The level of significance was evaluated by Student's t test and p < 0.05 was considered statistically significant.
Results Increased right and left ventricular hypertrophy in right ventricular overload. All three models of right ventricular overload resulted in significant elevations in right ventricular mass (Table I). The monocrotaline toxin treatment produced right ventricular hy-
Volume 84
LVH and RVH in right ventricular overload
Number 4
545
October. 1982
900.r------------------..
Fig. 1. Relationship of right ventricular and left ventricular hypertrophy to body weight following right ventricular overload.
pertrophy to 145% of control, shunt to 136% of control, and silica to 125% of control. Left ventricular hypertrophy was significant in 30 day studies of monocrotaline pressure overload (122% of control) and graftshunt volume overload (120% of control) but not in the 7 day silica treatment model. In the silica model, propranolol administered concurrently with silica blocked the significant increase in right ventricular mass. Elevated plasma epinephrine in response to pressure and volume overload of the right ventricle. The plasma epinephrine concentration was elevated threefold in the silica infusion model and the monocrotaline group and over fourfold in the graft-shunt model (Table II). Norepinephrine was elevated significantly only in the graft-shunt model to less than twofold of control (p < 0.05). In all cases, there was a high positive correlation between right and left ventricular hypertrophy and the plasma epinephrine concentration but not with plasma norepinephrine concentration (Table III). Fig. 1 demonstrates the high positive correlation between the left and right ventricular dry weight/body weight ratio (r = 0.758; P < 0.00001). Hemodynamic parameters. The hemodynamic measurements obtained in these conscious, unsedated dog models demonstrated that right ventricular enddiastolic pressure correlated with plasma epinephrine (r = 0.873; p < 0.001) and with ventricular dry
Table III. Correlation between ventricular dry weight to body weight ratios and plasma catecholamine concentrations (pg/ml) during right ventricular overload
I
Right ventricle vs. epinephrine Left ventricle vs. epinephrine Right ventricle vs. norepinephrine Left ventricle vs. norepinephrine
r Value
p Value
r = 0.821 r = 0.700
p < 0.000 P < 0.000 P < 0.008 p < 0.137
r = 0.473
r = 0.238
Legend: A pool of all experimental groups was analyzed using the Statistical
Package for Social Science.
weight/body weight ratios (r = 0.882; P < 0.001). In these models of right ventricular overload, the indirect index of left ventricular end-diastolic pressure, the pulmonary artery wedge pressure, did not correlate with plasma epinephrine levels or with ventricular dry weight/body weight ratios (Table IV). There was no consistent correlation between plasma epinephrine levels and heart rate, cardiac index, right ventricular stroke work index, or pulmonary vascular resistance. In the propranolol-treated dogs, the right ventricular end-diastolic pressure did not correlate to myocardial mass or plasma epinephrine release. In the silica pressure-overload model, propranolol administration did not have a direct effect on hemodynamic parame-
The Journal of Thoracic and Cardiovascular Surgery
546 Larson et al.
Table IV. Comparative preload measurements of the right and left ventricles Il'-R-V-E-V-P--.------PAW
Group ________ ...J~I
Control Silica Silica plus propranolol Monocrotaline Shunt
(mm Hg)
25 10 5 5 10
1.6 3.8 6.3 6.8 8.1
± ± ± ± ±
0.4 0.7* 0.9* 0.8* 1.4*
(mm Hg)
4.96 4.10 3.33 3.87 4.29
± ± ± ± ±
0.52 0.64 0.83 1.30 0.47
Legend: RVEDP. Right ventricular end-diastolic pressure. PAW, Pulmonary artery wedge pressure.
*p < 0.001.
ters except to decrease the heart rate and to increase the stroke volume index. Discussion
Plasma epinephrine concentration was correlated to the increment in myocardial mass irrespective of any alterations in hemodynamic parameters. We have demonstrated this relationship after increased pressure load to the left ventricle and after either pressure or volume overload to the right ventricle; in all cases, there was a highly significant positive correlation between the plasma epinephrine concentration and the extent of ventricular hypertrophy. 20-22 That the ~-adrenergic antagonist propranolol attenuates myocardial growth in the silica pressure-overload model may be related to (I) selective ~-receptor blockade of the myocardium and/or (2) decreased release of epinephrine from the adrenal medulla. In previous studies, total ablation of the endogenous source of epinephrine by denervation of the adrenal medulla inhibited myocardial growth in response to ventricular pressure overload.F' We suggest that cardiac overload, caused by either increased volume or pressure load, activates the sympathetically mediated release of epinephrine from the adrenal medulla. The resulting increased concentration of plasma epinephrine through its ~-adrenergic activity regulates cardiac hypertrophy. In the fetal murine heart, we29, 30 demonstrated the induction of ornithine decarboxylase, a growth marker enzyme, by epinephrine and its inhibition by propranolol administration. We31 further characterized the specific myocardial receptor in the fetal murine heart model coupled to increased ornithine decarboxylase activity as ~2 in nature. Baker and Potter" have suggested that most myocardial ~-receptors are located on the external sarcolemma rather than at the synapses, and that only plasma epinephrine concentration achieves the K, value required to activate the myocardial recep-
tors. Only in extreme conditions may norepinephrine approach the Kd value of the sarcolemmal ~-receptor for activation. These studies add further evidence to support hormonal regulation of cardiac hypertrophy by epinephrine through ~2-adrenergic stimulation. Terbutaline, a specific ~2-agonist, administered to dogs also resulted in marked cardiac hypertrophy and was blocked by a ~2-antagonist.33 Although left ventricular hypertrophy has been described at autopsy in patients with cor pulmonale, until now the cause has remained unknown. Studies have reported up to 86% of patients with cor pulmonale secondary to chronic obstructive pulmonary disease have hypertrophy of both the right and left ventricles. 34 Other studies demonstrated that patients with nonobstructive pulmonary disease such as emphysema or chronic bronchitis have both right and left ventricular hypertrophy." 4,6 We now suggest that both right and left ventricular hypertrophy may be due to chronically elevated plasma epinephrine levels. In summary, stress, such as ventricular overload, cor pulmonale, chronic obstructive pulmonary disease, or upper airway obstruction, appears sufficient to produce a sympathetically mediated release of medullary epinephrine which mediates both right and left ventricular hypertrophy in a dose-dependent manner.
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REFERENCES Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56-64, 1975 Rao BS, Cohn KE, Eldridge FL, Hancock EW: Left ventricular failure secondary to chronic pulmonary disease. Am J Med 45:229-241, 1968 Murphy ML, Adamson J, Hutcheson F: Left ventricular hypertrophy in patients with chronic bronchitis and emphysema. Ann Intern Med 81:307-313, 1974 Kountz WB, Alexander HL, Prinzmetal M: The heart in emphysema. Am Heart J 11: 163-172, 1936 Michelson N: Bilateral ventricular hypertrophy due to chronic pulmonary disease. Chest 38:435-446, 1960 Fluck DC, Chandrasekar RG, Gardner FV: Left ventricular hypertrophy in chronic bronchitis. Br Heart J 28:9297, 1966 Altschule MD: Cor pulmonale. A disease of the whole heart. Chest 41:398-403, 1962 Baum GL, Schwartz A, Llamas R, Castillo C: Left ventricular function in chronic obstructive lung disease. N Engl J Med 285:361-365, 1971 Burrows B, Kettel LJ, Niden AH, Rabinowitz M, Diener CF: Patterns of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med 286:912-918, 1972 Bahler RC: Assessment of left ventricular function in
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LVH and RVH in right ventricular overload
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October. 1982
chronic obstructive pulmonary disease. Chest 68: 132133, 1975 11 Unger K, Shaw D, Karliner JS, Crawford M, O'Rourke RA, Moser KM: Evaluation of left ventricular performance in acutely ill patients with chronic obstructive lung disease. Chest 68:135-142, 1975 12 Christianson LC, Shah A, Fisher VJ: Quantitative left ventricular cineangiography in patients with chronic obstructive pulmonary disease. Am J Med 66:399-404, 1979 13 Steele P, Ellis JH, Van Dyke D, Sutton F, Creagh E, Davies H: Left ventricular ejection fraction in severe chronic obstructive airways disease. Am J Med 59:21-28, 1975 14 Williams JF, Childress RH, Boyd OL, Higgs LM, Behnke RH: Left ventricular function in patients with chronic obstructive pulmonary disease. J Clin Invest 47:1143-1153,1968 15 Kline LE, Crawford MH, MacDonald WJ, Schelbert H, O'Rourke RA, Moser KM: Noninvasive assessment of left ventricular performance in patients with chronic obstructive pulmonary disease. Chest 72:558-570, 1977 16 Kachel RG: Left ventricular function in chronic obstructive pulmonary disease. Chest 74:286-290, 1978 17 Buccino RA, Harris E, Spann JF, Sonnenblick EH: Response of myocardial connective tissue to development of experimental hypertrophy. Am J Physiol 216:425-428, 1969 18 Pool PE, Spann JF, Buccino RA, Sonnenblick EH, Braunwald E: Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure. Circ Res 21:365373, 1967 19 Chidsey CA, Kaiser GA, Sonnenblick EH, Spann JF, Braunwald E: Cardiac norepinephrine stores in experimental heart failure in the dog. J Clin Invest 43:23862393, 1964 20 Womble JR, Haddox MK, Russell DH: Epinephrine elevation in plasma parallels canine cardiac hypertrophy. Life Sci 23:1951-1958,1978 21 Larson DF, Womble JR, Copeland JG, Huxtable RJ, Russell DH: Plasma epinephrine levels predict right ventricular hypertrophy. Fed Proc 40: 2892, 1981 22 Larson DF, Womble JR, Copeland JG, Russell DH: Epinephrine regulates compensatory right and left ventricular hypertrophy. J Mol Cell Cardiol 13:48, 1981
23 Womble JR, Larson OF, Copeland JG, Brown BR, Haddox MK, Russell OH: Adrenal medulla denervation prevents stress-induced epinephrine plasma elevation and cardiac hypertrophy. Life Sci 27:2417-2420, 1980 24 Stanton HC, Brenner G, Mayfield ED: Studies on isoproterenol-induced cardiomegaly in rats. Am Heart J 77:72-80, 1969 25 Byus CV, Chubb JM, Huxtable RJ, Russell DH: Increase in type I adenosine 3' ,5'-monophosphate-dependent protein kinase during isoproterenol-induced cardiac hypertrophy. Biochem Biophys Res Commun 73:694-702, 1976 26 Laks MM, Morady F, Swan HJC: Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 64:74-78, 1973 27 Russell DH, Durie BGM: Polyamines as Biochemical Markers of Normal and Malignant Growth, New York, 1978, Raven Press, pp 79-81 28 Huxtable R, Ciaramitaro D, Eisenstein D: The effect of a pyrrolizidine alkaloid, rnonocrotaline, and a pyrrole, dehydroretronecine, on the biochemical functions of the pulmonary endothelium. Mol Pharmacol 14: 1189-1203, 1978 29 Russell DH, Byus CV, Manen CA: Proposed model of major sequential biochemical events of a trophic response. Life Sci 19:1297-1306,1976 30 Haddox MK, Womble JR, Larson DF, Roeske WR, Russell DH: Isoproterenol stimulation of ornithine decarboxylase blocked by propranolol during ontogeny of the murine heart. Mol Pharmacol 20:382-386, 1981 31 Copeland JG, Larson DF, Roeske WR, Russell DH, Womble JR: ,B2-adrenoceptors regulate induction of myocardial ornithine decarboxylase in mice in vivo. Br J Pharmacol 75:479-483, 1982 32 Baker SP, Potter LT: Biochemical studies of cardiac ,B-adrenoceptors, and their clinical significance. Circ Res 46:138-142, 1980 33 Womble JR, Larson OF, Copeland JG, Russell DH: Low dose oral terbutaline rapidly induces significant cardiac hypertrophy. Clin Pharmacol Ther 31:283, 1982 34 Zimmerman HA, Ryan JM: Cor pulmonale. Chest 20:286-289, 1951
Concurrent left and right ventricular hypertrophy in dog models of right ventricular overload In two pressure and volume overload models of canine right ventricular hypertrophy, we have demonstrated significant hypertrophy of both the left and the right ventricles. The extent of hypertrophy was correlated positively to the extent of the increase in plasma epinephrine in both volume and pressure overload models. Attenuation or ablation of plasma epinephrine through the administration of propranolol, a {3-adrenergic blocker, or by denervation of the adrenal medulla prevented the hypertrophy process. No hemodynamic parameter was altered consistently in a parallel manner to hypertrophy. This is the first report of concurrent right and left ventricular hypertrophy in response to pressure or volume overload of the right ventricle. These studies further implicate epinephrine as a major trophic hormone of the heart.
Douglas F. Larson, M.S. (by invitation), J. R. Womble, Ph.D. (by invitation), J. G. Copeland, M.D. (by invitation), and Diane Haddock Russell, Ph.D. (by invitation), Tucson, Ariz. Sponsored by Norman E. Shumway, M.D., Stanford, Calif.
Selective right and left ventricular hypertrophy generated by pressure or volume overload to the right or left ventricle has been thought to be related to the alteration of hemodynamic parameters such as peak systolic or end-diastolic pressure.' However, chronic pulmonary disease in man (cor pulmonale), which results in chronic right ventricular overload and hypertrophy, also is associated with left ventricular hypertrophy":" but is not associated with known hemodynamic alterations in the left ventricle."?" Further, studies of pulmonary artery banding in animals result in similar morphologic and biochemical changes in both the right and left ventricles, although, again, as in cor pulmonale, no altered hemodynamic parameters of the left ventricle have been detected.F"!" Evidence is accumulating that a chronic elevation in plasma epinephrine concentration is a major contributing event in myocardial hypertrophy. We 2 lT- 22 reported
previously that. the plasma epinephrine concentration remained markedly elevated during left ventricular hypertrophy in dogs in response to aortic constriction. Ablation of the endocrine source of epinephrine through denervation of the adrenal medulla resulted in atrophy of the left ventricle in the presence of continued cardiac overload. 23 Further, the exogenous administration of epinephrine or other ~-adrenergic agonists resulted in both right and left ventricular hypertrophy. 24-27 In this paper, we report that after 30 days of volume or pressure overload to the right ventricle, both right and left ventricular hypertrophy occurred. The extent 0 hypertrophy was correlated positively with the elevation in plasma epinephrine and was not consistently related to alterations in hemodynamic parameters such as ventricular end-diastolic pressure. Methods
From the Departments of Surgery and Pharmacology, University of Arizona Health Sciences Center, Tucson, Ariz. Read at the Sixty-second Annual Meeting of The American Association for Thoracic Surgery, Phoenix, Ariz., May 3-5,1982. Address for reprints: Diane H. Russell, Ph.D., Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Ariz. 85724.
A total of 55 adult mongrel dogs, male or female, 12 to 25 kg, preconditioned to kennel environment and free of microfilaria, were used in these studies. A Swan-Ganz thermodilution catheter (7 Fr., No. 93132-7F, Edwards Laboratories, Inc., Santa Ana, Calif.) was inserted through a permanently implanted external jugular Cordis Introducer (8 Fr., No. 501-608, Cordis Corp., Miami, Fla.) to position the distal tip of the
© 1982 The C. V. Mosby Co.
543
0022-5223/82/100543+05$00.50/0
The Journal of
544 Larson et al.
Thoracic and Cardiovascular Surgery
Table I. Ventricular dry weight/body weight ratios following right ventricular overload Dry weight/body weight (mg/kg) ratio (mean ± SEM) Right ventricle
Control (n = 25) Silica (n = 10) Silica plus propranolol (n = 5) Monocrotaline (n = 5) Shunt (n = 10)
300 374 341 434 407
± 8 ± 15* ± 15 ± 3* ± 18*
Septum
269 304 285 298 295
± 6 ± 18t ± 44 ± 17 ± 18
Left ventricle
566 628 631 691 675
± 19 ± 31 ± 16 ± 43t ± 33t
Total
1135 1306 1257 1423 1376
± 28 ± 54t ± 18 ± 48* ± 60*
'Data differ from controls (p < 0.(01). tData differ from controls (p < 0.01).
Table II. Plasma epinephrine and norepinephrine levels Norepinephrine (pg/ml)
Control (n = 25) Silica infusion (n = 10) Silica plus propranolol (n = 5) Monocrotaline (n = 5) Graft-shunt (n = 10)
105 302 154 322 495
± 8 ± 53* ± 16t ± 7\' ± 110*
278 ± 35 399 ± 103 171 ± 92 322 ± 53 476 ± 96t
Legend: Data are expressed as the mean ± SEM. Each value represents a minimum of five different dog plasma samples collected prior to termination and measured in duplicate. -
'Data differ from controls (p < 0.(01). f Data differ from controls (p < 0.05).
catheter in the pulmonary artery. All hemodynamic measurements and blood samples were obtained with the Swan-Ganz catheter. Mixed venous plasma catecholamine concentrations were analyzed with the Cat-A-Kit (Upjohn Diagnostics, Kalamazoo, Mich.). The hemodynamic and catecholamine sampling studies were accomplished in a dimly illuminated, quiet room with the dogs standing in a Pavlov harness apparatus. The dogs were maintained on a 7 A.M. to 7 P.M. photoperiod and fed standard dog chow and water ad libitum. At the completion of the designated study period, plasma samples were collected for catecholamine determinations, and the animals were put to death by intravenous pentobarbital; the hearts were removed and dissected free of the atria, valves, and great vessels. The right and left ventricles were dissected from the septum, and wet tissue weights were obtained. Tissues were dried for 48 hours at 50° C and - 20 psi, and dry tissue weight/body weight ratios were calculated and expressed as milligrams per kilogram. A progressive right ventricular pressure overload was produced in 15 dogs for a 7 day study by daily intravenous injections of silica particles (diatomaceous
earth, grade 1, Sigma Chemical Co., St. Louis, Mo.) in a concentration of 12.5 mg/kg suspended in 50 ml of 0.9% sodium chloride with 2 units/ml of sodium heparin (The Upjohn Company, Kalamazoo, Mich.). Five dogs in this group also were administered propranolol hydrochloride, 15 mg/kg/day, orally (Ayerst Laboratories, New York, N. Y.). Another model of progressive right ventricular pressure overload (studied for 30 days) was induced by injection of the plant alkaloid monocrotaline in 3 intraperitoneal doses of 10 mg/kg on consecutive days, a total dose of 30 mg/kg per dog. Monocrotaline has been demonstrated to produce right ventricular hypertrophy in rodents because of toxininduced pulmonary artery fibrosis.f" Volume overload of the right ventricle was accomplished by surgically implanting a pulmonary artery outflow tract-to-right atrial shunt graft (16 mm inner diameter by 8 em; Microvel double velour, No. 081608, Meadox Medicals, Inc., Oakland, N. J.). Simultaneous shunt to cardiac output ratios were measured (Statham electromagnetic blood flow meter, Model 2204, Statham Instruments, Inc., Oxnard, Calif.) during the initial shunt placement and at the completion of the 30 day study. Control blood sampling and hemodynamic measurements were conducted 4 to 5 days after placement of the Cordis Introducer and Swan-Ganz catheter prior to sacrifice with pentobarbital. Statistical analysis. Data are expressed as the mean ± SEM. The level of significance was evaluated by Student's t test and p < 0.05 was considered statistically significant.
Results Increased right and left ventricular hypertrophy in right ventricular overload. All three models of right ventricular overload resulted in significant elevations in right ventricular mass (Table I). The monocrotaline toxin treatment produced right ventricular hy-
Volume 84
LVH and RVH in right ventricular overload
Number 4
545
October. 1982
900.r------------------..
Fig. 1. Relationship of right ventricular and left ventricular hypertrophy to body weight following right ventricular overload.
pertrophy to 145% of control, shunt to 136% of control, and silica to 125% of control. Left ventricular hypertrophy was significant in 30 day studies of monocrotaline pressure overload (122% of control) and graftshunt volume overload (120% of control) but not in the 7 day silica treatment model. In the silica model, propranolol administered concurrently with silica blocked the significant increase in right ventricular mass. Elevated plasma epinephrine in response to pressure and volume overload of the right ventricle. The plasma epinephrine concentration was elevated threefold in the silica infusion model and the monocrotaline group and over fourfold in the graft-shunt model (Table II). Norepinephrine was elevated significantly only in the graft-shunt model to less than twofold of control (p < 0.05). In all cases, there was a high positive correlation between right and left ventricular hypertrophy and the plasma epinephrine concentration but not with plasma norepinephrine concentration (Table III). Fig. 1 demonstrates the high positive correlation between the left and right ventricular dry weight/body weight ratio (r = 0.758; P < 0.00001). Hemodynamic parameters. The hemodynamic measurements obtained in these conscious, unsedated dog models demonstrated that right ventricular enddiastolic pressure correlated with plasma epinephrine (r = 0.873; p < 0.001) and with ventricular dry
Table III. Correlation between ventricular dry weight to body weight ratios and plasma catecholamine concentrations (pg/ml) during right ventricular overload
I
Right ventricle vs. epinephrine Left ventricle vs. epinephrine Right ventricle vs. norepinephrine Left ventricle vs. norepinephrine
r Value
p Value
r = 0.821 r = 0.700
p < 0.000 P < 0.000 P < 0.008 p < 0.137
r = 0.473
r = 0.238
Legend: A pool of all experimental groups was analyzed using the Statistical
Package for Social Science.
weight/body weight ratios (r = 0.882; P < 0.001). In these models of right ventricular overload, the indirect index of left ventricular end-diastolic pressure, the pulmonary artery wedge pressure, did not correlate with plasma epinephrine levels or with ventricular dry weight/body weight ratios (Table IV). There was no consistent correlation between plasma epinephrine levels and heart rate, cardiac index, right ventricular stroke work index, or pulmonary vascular resistance. In the propranolol-treated dogs, the right ventricular end-diastolic pressure did not correlate to myocardial mass or plasma epinephrine release. In the silica pressure-overload model, propranolol administration did not have a direct effect on hemodynamic parame-
The Journal of Thoracic and Cardiovascular Surgery
546 Larson et al.
Table IV. Comparative preload measurements of the right and left ventricles Il'-R-V-E-V-P--.------PAW
Group ________ ...J~I
Control Silica Silica plus propranolol Monocrotaline Shunt
(mm Hg)
25 10 5 5 10
1.6 3.8 6.3 6.8 8.1
± ± ± ± ±
0.4 0.7* 0.9* 0.8* 1.4*
(mm Hg)
4.96 4.10 3.33 3.87 4.29
± ± ± ± ±
0.52 0.64 0.83 1.30 0.47
Legend: RVEDP. Right ventricular end-diastolic pressure. PAW, Pulmonary artery wedge pressure.
*p < 0.001.
ters except to decrease the heart rate and to increase the stroke volume index. Discussion
Plasma epinephrine concentration was correlated to the increment in myocardial mass irrespective of any alterations in hemodynamic parameters. We have demonstrated this relationship after increased pressure load to the left ventricle and after either pressure or volume overload to the right ventricle; in all cases, there was a highly significant positive correlation between the plasma epinephrine concentration and the extent of ventricular hypertrophy. 20-22 That the ~-adrenergic antagonist propranolol attenuates myocardial growth in the silica pressure-overload model may be related to (I) selective ~-receptor blockade of the myocardium and/or (2) decreased release of epinephrine from the adrenal medulla. In previous studies, total ablation of the endogenous source of epinephrine by denervation of the adrenal medulla inhibited myocardial growth in response to ventricular pressure overload.F' We suggest that cardiac overload, caused by either increased volume or pressure load, activates the sympathetically mediated release of epinephrine from the adrenal medulla. The resulting increased concentration of plasma epinephrine through its ~-adrenergic activity regulates cardiac hypertrophy. In the fetal murine heart, we29, 30 demonstrated the induction of ornithine decarboxylase, a growth marker enzyme, by epinephrine and its inhibition by propranolol administration. We31 further characterized the specific myocardial receptor in the fetal murine heart model coupled to increased ornithine decarboxylase activity as ~2 in nature. Baker and Potter" have suggested that most myocardial ~-receptors are located on the external sarcolemma rather than at the synapses, and that only plasma epinephrine concentration achieves the K, value required to activate the myocardial recep-
tors. Only in extreme conditions may norepinephrine approach the Kd value of the sarcolemmal ~-receptor for activation. These studies add further evidence to support hormonal regulation of cardiac hypertrophy by epinephrine through ~2-adrenergic stimulation. Terbutaline, a specific ~2-agonist, administered to dogs also resulted in marked cardiac hypertrophy and was blocked by a ~2-antagonist.33 Although left ventricular hypertrophy has been described at autopsy in patients with cor pulmonale, until now the cause has remained unknown. Studies have reported up to 86% of patients with cor pulmonale secondary to chronic obstructive pulmonary disease have hypertrophy of both the right and left ventricles. 34 Other studies demonstrated that patients with nonobstructive pulmonary disease such as emphysema or chronic bronchitis have both right and left ventricular hypertrophy." 4,6 We now suggest that both right and left ventricular hypertrophy may be due to chronically elevated plasma epinephrine levels. In summary, stress, such as ventricular overload, cor pulmonale, chronic obstructive pulmonary disease, or upper airway obstruction, appears sufficient to produce a sympathetically mediated release of medullary epinephrine which mediates both right and left ventricular hypertrophy in a dose-dependent manner.
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REFERENCES Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56-64, 1975 Rao BS, Cohn KE, Eldridge FL, Hancock EW: Left ventricular failure secondary to chronic pulmonary disease. Am J Med 45:229-241, 1968 Murphy ML, Adamson J, Hutcheson F: Left ventricular hypertrophy in patients with chronic bronchitis and emphysema. Ann Intern Med 81:307-313, 1974 Kountz WB, Alexander HL, Prinzmetal M: The heart in emphysema. Am Heart J 11: 163-172, 1936 Michelson N: Bilateral ventricular hypertrophy due to chronic pulmonary disease. Chest 38:435-446, 1960 Fluck DC, Chandrasekar RG, Gardner FV: Left ventricular hypertrophy in chronic bronchitis. Br Heart J 28:9297, 1966 Altschule MD: Cor pulmonale. A disease of the whole heart. Chest 41:398-403, 1962 Baum GL, Schwartz A, Llamas R, Castillo C: Left ventricular function in chronic obstructive lung disease. N Engl J Med 285:361-365, 1971 Burrows B, Kettel LJ, Niden AH, Rabinowitz M, Diener CF: Patterns of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med 286:912-918, 1972 Bahler RC: Assessment of left ventricular function in
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chronic obstructive pulmonary disease. Chest 68: 132133, 1975 11 Unger K, Shaw D, Karliner JS, Crawford M, O'Rourke RA, Moser KM: Evaluation of left ventricular performance in acutely ill patients with chronic obstructive lung disease. Chest 68:135-142, 1975 12 Christianson LC, Shah A, Fisher VJ: Quantitative left ventricular cineangiography in patients with chronic obstructive pulmonary disease. Am J Med 66:399-404, 1979 13 Steele P, Ellis JH, Van Dyke D, Sutton F, Creagh E, Davies H: Left ventricular ejection fraction in severe chronic obstructive airways disease. Am J Med 59:21-28, 1975 14 Williams JF, Childress RH, Boyd OL, Higgs LM, Behnke RH: Left ventricular function in patients with chronic obstructive pulmonary disease. J Clin Invest 47:1143-1153,1968 15 Kline LE, Crawford MH, MacDonald WJ, Schelbert H, O'Rourke RA, Moser KM: Noninvasive assessment of left ventricular performance in patients with chronic obstructive pulmonary disease. Chest 72:558-570, 1977 16 Kachel RG: Left ventricular function in chronic obstructive pulmonary disease. Chest 74:286-290, 1978 17 Buccino RA, Harris E, Spann JF, Sonnenblick EH: Response of myocardial connective tissue to development of experimental hypertrophy. Am J Physiol 216:425-428, 1969 18 Pool PE, Spann JF, Buccino RA, Sonnenblick EH, Braunwald E: Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure. Circ Res 21:365373, 1967 19 Chidsey CA, Kaiser GA, Sonnenblick EH, Spann JF, Braunwald E: Cardiac norepinephrine stores in experimental heart failure in the dog. J Clin Invest 43:23862393, 1964 20 Womble JR, Haddox MK, Russell DH: Epinephrine elevation in plasma parallels canine cardiac hypertrophy. Life Sci 23:1951-1958,1978 21 Larson DF, Womble JR, Copeland JG, Huxtable RJ, Russell DH: Plasma epinephrine levels predict right ventricular hypertrophy. Fed Proc 40: 2892, 1981 22 Larson DF, Womble JR, Copeland JG, Russell DH: Epinephrine regulates compensatory right and left ventricular hypertrophy. J Mol Cell Cardiol 13:48, 1981
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