Robert C. Tarazi

Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Ventricular weight in spontaneously hypertensive rats (F26 generation, Okamoto-Aoki strain) was significantly higher (P < 0.001) than that in body weight-matched American Wistar and Kyoto-Wistar normotensive rats, not only among older groups of rats but also among younger groups that had not developed significant hypertension. Deoxyribonucleic acid (DNA) concentration in ventricular muscle was not different from normal in the youngest group (P < 0.4) but was significantly reduced in the older spontaneously hypertensive rats (P < 0.01). Plasma renin activity was significantly increased in younger spontaneously hypertensive rats before the development of established hypertension; moreover, ventricular weight and plasma renin activity were significantly correlated in younger rats (r = 0.788, P < 0.005 for all rats, r = 0.644, P < 0.01 for spontaneously hypertensive rats). Antihypertensive therapy with either α-methyldopa or hydralazine reduced blood pressure, especially in hypertensive rats; however, ventricular weight was reduced by methyldopa (P < 0.01) but not by hydralazine. Plasma renin activity was reduced by methyldopa but increased by hydralazine (P < 0.01). DNA concentration was reversed toward normal by methyldopa but not by hydralazine. Similar results were obtained when methyldopa and hydralazine were given to younger rats to prevent hypertension. The changes in ventricular weight with the onset of hypertension and with its reversal or its prevention suggest that blood pressure might not be the sole factor contributing to cardiac hypertrophy in the spontaneously hypertensive rat and that the renin-angiotensin system might play a permissive role enhancing myocardial hypertrophy.

Beta adrenergic blockade in hypertension: Practical and theoretical implications of long-term hemodynamic variations☆

The effectiveness of propranolol, used alone, in reducing arterial pressure was reevaluated in 52 hypertensive patients (42 with essential and 10 with renovascular hypertension) with special regard to the hemodynamic basis for patient selection and the relation of variations in cardiac output to control of blood pressure. Repeated hemodynamic studies were performed before and during chronic treatment with propranolol, and in all the efficacy of beta adrenergic blockade was demonstrated by inhibition of chronotropic response to infusion of isoproterenol. Four patients discontinued propranolol because of side effects; among the rest, arterial pressure was reduced in 26 and unchanged in 22. There was no difference in responsiveness between subjects with essential and renovascular hypertension. Arterial pressure responses could not be predicted from hemodynamic values before treatment; although increased cardiac output was more frequent among responders than among nonresponders (59 vs. 37 percent), group averages were not significantly different. Treatment reduced cardiac output in both groups, so that effect on arterial pressure was related to changes in total peripheral resistance (r = 0.737, P <0.001) not to changes in output (r = 0.067). Thus, the hypertensive effect of propranolol seemed to imply a long-term adaptation of peripheral resistance to chronic reduction of output. The prolonged follow-up and repeat studies allowed a hemodynamic characterization of the occasional hypertensive responses to office visits and investigative procedures. These transient responses were not prevented during treatment although their hemodynamic basis was altered so that they were always related to increased peripheral resistance. Used in combination with other antihypertensive agents (12 patients), administration of propranolol nearly always controlled any tachycardia due to or persisting despite the other drugs and often improved the response of blood pressure.

Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function

Initial studies of diastolic cardiac function in hypertension demonstrated that slowing of the maximal rate of left ventricular filling occurred before alterations in either ejection fraction or cardiac output. The present study was undertaken to determine: 1) the relation between hypertension, increased left ventricular mass and impaired left ventricular filling, and 2) the correlation between abnormalities in left ventricular diastolic function and its systolic performance. Eleven normal subjects (Group 1), 5 hypertensive patients without evidence of left ventricular hypertrophy (Group 2) and 18 hypertensive patients with increased left ventricular mass by echocardiography (Group 3) were studied by M-mode echocardiography, radionuclide (technetium-99m human serum albumin) first pass technique and gated blood pool scintigraphy. Indexes of systolic function (ejection fraction, maximal rate of ejection and percent left ventricular shortening) were essentially similar in hypertensive and normotensive subjects. No correlation was found between systolic blood pressure and left ventricular mass (r = 0.20, not significant). Maximal rate of left ventricular filling (P dV/dt) and fast filling fraction decreased progressively from Group 1 to Group 3 (2.36 +/- 0.4 [mean +/- standard deviation], 2.17 +/- 0.3 and 1.97 +/- 0.4 s-1, respectively, for P dV/dt and 46 +/- 7, 48 +/- 9 and 38 +/- 11%, respectively, for fast filling fraction); the difference from values in normal subjects reached statistical significance in hypertensive patients with left ventricular hypertrophy. Left ventricular maximal filling rate correlated inversely with left ventricular mass and left ventricular end-systolic diameter (r = -0.74), but positively with left ventricular fractional shortening and ejection fraction (r = 0.70).(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating and urinary catecholamines in pheochromocytoma. Diagnostic and pathophysiologic implications.

Three biochemical tests for the diagnosis of pheochromocytoma were evaluated in 24 patients with proved tumors and 40 patients whose clinical picture was suspect but who had no evidence of the disease. Measurement of resting, supine plasma catecholamines (by radioenzymatic assay) was more useful than either 24-hour urinary vanillylmandelic acid (VMA) or metanephrines or both. In only one of 23 patients with pheochromocytoma were plasma catecholamines within the range of those in patients without pheochromocytoma, as compared with urinary VMA in 11 of 22, urinary metanephrines in five of 22 and both metabolites in three of 22. These studies reaffirm the value of plasma catecholamines in the diagnosis of pheochromocytoma and indicate that urinary catecholamine metabolites are less useful. The poor correlation between the height of arterial pressure and circulating levels of catecholamines suggests that the regulation of arterial pressure in pheochromocytoma is complex.

Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy

Increased arterial pressure is obviously the major stimulus to cardiac hypertrophy in hypertension. However, different studies suggest that in addition to the pressure load, other factors could play participating roles in determining the degree of ventricular hypertrophy in response to the hypertensive disease as well as the degree of its reversal after control of arterial pressure. These other mechanisms include genetic factors and concimitant processes such as aging and the presence of cardiomyopathy or other disease. Two neurohumoral influences, namely, the adrenergic and the renin-angiotensin systems, may also participate, and the early evidence supporting these possible contributing factors is cited. Further studies are needed to determine the relative importance of each of these factors in different types of hypertension and in their response to different modes of antihypertensive therapy.

Clonidine-suppression test: a useful aid in the diagnosis of pheochromocytoma.

THE diagnosis of pheochromocytoma is considered secure when typical signs and symptoms (e.g., hypertension, sweating, palpitation, and headaches) are associated with unequivocal biochemical evidenc...

The Paradox of Beta-Adrenergic Blockade in Hypertension

The effects of long-term treatment with propranolol, a beta-adrenergic blocking drug, were determined in 19 hypertensive patients (five with renal arterial disease, two with renal parenchymal disease, and 12 with essential hypertension) whose vascular disease was of mild to moderate severity. The drug reduced arterial pressure in 16 patients during 32 weeks of treatment (average); daily dose was 180 mg (average). No side effects required discontinuance of treatment. Orthostatic hypotension did not occur, an unusual finding for an antihypertensive drug which acts to inhibit autonomic neural function. In seven patients, hemodynamic studies, performed during treatment (after 10 months, average), confirmed reduction of arterial pressure and heart rate, and demonstrated associated diminution of cardiac output and increased peripheral resistance.

Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa: Lack of association with blood pressure control

Ten patients with essential hypertension and left ventricular hypertrophy were treated with relatively small doses of methyldopa (500 to 750 mg/day) added to long-term diuretic therapy. Sequential M mode echocardiography showed significant reduction in left ventricular mass 36 weeks after addition of methyldopa in four patients (359 +/- 77 [standard error of the mean] to 235 +/- 63 g) although blood pressure was not significantly altered by the added treatment. In three of these patients, reduction of left ventricular mass was observed as early as 12 weeks of treatment (384 to 262 g). Neither left ventricular mass to left ventricular volume ratio nor fractional shortening was significantly altered by reduction in left ventricular mass (3.21 +/- 0.26 to 2.74 +/- 0.24 and 0.42 +/- 0.03 to 0.44 +/- 0.02, respectively). There was no apparent relation in these patients between changes in blood pressure and changes in left ventricular mass. Thus, reversal of cardiac hypertrophy with antihypertensive treatment is possible in human beings; however, it seems to depend on other factors besides blood pressure control.

Regression of left ventricular hypertrophy from systemic hypertension by enalapril

Reversal of left ventricular (LV) hypertrophy with medical therapy has been studied increasingly in patients with systemic hypertension. However, serial changes of LV function are not found during reversal of LV hypertrophy in hypertensive patients. Seven patients with LV hypertension were studied to evaluate serial changes of LV mass and function after the initiation of the new converting enzyme inhibitor MK-421. LV mass and function were determined serially at the end of a placebo period and at 5 days, 1 month, 3 months and 7 months after the initiation of MK-421, using both 2-dimensional (2-D) guided M-mode echocardiography and radionuclide techniques. All patients except 1 had LV hypertrophy and all had normal LV function (ejection fraction derived from gated blood pool method greater than 49%). There was an inverse relation between LV fractional shortening (percent FS) and end-systolic stress before medication (r = -0.81, p less than 0.05). LV mass decreased significantly at 3 months and at 7 months (-10%, p less than 0.05, and -12%, p less than 0.01, respectively) accompanied with persistent decrease of mean blood pressure, which occurred as early as 5 days after start of therapy (133 +/- 5 mm Hg at control, to 112 +/- 4 mm Hg at day 5). During reversal of LV hypertrophy, the inverse correlation between FS and end-systolic stress remained significant (r = -0.80 to -0.95, p less than 0.025 for all), with no difference from the placebo period and from this relation in the normal group. Moreover, percent FS, ejection fraction and stroke index remained unchanged. Thus, LV hypertrophy in patients with systemic hypertension can be reversed without deterioration of LV function. Moreover, overall LV function is likely to be determined by afterload even after reversal of LV hypertrophy.

Plasma Volume in Men with Essential Hypertension

Abstract Plasma volume (RISA) was measured in 37 men with essential hypertension uncomplicated by cardiac or renal failure, and results compared with values obtained in 20 normal male subjects. Body height was found to be a better reference index than weight for expressing results, but conclusions were identical whatever the frame of reference used. Plasma volume was diminished in hypertensive men. This decrease was greater the higher the diastolic pressure (r equal to -0.434; p less than 0.01), so that it was only evident in the patients with diastolic blood pressures over 105 mm of mercury. Plasma volume measured 19.4 ml per centimeter in normotensive, and 19.6 ml per centimeter in hypertensive men with diastolic pressure less than 105 mm of mercury, and 16.9 ml per centimeter in those with higher blood pressure (p less than 0.02). These findings contrast with reports of expanded plasma volume in primary aldosteronism and renoprival hypertension, and emphasize the importance of diagnostic grouping in st...