Jacques de Champlain

Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril.

OBJECTIVES This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation. BACKGROUND Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure. METHODS In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors. RESULTS By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations. CONCLUSIONS Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Enhanced superoxide anion formation in vascular tissues from spontaneously hypertensive and desoxycorticosterone acetate-salt hypertensive rats.

Objectives To investigate the basal and NADH-stimulated superoxide (⋅ O2−) production and inactivation by Cu/Zn superoxide dismutase (SOD) in aorta from spontaneously hypertensive rats (SHR) and from desoxycorticosterone acetate (DOCA)-salt hypertensive (DOCA-HT) rats. Methods Tissue ⋅ O2− levels were estimated with the lucigenin-enhanced chemiluminescence method in aorta and cultured smooth muscle cells (SMCs) from SHR and in aorta from DOCA-HT rats treated for 4 weeks. Results The basal aortic ⋅ O2− generation was increased by 135 and 100%, and the NADH stimulated ⋅ O2− production was also increased 37 and 22% in SHR and in DOCA-HT rats compared to their normotensive controls, respectively. Although no difference existed in blood pressure as well as in basal and in NADH stimulated ⋅ O2− production between Wistar–Kyoto (WKY) rats and SHR rats at age of 6 weeks, O2− production and blood pressure increased concomitantly in SHR aged 9 and 12 weeks. Basal and NADH-stimulated ⋅ O2− production, in cultured SMCs, was also 80 and 64% higher, respectively, in SHR compared to WKY rats. The NADH oxidase activity was found to be increased in aorta from both SHR and DOCA-HT rats but SOD activity was reduced only in aorta from DOCA-HT rats. Conclusions An enhanced ⋅ O2− formation resulting from an increased NADH oxidase activity was found in aorta from SHR and DOCA-HT rats. Cultured arterial SMCs from SHR also generated excessive ⋅ O2− formation under basal and stimulated conditions. The age-related increase in vascular ⋅ O2− formation in association with the rise in blood pressure in SHR suggests that the oxidative stress might contribute to the development of hypertension. NADH oxidase activity was greater in aorta of both hypertension models, but a decrease of Cu/Zn SOD activity could also contribute to the high level of aortic ⋅ O2− in DOCA-HT rats.

Regulation of Blood Pressure by Sympathetic Nerve Fibers and Adrenal Medulla in Normotensive and Hypertensive Rats

The respective roles of the sympathetic nerve fibers and adrenal medulla in the regulation of blood pressure and heart rate were studied in normotensive and hypertensive rats. Chemical sympathectomy alone, by treatment with 6-OH-DA, or bilateral adrenalectomy reduced blood pressure only slightly in normotensive animals. In animals made hypertensive with deoxycorticosterone (DOCA) and saline, each of these procedures reduced blood pressure to a greater extent than in normotensive animals, but the blood pressure remained at hypertensive levels. The combination of both procedures resulted in a greater fall in blood pressure than could have been predicted from individual effects, suggesting that the removal of one component of the sympathetic system can be compensated for by a hyperactivity of the remaining component. After chemical sympathectomy, adrenalectomy produced a rapid and marked fall in blood pressure in both normotensive and hypertensive animals and the blood pressure stabilized around 50 mm Hg within 1 hour after adrenalectomy. Since the basal blood pressure was identical in normotensive and hypertensive animals after removal of both components of the sympathetic system, this suggests that the most likely factor which would account for an elevated blood pressure in rats treated with DOCA and sodium is a synergic hyperactivity of the sympathetic fibers and adrenal medulla.

Activation of neurohumoral systems in postinfarction left ventricular dysfunction

OBJECTIVES This study was conducted to evaluate the degree of neurohumoral activation around the time of hospital discharge after myocardial infarction. BACKGROUND Because pharmacologic interventions that block the effects of neurohumoral activation improve the prognosis after infarction, we hypothesized that widespread neurohumoral activation persists in some patients until at least the time of hospital discharge and that the determinants of activation vary from one system to another. METHODS Five hundred nineteen patients in the Survival and Ventricular Enlargement Study (SAVE) had plasma neurohormones measured before randomization at a mean of 12 days after infarction. All patients had left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt heart failure. RESULTS Although all neurohormones except epinephrine were increased compared with values in age-matched control subjects, plasma norepinephrine (301 +/- 193 vs. 222 +/- 87 pg/ml, p < 0.001), renin activity (3.0 +/- 3.7 vs. 1.2 +/- 1.2 ng/ml per h, p < 0.001), arginine vasopressin (1.9 +/- 6.9 vs. 0.7 +/- 0.3 pg/ml, p < 0.001) and atrial natriuretic peptide (75 +/- 75 vs. 21 +/- 9 pg/ml, p < 0.001) values ranged from normal to very high, indicating a wide spectrum of neurohumoral activation. Activation of one system did not correlate with activation of another. The clinical and laboratory variables most closely associated with neurohumoral activation were Killip class, left ventricular ejection fraction, age and use of diuretic drugs. The association between neurohumoral activation and clinical and laboratory variables varied from one neurohormone to another. CONCLUSIONS Neurohumoral activation occurs in a significant proportion of patients at the time of hospital discharge after infarction. Which neurohormone is activated and which clinical and laboratory variables determine this activation vary from one neurohormone to another.

Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production

BACKGROUND The present study was designed to investigate whether the effects of dietary supplementation with alpha-lipoic acid could prevent the increase in mitochondrial superoxide production in the heart as well as the enhanced formation of advanced glycation end-products (AGE) that are associated with the development of hypertension and insulin resistance in chronically glucose-fed rats. METHODS Sprague Dawley rats were either given or not given a 10% D-glucose solution to drink during 4 weeks, combined either with a normal chow diet or with alpha-lipoic acid supplemented diet. The oxidative stress was evaluated by measuring the heart mitochondrial superoxide production using the lucigenin chemiluminescence method. The formation of AGE was also assessed in plasma and aorta. RESULTS Chronic administration of glucose resulted in a 29% increase in blood pressure, 30% increase in glycemia, 286% increase in insulinemia, and 408% increase in insulin resistance index. Chronic glucose feeding also resulted in a 22% greater mitochondrial superoxide anion production in heart and in an increase of 63% in AGE content in aorta. Increases in blood pressure, aorta AGE content and heart mitochondrial superoxide production were prevented in the rats fed glucose supplemented with lipoic acid. The simultaneous treatment with lipoic acid also attenuated the rise in insulin levels as well as in insulin resistance in the glucose fed rats. CONCLUSIONS These findings demonstrate that alpha-lipoic acid supplementation prevents development of hypertension and hyperglycemia, presumably through its antioxidative properties, as reflected by prevention of an increase in heart mitochondrial superoxide anion production and in AGE formation in the aorta of chronically glucose treated rats.

Relationship between Sodium Intake and Norepinephrine Storage during the Development of Experimental Hypertension

It has been reported that storage of norepinephrine by the sympathetic nervous system was decreased in rats made hypertensive by the administration of desoxycorticosterone trimethylacetate (DOCA) and sodium chloride. The present investigation indicated that the storage of norepinephrine was impaired at an early stage of treatment with DOCA and NaCl (1 week), and preceded the appearance of hypertension. The role of sodium and sympathetic activity, the two major factors suspected of contributing to the development of the abnormality in storage of norepinephrine, was studied in normotensive and hypertensive rats. The withdrawal of sodium from the diet of hypertensive rats for 2 weeks lowered the blood pressure to normotensive levels and simultaneously restored to normal the storage and binding capacity as well as the endogenous norepinephrine content of the sympathetic storage granules in the heart. Sodium restriction or depletion in normotensive rats caused a slight decrease in blood pressure and the retention of norepinephrine in the storage granules was increased. These findings suggested that the capacity of the sympathetic granules to bind and store norepinephrine was influenced by the state of sodium balance and showed that the capacity of storage could be correlated with the level of blood pressure. The finding that treatment with a long-acting ganglionic blocker could restore the blood pressure and the norepinephrine storage capacity in hypertensive animals to normal suggested a neurogenic component in the development of this form of hypertension.

Activation of neurohumoral systems following acute myocardial infarction

Previous studies have indicated that patients with an acute myocardial infarction have marked activation of all neurohumoral systems on admission to the hospital. This activation begins to subside within the first 72 hours so that by 7-10 days, all plasma neurohormones have returned to normal. The only documented exceptions were found to occur in patients with left ventricular dysfunction and overt heart failure, where both plasma renin activity and atrial natriuretic peptide were increased, and in patients with left ventricular dysfunction but no overt heart failure, where only atrial natriuretic peptide was increased. Although these studies suggest that neurohumoral activation rarely occurs at the time of hospital discharge, they were small and may have missed an important subgroup of patients with persistent neurohumoral activation. In the Survival and Ventricular Enlargement (SAVE) study, 522 patients had plasma neurohumoral levels measured at a mean of 12 days postinfarction. All SAVE patients had left ventricular dysfunction (left ventricular ejection fraction less than or equal to 40%), but no overt heart failure. In this group of patients, all neurohumoral levels (plasma renin activity, norepinephrine, arginine vasopressin, and atrial natriuretic peptide) were found to be increased compared with age-matched control subjects. These results indicate that, in fact, a subgroup of patients without overt heart failure has persistent neurohumoral activation at the time of hospital discharge postinfarction, and that this activation involves several neurohumoral systems. Since patients with persistent neurohumoral activation postinfarction are likely those most at risk of developing complications and the ones most likely to benefit from pharmacologic interventions blunting the effects of neurohumoral activation, measurement of predischarge neurohumoral levels may be useful.

Turnover and Synthesis of Norepinephrine in Experimental Hypertension in Rats

The turnover of norepinephrine and the enzymes responsible for the synthesis of catecholamines were studied in various organs of rats made hypertensive by DOCA and NaCl. After inhibition of tyrosine hydroxylase by α-methyl- p -tyrosine, an increase in the rate of disappearance of endogenous norepinephrine in the heart, intestine, and spleen of hypertensive rats indicated an increased norepinephrine turnover rate in these organs: Similarly, the rate of decline of 3H-norepinephrine endogenously formed from 3H-dopamine seemed to be increased in the same organs from hypertensive animals. In contrast, the salivary glands showed no change in turnover of norepinephrine. The conversion of tyrosine to catecholamines was normal in the hearts of the hypertensive rats but it was increased in the adrenal glands. The β-hydroxylation of dopamine to norepinephrine was normal or slightly increased in the heart, spleen, intestine, and salivary glands of hypertensive animals. The phenylethanolamine N-methyl transferase activity was normal in the adrenal glands. It thus seems that in hypertension produced by DOCA and NaCl the turnover of norepinephrine is increased in various organs without any detectable change in the synthesis rate, with the exception of the adrenal gland, in which it was increased. This might explain the reduction of the endogenous norepinephrine levels observed in many tissues of animals made hypertensive by DOCA and sodium.

Chronic renal and neurohumoral effects of the calcium entry blocker nisoldipine in patients with congestive heart failure

Nisoldipine, a calcium entry blocker, was given to 10 patients with congestive heart failure. During a 2 month follow-up period, 7 of the 10 patients were readmitted with pulmonary edema; daily furosemide doses were increased (128 +/- 87 to 192 +/- 135 mg/day, p less than 0.01), and plasma creatinine increased (1.5 +/- 0.5 to 1.8 +/- 0.6 mg/dl, p less than 0.05) (all values mean +/- SD). Despite this unfavorable clinical course, nisoldipine caused some beneficial chronic (1 month) hemodynamic effects. It decreased systemic vascular resistance (from 1,781 +/- 229 to 1,306 +/- 345 dynes X s X cm-5, p less than 0.01), decreased mean arterial pressure (from 88 +/- 0 to 74 +/- 4 mm Hg, p less than 0.001) and increased stroke volume index (from 27 +/- 6 to 33 +/- 9 ml/min per m2, p less than 0.02). Heart rate, pulmonary capillary wedge pressure and stroke work index did not change. However, nisoldipines chronic renal and neurohumoral effects were not as favorable. These were assessed during a 5 hour water load (15 ml/kg body weight of 5% dextrose in water) and compared with the effects of a water load before therapy. Nisoldipine did not change creatinine clearance or sodium excretion, but decreased water excretion (from 58 +/- 35 to 46 +/- 40% of water load in 5 hours). Over this 5 hour study, mean plasma vasopressin was also higher with nisoldipine (1.9 +/- 2.3 versus 2.7 +/- 3.2 pg/ml, p less than 0.05), but mean plasma aldosterone was lower (67 +/- 31 to 47 +/- 27 mg/dl, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased plasma catecholamine levels in patients with symptomatic mitral valve prolapse

Total plasma catecholamine levels, plasma norepinephrine levels, heart rate, and systolic and diastolic pressures were measured in 15 symptomatic patients with mitral valve prolapse and in 19 normal subjects in supine baseline conditions and in a standing position. In the 15 symptomatic patients, total plasma catecholamine levels and plasma norepinephrine levels were significantly elevated in both positions, and heart rate was lower than in normal subjects in the supine position but returned to normal in the upright position. Thus, symptomatic patients with mitral valve prolapse demonstrate increased resting sympathetic tone. In addition, the associated supine bradycardia suggested that increased vagal tone might also be present at rest. These observations support the hypothesis of a dual autonomic dysfunction in these patients and could account for some of the clinical manifestations of the mitral valve prolapse syndrome.