Several studies have demonstrated that left ventricular

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1 Differences in Left Ventricular Structural and Functional Changes Between Pheochromocytoma and Essential Hypertension Role of Elevated Circulating Catecholamines Fetnat M. Fouad-Tarazi, Mitsuhide Imamura, Emmanuel L Bravo, Gianpaolo Rossi Hassan K. Nagi, Wu-Wei Lin, Michael Cressman, and Pierre Wicker Experimental findings suggest that catecholamines increase protein synthesis and play a role in cardiac hypertrophy. We hypothesize that elevated circulating plasma catecholamines in pheochromocytoma influence cardiac structural and functional remodeling. We compared 15 patients with surgically proven pheochromocytoma and 15 with untreated essential hypertension; we matched the patients for age, sex, body surface area, and blood pressure (BP) levels. Left ventricular hypertrophy (LVH) was identified by M-mode echocardiography in six patients with pheochromocytoma and in four with essential hypertension. Among both groups there were no differences in cardiac structure, no correlation between left ventricular mass and BP, no significant differences in mitral E-F slope, no correlation between either plasma norepinephrine or plasma epinephrine levels, and no differences in the left ventricular structural indices measured. In the pheochromocytoma group, left ventricular end systolic stress and end systolic diameter were significantly lower and left ventricular percent fractional shortening was higher. Plasma norepinephrine levels were higher in the pheochromocytoma group, but did not differ among patients of that group with and without LVH. We conclude that in both pheochromocytoma and essential hypertension, only a subset of patients develop evidence of LVH, and that in pheochromocytoma, the elevation of circulating plasma catecholamines is not necessarily associated with LVH. These results indicate that factors other than catecholamines and BP determine the development of LVH in pheochromocytoma. Am J Hypertens 1992;5: KEY WORDS: Left ventricular hypertrophy, plasma catecholamines, pheochromocytoma, essential hypertension. Several studies have demonstrated that left ventricular hypertrophy (LVH) cannot be attributed solely to pressure overload in the spontaneously hypertensive rat and in essential hypertension in humans. 1-8 Nonhemodynamic factors such as catecholamines and angiotensin compounds have been im- From The Cleveland Clinic Foundation, Cleveland, Ohio Address correspondence and reprint requests to Fetnat M. Fouad- Tarazi,MD. Department of Heart and Hypertension Research, The Cleveland Clinic Foundation, One Clinic Center FF10-2b, 9500 Euclid Avenue, Cleveland, OH plicated in the hypertrophy process of the left ventricle in hypertension The "catecholamine hypothesis" of hypertensive cardiac hypertrophy has received considerable experimental support, 6 ' 7 ' 14 ' 15 ' 18 " 22 but it is difficult to prove the applicability of this hypothesis to patients. Our study uses the "experiment of nature" provided by pheochromocytoma to determine whether chronic increase in catecholamine production would lead to a significantly greater degree of LVH than is expected for the level of blood pressure (BP). To assess this hypothesis, we reviewed the echocardiographic history and indices of excessive catecholamine production in 15 patients

2 with surgically proven pheochromocytoma and 15 patients with untreated essential hypertension matched for age, sex, body surface area, and BP levels. MATERIALS AND METHODS Patients We compared 15 patients with surgically proven pheochromocytoma (Table 1) with 15 untreated essential hypertensive patients matched individually (paired as close as possible) for age, sex, body surface area, and BP levels. Each patient's heart was examined by M-mode echocardiography obtained under 2-dimensional echocardiographic monitoring. Techniques M-Mode Echocardiography M-Mode echocardiography was recorded under two-dimensional echocardiographic monitoring. We obtained ventricular cavity dimensions at the level of the tip of the mitral valve and calculated measurements according to the criteria of the American Society of Echocardiography. 23 We used the Devereux correction method 24,25 to calculate left ventricular mass and normalized the left ventricular mass for body surface area. Left ventricular meridional end-systolic wall stress was calculated by a method described by Wilson et al. 26 Blood pressure was obtained by a mercury sphygmomanometer immediately before and after the echocardiographic session. Left ventricular hypertrophy was defined as left ventricular mass index above the published upper limits of normal using the Devereux method (> 110 g/m 2 for women and > 134 g/m 2 for men). Blood Pressure Blood pressure was obtained noninvasively by mercury sphygmomanometer with the subject in the supine position. We used the disappearance of arterial sounds (Phase V) as a measure of diastolic blood pressure; we took an average of the readings for analysis of the data. Moreover, we evaluated patients' BP obtained within 3 months before the echocardiographic session. This time limit was adopted because patients with pheochromocytoma were subjected to surgery as soon as the diagnosis was confirmed; the work-up and decision for surgery were normally done within 3 months. These BP were not used to calculate derived echocardiographic indices but were examined to identify patients with sustained or labile hypertension. Heart Rate Heart rate was calculated from the electrocardiographic tracing recorded during the echocardiographic imaging. Plasma Catecholamine We obtained blood samples for plasma catecholamine determination after the patients rested quietly for 15 min in the supine position. We used an indwelling catheter inserted at least 15 min before sampling blood. Plasma catcholamines were measured by a radioenzymatic assay. 27 Antihypertensive Therapy As illustrated in Table 2, all essential hypertensive patients were untreated at the time of echocardiography. However, medications could not be discontinued in six pheochromocytomic patients, TABLE 1. ANATOMICAL SITE OF CATECHOLAMINE-PRODUCING TUMOR, AND CATECHOLAMINE LEVELS IN PHEOCHROMOCYTOMA PATIENTS Plasma Urinary Subject NE/E NMN and MN Number Anatomical Site (pg/ml) (mg/24 h) 1 Left adrenal 5551/ Extraadrenal (left periaortic infrarenal paraganglioma) 4926/ Extraadrenal (urinary bladder) 2073/ Extraadrenal (hepatic) 13,034/ Left adrenal 1673/ Bilateral adrenal 1040/ Right adrenal 3577/ Right adrenal 299/ Right adrenal 5975/ Bilateral adrenal (MEA II, Sipple syndrome) 1163/ Bilateral adrenal (Von Hippel Lindau) 511/ Bilateral adrenal 933/ Right adrenal 926/ Extraadrenal (malignant left periaortic chromaffin paraganglioma) 4051/ Left adrenal 488/ Upper limits of normal values: plasma norepinephrine (NE): < 402 pg/ml; plasma epinephrine (Ε): ^ 78 pg/mh; urinary normetanephrine (NMN) and metanephrine (MN): < 1.3 mg/24 h).

3 TABLE 2. CLINICAL PROFILE OF STUDY POPULATION Average of Blood Subject Age BSA Casual Office Pressure Rx Number Diagnosis (year) Sex (m 2 ) Blood Pressure During ECHO During ECHO 1 Pheo-LVH 39 Μ / /100 Nifedipine 2 Pheo-LVH 26 F / /110 Propranolol + Dibenzylene 3 Pheo-LVH 51 F /97 200/ Pheo-LVH 55 F /98 220/102 0 (Procardia, prn) 5 Pheo-LVH 51 F /93 141/95 Prazosin 6 Pheo 21 F / / Pheo 35 Μ / /102 Verapamil 8 Pheo 28 Μ /72 108/84 0 (121/56-140/92) 9 Pheo 23 F / / Pheo-LVH 51 F /72 112/76 0 (118/70-140/74) 11 Pheo 26 Μ /60 150/ Pheo 39 F /91 140/ Pheo 34 Μ / / Pheo 39 Μ / /106 Diuril 15 Pheo 62 F /87 152/ EH-LVH 57 F /94 160/ EH-LVH 57 F / / EH-LVH 35 Μ /93 136/ EH-LVH 18 Μ / EH 24 F /70 128/ EH 35 Μ /95 140/ EH 57 F /87 180/ EH 20 Μ /93 137/ EH 37 F /90 157/ EH 43 Μ /95 140/ EH 40 F /94 146/ EH 46 F /91 146/ EH 31 F / / EH 58 F /91 194/ EH 34 Μ / /115 0 ECHO = echocardiogram, EH = essential hypertension, Pheo = pheochromocytoma, Rx = antihypertensive therapy, LVH = left ventricular hypertrophy, BSA = body surface area. The range of blood pressures is described for the two pheochromocytoma subjects who had otherwise normal blood pressure levels. Baseline Characteristics and Blood Pressure Levels Baseline characteristics of patients with essential hypertension and pheochromocytoma are illustrated in Tables 2 and 3. Among the 15 pheochromocytomic patients, nine had sustained hypertension, five had labile BP, and one was normotensive throughout follow-up (Patient 10). Plasma norepinephrine and epinephrine levels were significantly higher in patients with pheochromocytoma compared with those with essential hypertension. Differences between the two pheochromocytoma groups were not significant although averwhose BP was still in the hypertensive range despite treatment; the medications given these patients are shown in Table 2. Four of these patients had LVH as demonstrated by echocardiography. STATISTICAL ANALYSIS All data are presented as mean ± SD. Analysis of variance followed by Newman-Keuls test was used to compare values between groups. 28 We analyzed data on norepinephrine and epinephrine by Kruskal-Wallis ANOVA by ranks and by Mann-Whitney test because of nonnormal distribution. The correlation coefficient between the two variables was calculated by Pearson's method or Spearman's rank order method. Differences between groups were considered significant if Ρ <.05. RESULTS

4 TABLE 3. BASELINE CHARACTERISTICS IN STUDY GROUPS Essential Hypertension Pheochromocytoma Ν Age (year) 39.5 ± ± 13 NS BW (kg) 79.6 ± ± 15 NS SBP (mm Hg) 156 ± ± 32 NS DBP (mm Hg) 102 ±10 97± 11 NS HR (beats per minute) 66 ± ±20.08 [69] [71] NE (pg/ml) 271 ± ± [217] [1873] Ε (pg/ml) 68 ± ± [47] [102] NE + Ε (pg/ml) 339 ± ± [266] [1946] BW = body weight, SBP = systolic blood pressure, DBP = diastolic blood pressure, HR = heart rate, NE = plasma norepinephrine, Ε = plasma epinephrine. [ ] = median in nonnormal distributions. Rank Sum Test used in nonnormal distributions. Mean ± SD. age values tended to be higher in pheochromocytoma patients with LVH compared with those without LVH (Table 3). Left Ventricular Structural and Functional Indices According to the definition discussed above, six (40%) pheochromocytoma patients were found to have hypertrophied left ventricles and nine had normal left ventricles (Figure 1). In essential hypertensive patients, 4 patients (26.7%) had hypertrophied left ventricles and 11 had normal left ventricles (P =.7 by Fisher exact test, ie, NS). Left ventricular mass index was not significantly different between the pheochromocytoma group was a whole and the essential hypertension group as a whole (108.5 ± 32 ν ± 19 g/m 2 ). Table 4 shows echocardiographic data on the 15 essential hypertensive patients and the 15 pheochromocytomic patients. There were no structural differences between essential hypertensive and pheochromocytoma patients. There was no correlation between left ventricular mass and mean arterial BP in both essential hypertensive and pheochromocytoma patients (r = 0.10 and 0.46, respectively, Ρ = NS for both). Moreover, in pheochromocytoma patients, there was no relationship between left ventricular mass and the time course of BP (sustained hypertension, labile hypertension, or normotension). There was no correlation between either plasma norepinephrine or plasma epinephrine and any of the left ventricular structural indices measured. It should be mentioned, however, that plasma catecholamine levels tended to be slightly higher in pheochromocytoma patients with LVH compared with pheochromocytoma patients without LVH (4737 ± 4445 pg/ml ν 2108 ± 2134 for plasma norepinephrine, and 211 zt 244 ν 115 ± 87 for plasma epinephrine), but the differences between the two groups were not statistically significant. In essential hypertensive patients, these values were 230 ± 109 pg/ml ν 282 ± 199, and 63 ± 25 ν 69 ± 94 respectively, Ρ = NS for both. In the subset of pheochromocytoma patients in whom urinary catecholamines were measured, four out of five with LVH had higher values of urinary metanephrines and normetanephrines compared with the pheochromocytoma group without LVH. Left ventricular end systolic stress and left ventricular end systolic diameter were significantly lower in patients with pheochromocytoma. Consequently, the left ventricular systolic functional index, percent fractional shortening, was enhanced in pheochromocytoma compared with essential hypertension. On the other hand, mitral E-F slope (an index of left ventricular rapid filling rate) was not significantly different among groups. There was no correlation between either plasma norepinephrine or plasma epinephrine and any of the left ventricular functional indices measured. DISCUSSION In pheochromocytoma, circulating plasma catecholamine levels may be elevated for prolonged periods. Since the mammalian myocardium is rich in sympathetic postganglionic fibers with high norepinephrine affinity, 17 it would be tempting to postulate that chronically elevated circulating plasma norepinephrine in pheochromocytoma patients produce structural and functional remodeling in the heart in excess of that ob-

5 FIGURE 1. Individual values of left ventricular mass index (LVMI) in patients with essential hypertension and patients with pheochromocytoma. Left ventricular mass was calculated by cube formula, then Devereux correction factor was applied. 11 LVMI = left ventricular mass index, LVH = left ventricular hypertrophy, female, Ο male. s CP t LVMI CALCULATED BY DEVEREUX METHOD Ο ο 8 Ο e TABLE 4. ECHOCARDIOGRAPHIC FINDINGS ο οο ο : EH NOLVH EH LVH PHEO NOLVH PHEO LVH served in essential hypertensive patients matched for age, sex, body surface area, and BP levels. However, analysis of our data did not support this hypothesis. Thus, echocardiographic evidence of LVH was noted only in six of our 15 pheochromocytoma patients and in four of the 15 essential hypertensive patients (40% ν 26.7%, Ρ = NS). Our findings on pheochromocytoma patients are in agreement with previous reports by Shub et al 29 that the majority of patients with pheochromocytoma (80%) have normal left ventricular mass. The time course also showed no direct relationship to left ventricular mass in our patients with pheochromocytoma. These findings suggest that neither plasma catecholamine nor BP per se, is the sole factor influencing the development of LVH in hypertension. The lack of evidence of LVH in nine of the 15 pheochromocytoma patients raises an additional point. Since the group without LVH also had elevated BP and plasma norepinephrine, it is possible that other factors are important in the development of LVH, such as duration of hypertension, the level of BP during normal activity, 1 the volume load pumped by the heart, 30 and heredity. 31 The dissociation between left ventricular mass and circulating plasma catecholamines in pheochromocytoma suggest that the local delivery of catecholamines to receptors may be more important than their passage through the circulation to induce LVH. However, this mechanism did not seem to be important in our patients as left ventricular systolic function was significantly enhanced in pheochromocytoma patients, compared with essen- Essential Hypertension Pheochromocytoma Ρ Ν LVMI-D (g/m 2 ) 107 ± ±32 NS PWd (cm) 1.01 ± ±0.21 NS SWd (cm) 1.18 ± ±0.29 NS EDD (cm) 4.77 ± ± 0.66 NS ESD (cm) 3.23 ± ± ESS (dynes/cm 2 ) 76 ±20 58 ± FS (%) 32 ±5 41 ±8.001 Μ Slope (cm/sec) 12 ± ±2.9 NS LVMI-D = left ventricular mass index Devereux correction, PWd = diastolic posterior wall thickness, SWd = diastolic septal wall thickness, EDD = end diastolic diameter of left ventricle, ESD end systolic diameter of left ventricle, ESS = end systolic stress, FS = fractional shortening, Μ Slope = mitral E-F slope. Mean ± SD.

6 tially hypertensive patients, which suggests that plasma catecholamine interacts with receptors. Moreover, the correlation between plasma catecholamines or BP and left ventricular mass may have been weakened by the fluctuations of BP and plasma catecholamines that can occur in patients with pheochromocytoma. Perhaps catcholamines, as well as BP, were not elevated for a sufficient time to produce severe or deleterious cardiac effects in our patients. It is difficult to determine whether BP or catecholamines were continuously elevated for more than 3 months in our patients. The secretion of catecholamines from a pheochromocytoma can be highly discontinuous. Given the short half-life of catecholamines in plasma, plasma samples at any single time may not coincide with a burst of excess catecholamine secretion. This is reflected in the high standard deviations of catecholamine measurements in our pheochromocytoma patients, for whom statistical significance was not achieved, despite a change greater than a factor of two in the mean plasma norepinephrine concentration between patients with and without LVH. Despite various reports, there was no evidence of dynamic left ventricular outflow tract obstruction in our pheochromocytoma patients. 32,33 Also, previous reports had recognized post mortem cardiac anatomic and functional abnormalities in approximately 92% of pheochromocytoma patients who had clinical evidence of myocardial hypertrophy 34,35 ; however, we did not observe left ventricular dilation or heart failure in our patients compared with these and other findings. 31,36-39 Indeed, our pheochromocytoma patients, both with or without LVH, had evidence of normal or mildly enhanced systolic cardiac performance. This lack of cardiac damage in our patients may have resulted from the BP in these patients being better controlled than the BP in patients whose autopsies showed pheochromocytoma. A performance of the most valid correlation of these variables would require constant monitoring of both BP and plasma catecholamines in patients with pheochromocytoma who are not receiving treatment; this could have been assessed by 24 h BP and 24 h urinary catecholamine measurements. Indeed, it is interesting that in our pheochromocytoma patients in whom urinary metanephrines were measured, four of five patients with LVH had higher values than patients without LVH. Unfortunately, we did not record 24 h ambulatory BP in our patients. Another limitation to this study should be mentioned. It is not possible to completely eliminate any effect which antihypertensive medication may have had on pheochromocytoma patients receiving therapy. 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