Neurohormonal Status Research Articles

Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status

Experimental and clinical studies have shown that the administration of recombinant human growth hormone can improve deteriorated left ventricular function and hemodynamics in patients with heart failure. Herein, we compared the effects of growth hormone versus placebo upon resting left ventricular ejection fraction, exercise capacity and neurohormonal status in patients with advanced heart failure. Nineteen patients with advanced cardiac heart failure (ejection fraction <30%) were studied at baseline and after 8 weeks of treatment with growth hormone (0.03 U/kg per day) or placebo. Primary end points were resting left ventricular ejection fraction, peak oxygen consumption and neurohormonal status, including plasma norepinephrine levels and insulin like growth factor-1 and its binding protein-3. Results are presented as median and interquartile ranges. Patients receiving growth hormone had a significant increase in insulin growth factor-1 plasma levels (median difference growth hormone=83 ng/ml [57–170] versus placebo=−6 ng/ml [−23–6], P<0.05) and its binding protein-3. However, no significant increase in left ventricular ejection fraction after growth hormone treatment (ejection fraction pre=16% [13–18] and post=17% [14–27]) was noticed when compared to placebo (ejection fraction pre=20% [15–24] and post=20% [15–26]). Also, no significant effect of growth hormone treatment was seen on peak oxygen consumption or norepinephrine plasma levels. Although the administration of growth hormone to patients with advanced cardiac heart failure was associated with a significant increase in insulin growth factor-1, there were no significant changes in ejection fraction, exercise capacity and/or neurohormonal status.

Adición de un ARAII al tratamiento con dosis máximas de IECA en la insuficiencia cardíaca

In heart failure, the benefits of adding angiotensin-receptor blockade to ACE inhibitors have been studied only with submaximal doses of ACE inhibitors. We included 20 patients (LVEF 24 7%, NYHA II-III), with no clinical or therapeutic variations in the previous three months, who were receiving maximal doses of ACE inhibitors. We added losartan 50 mg once a day. At six months, SBP decreased (115 8 vs. 106 9 mmHg; p = 0.001), LVEF increased (24.4 7 vs. 34.1 7%; p < 0.001), ventricular end-diastolic volumes decreased (220 58 vs 190 46 ml; p = 0.007), and SPAP decreased (43 8 vs. 35 7 mmHg; p < 0.001). Seven patients improved one degree on the NYHA scale (p = 0.004), but VO2max did not change (20.8 5.2 vs. 21.8 5.0 ml/kg/min, p = 0.120). Plasma levels of norepinephrine, at rest and maximal exercise, brain natriuretic peptide, and renin were similar. After maximum ACE inhibitor doses, the addition of losartan is safe and associated with an improvement in ventricular function and NYHA functional class, but with no change in neurohormonal status.

Immune and neurohormonal pathways in chronic heart failure.

Chronic heart failure is a complex disorder with interactions among the cardiovascular, immune, and neurohormonal systems. The concept that the progression of heart failure is due to neurohormonal abnormalities has received the greatest attention to date, leading to substantial therapeutic benefits. Although many current therapies are also thought to exert a variety of immunologic effects, this has been much less studied. In this review, the authors discuss a number of interactions among immune pathways and neurohormonal abnormalities relevant to heart failure. Cytokines, in particular tumor necrosis factor-alpha, have tremendous interactive opportunities within a regulatory network of energy metabolism, immune function, and neuroendocrine and hormonal function. Inflammatory cytokines are known to contribute to the progression of heart failure, and have been related to patients' prognosis. Advanced heart failure can be considered a state of chronic (low-grade) inflammation, and there are many reasons to suggest that anticytokine therapy could be successful in these patients. These novel approaches are certainly not without some risk, and many of them are very expensive, which may limit their application to certain subgroups of patients. In the future, it may not be enough to monitor cardiac function alone. Rather, the immune and neurohormonal status of patients may also need to be included in the performance of a complete assessment.

Imbalance of catabolic and anabolic pathways in chronic heart failure

Chronic heart failure (CHF) is a complex metabolic disorder with multiple interactions between the immune, neurohormonal and cardiovascular systems. That the progression of CHF is due to neurohormonal abnormalities is now considered to be established and has led to major therapeutic benefits. Many current therapies are also thought to exert a variety of immunological effects and this has been much less studied. This review aims to discuss interactions between immune pathways and neurohormonal abnormalities relevant to disease progression in CHF and to the development of cardiac cachexia. Cytokines, in particular tumour necrosis factor-a, have many interactive opportunities within a regulatory network of energy metabolism, immune function and neuroendocrine function. Inflammatory cytokines are known to contribute to the progression of CHF, being related to patients’ prognosis. Advanced CHF can be considered to be a state of chronic (low-grade) inflammation and ca tabolism. Anti-cytokine therapy could be successful in patients with proven immune abnormalities as in cardiac cachexia. In addition, anabolic therapies appear to be indicated in cachectic CHF patients. These novel approaches are certainly not without some risk and many of them are very expensive, which may limit their application to certain subgroups of patients. In the future it may not be enough to monitor only the cardiac function of patients; rather, the immune and neurohormonal status of patients may also need to be included to perform a complete assessment. Keywords: Chronic heart failure, cachexia, wasting, hormones, cytokines, endotoxin.

Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model.

Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E(max)) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E(max) gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.

Initial Effects of the Left Ventricular Repair by Plication May Not Last Long in a Rat Ischemic Cardiomyopathy Model

Background Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. Methods and Results Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E max ) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E max gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. Conclusions Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.

Exercise in the geriatric patient with congestive heart failure.

The benefits of exercise in the elderly patient with heart failure have been well documented, but the studies have been limited by restrictive inclusion criteria. Most studies have involved patients who are younger and healthier than those normally seen in clinical practice. Improvements in neurohormonal, metabolic, and vascular status have been well documented in the relatively young patients who have been evaluated. Consequently, peak exercise time, oxygen consumption, submaximal exercise, and quality of life have also improved. Studies suggest that older, more severely limited patients may also benefit from exercise. However, they are less likely to tolerate an exercise program and may not improve their quality of life if the exercise is excessive. Caution is warranted when exercise is prescribed to elderly patients with heart failure.

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: Prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction

OBJECTIVESWe sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo.BACKGROUNDAlthough neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported.METHODSPlasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients’ clinical outcomes, including mortality and heart failure events, were recorded for 18 months.RESULTSAbove-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2–10.9] and 3.92 [1.76–8.7], respectively) and hospital admission with heart failure (4.7 [2.2–10.3] and 2.4 [1.3–4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value.CONCLUSIONSIn patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.

Mechanoelectric contributions to sudden cardiac death.

Time for primary review 28 days. Sudden death, a major problem in developed countries and increasingly so in some underdeveloped countries, justifies research on the mechanisms and identification of patients at high risk of sudden death. Most sudden deaths are secondary to ventricular tachyarrhythmias [1,2]. Primary electrical disturbances, such as Brugada syndrome, long QT syndrome, are rare and account for few sudden deaths. Sudden death as a rule complicates the situation with an underlying cardiac disease with different classes of heart failure [2]. The alteration of the cardiac mechanical properties developing early in heart failure is accompanied by action potential lengthening [3], which is modulated by acute stretch [4–6]. The English theologian and philosopher William of Occam (1280–1349) stated: ‘Entia non sunt multiplicanda praeter necessitatum’. This is recognised as Occam's Razor. Roughly interpreted, it proposes that it is better to have one hypothesis to explain five observations than five hypotheses to explain each one. The cardiovascular clinical parameters used for predicting sudden arrhythmic death ranging through indices of neurohormonal status (i.e. heart rate variability) to indices of electrophysiological substrate (i.e. late potentials, QT dispersion, alternans) are influenced by and associated with mechanical disturbances in heart. Although some of these issues have been related to mechanical factors in previous reviews [6–12], this review describes the possibility that many of the mechano-arrhythmic factors affect a common pathway. Moreover, several arrhythmic mechanisms and their clinical correlates infringe such a pathway. That is, we will try to apply the Occam's Razor principle to this problem. We have to satisfy several criteria to support this contention (Fig. 1). First, the currently accepted situation (Fig. 1A). The black arrows represent the paths taken by the conventional dogma. The etiological factors (Fig. 1A top centre), through a variety of mechanisms act via … *Corresponding author. Tel.: +33-2-4747-4687; fax: +33-2-4747-5919 d.babuty{at}chu.med.univ-tours.fr

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.

Effect of mitral valve surgery on exercise capacity, ventricular ejection fraction and neurohormonal activation in patients with severe mitral regurgitation

OBJECTIVESThe purpose of this study was to prospectively investigate the effects of surgical correction of mitral regurgitation (MR) on exercise performance, cardiac function and neurohormonal activation.BACKGROUNDLittle is known about the effect of surgical correction of MR on functional status or on neurohormonal activation.METHODSCardiopulmonary exercise test, radionuclide angiography and blood samples for assessment of neurohormonal status were obtained in 40 patients with nonischemic MR before and within one year (216 ± 80 days) after surgery. Twenty-four patients underwent mitral valve repair (MVr), and 16 underwent valve replacement (VR) with anterior chordal transection.RESULTSDespite an improvement in New York Heart Association functional class, exercise performance did not change (peak oxygen consumption: 19.3 ± 6.1 to 18.5 ± 5.6 ml/kg/min, percentage of maximal predicted oxygen consumption: 79.5 ± 18.2% to 76.8 ± 16.9%). After surgery, left ventricular (LV) ejection fraction (EF) decreased (64.2 ± 10.3% to 59.9 ± 11.4%, p = 0.003) while right ventricular (RV) EF increased (41.4 ± 9.6% to 44.7 ± 9.5%, p = 0.03). Left ventricular EF did not change after MVr (64.3 ± 11.5% to 61.5 ± 12.2%), but RVEF improved (40.4 ± 9.2% to 46.0 ± 10.0%, p = 0.02). In contrast, VR was associated with an impairment of LV function in the apicolateral area and a decrease in LVEF (64.1 ± 8.5% to 57.4 ± 10.0%, p = 0.01), whereas RVEF did not change (42.9 ± 10.3% to 42.8 ± 8.6%). Moreover, there was only a slight decrease in neurohormonal activation after surgery.CONCLUSIONSDespite an improvement in symptomatic status, exercise performance was not improved seven months after either MVr or VR for MR, and neurohormonal activation persisted. Compared with MVr, VR resulted in a significant impairment of cardiac function in this study.

Amlodipine therapy in congestive heart failure: hemodynamic and neurohormonal effects at rest and after treadmill exercise

This study examined the acute effects of amlodipine treatment on left ventricular pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF), both at rest and with treadmill exercise. A total of 14 pigs were studied under control conditions and after the development of pacing-induced CHF (240 beats per minute, 3 weeks, n = 7) or with CHF and acute amlodipine treatment for the last 3 days of pacing (1.5 mg/kg per day, n = 7). Under resting conditions, left ventricular stroke volume (mL) was reduced with CHF compared with the normal state (15 ± 2 vs 31 ± 1, p <0.05) and increased with amlodipine treatment (23 ± 4, p <0.05). At rest, systemic vascular resistance increased with CHF compared with the normal state (3,078 ± 295 vs 2,131 ± 120 dyne · s cm −5, p <0.05) and was reduced after amlodipine treatment (2,472 ± 355 dyne · s cm −5, p <0.05). With exercise, left ventricular stroke volume remained lower and systemic vascular resistance higher in the CHF group, but was normalized with amlodipine treatment. With exercise, left ventricular myocardial blood flow increased from resting values, but was reduced from the normal state with CHF (normal: 1.69 ± 0.12 to 7.62 ± 0.74 mL/min per gram vs CHF: 1.26 ± 0.12 to 4.77 ± 0.45 mL/min per gram, both p <0.05) and was normalized with acute amlodipine treatment (1.99 ± 0.35 to 6.29 ± 1.23 mL/min per gram). Resting plasma norepinephrine was increased by >5-fold in the CHF group at rest and was not affected by amlodipine treatment. However, with exercise, amlodipine treatment blunted the increase in plasma norepinephrine by >50% when compared with untreated CHF values. Resting plasma endothelin levels increased with CHF compared with the normal state (10.9 ± 0.9 vs 2.8 ± 0.4 fmol/mL, p <0.05) and was reduced with amlodipine treatment (7.5 ± 1.5 fmol/mL, p <0.5). In other vascular beds, acute amlodipine treatment with CHF improved pulmonary and renal blood flow both at rest and with exercise; however, there were no effects observed on skeletal muscle blood flow. With the development of CHF, acute amlodipine treatment does not negatively influence left ventricular pump function, but rather may provide favorable hemodynamic and neurohormonal effects.

Chronic amlodipine treatment during the development of heart failure.

This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined. Sixteen pigs were studied under normal control conditions and after the development of chronic pacing-induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg . kg-1 . d-1, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16+/-2 versus 31+/-2, P<0.05) and increased with concomitant amlodipine treatment (29+/-2, P<0.05). At rest, systemic and pulmonary vascular resistance (dyne . s-1 . cm-5) increased with CHF compared with the normal control state (3102+/-251 versus 2156+/-66 and 1066+/-140 versus 253+/-24, respectively, both P<0.05) and were reduced with amlodipine treatment (2108+/-199 and 480+/-74, respectively, P<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4+/-0.9 versus 3.1+/-0.3, P<0.05) and was reduced with amlodipine treatment (6.6+/-1.1, P<0.5). With CHF, LV myocyte velocity of shortening ( microm/s) was reduced compared with normal controls (39+/-1 versus 64+/-1, P<0.05) and was increased with chronic amlodipine treatment (52+/-1, P<0.05). Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.

Chronic amlodipine treatment improves left ventricular function, systemic hemodynamics and neurohormonal status with congestive heart failure

Chronic amlodipine treatment improves left ventricular function, systemic hemodynamics and neurohormonal status with congestive heart failure

Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD)

This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.

Neurohormonal Activation and Exercise Function in Patients With Severe Heart Failure and Patients With Left Ventricular Assist System: A Comparative Study

The aim of this study was to evaluate the effects of implantation of a left ventricular assist system (LVAS) on the neurohormonal status, exercise capacity and symptomatic state in patients with severe congestive heart failure (CHF).Severe CHF is characterized by decreased exercise tolerance and activation of several neurohormonal systems.Parameters of neurohormonal activation and exercise capacity in patients with LVAS (n = 7) were compared with those in groups of New York Heart Association (NYHA) class 3 (n = 121) and class 4 (n = 81) patients. Plasma levels of norepinephrine (NE), plasma renin activity (PRA), and atrial natriuretic peptide (ANP) and maximal and submaximal exercise capacities were measured monthly in LVAS patients and compared with results in CHF patients.Plasma NE and PRA levels were significantly lower in LVAS patients than in NYHA class 4 patients, and plasma ANP levels in LVAS patients were significantly lower than those in NYHA class 3 and 4 patients. The distance walked during submaximal exercise testing and peak oxygen consumption during maximal exercise testing were similar for the LVAS and NYHA class 3 patients. The class 4 patients were unable to exercise.We conclude that the LVAS lessens the neurohormonal activation and exercise intolerance characteristic of the CHF state and that the exercise capacity early after LVAS (< 4 months) is similar to that observed in NYHA class 3 patients.

Effects of nisoldipine therapy on myocardial perfusion and neuro-hormonal status in patients with severe ischaemic left ventricular dysfunction

The effects of nisoldipine on regional myocardial perfusion and neuro-hormonal status were assessed in a double-blind, placebo-controlled study of 32 patients. All patients had ischaemic left ventricular dysfunction, with a left ventricular ejection fraction between 25% and 35%; per protocol, they were stratified according to concomitant use of ACE inhibitors. After baseline measurements at rest, including single photon emission computed tomography (SPECT) with Tc-MIBI, plasma neuro-hormones (norepinephrine, renin, arginine vasopressin, atrial natriuretic peptide) and echocardiography, the patients were randomized to nisoldipine (core coat tablet, 20 mg once daily; n = 16) or placebo (n = 16). Measurements were repeated after 8 weeks. SPECT data were analysed qualitatively (visual comparison by blinded observer) and quantitatively to derive an index of hypoperfusion representing the percentage of the left ventricular mass with Tc-MIBI activity below normal. At baseline, all patients had left ventricular areas with reduced Tc-MIBI uptake and 29 patients also had increases in plasma neuro-hormones. With nisoldipine, the extent of hypoperfusion (quantitative analysis) was reduced in 8/14 patients vs only 2/14 patients with placebo (P = 0.046, 2-tailed test). The benefit of nisoldipine was similar in patients with or without ACE inhibitor therapy and was also confirmed by the visual analysis of the data. Further, none of the neuro-hormones examined was significantly modified by nisoldipine. Thus, chronically underperfused areas are present at rest in patients with ischaemic left ventricular dysfunction, and nisoldipine significantly improved Tc-MIBI uptake in these areas without evidence of detrimental changes in plasma neuro-hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor

Left ventricular function and neurohormonal status in patients with heart failure remaining symptomatic during therapy with angiotensin-converting enzyme inhibitors were assessed, and the effects of dopaminergic receptor stimulation in this setting were determined. Neurohormonal and left ventricular function (radionuclide anglography) data were obtained in 19 patients with symptomatic ischemic heart failure. Measurements were repeated after 4 to 6 weeks of therapy with the dopamine agonist ibopamine (100 mg, 3 times/day) or placebo administered in a double-blind, randomized, parallel group design. At baseline, despite therapy with enalapril, the angotensin II levels (mean 39.4 pg/ml; p <0.01 vs controls) were significantly increased, as were plasma norepinephrine (497 ± 240 pg/ml; p <0.01 vs controls), endothelin-1, atrial natriuretic peptide and argnine vasopressin. Moreover, in comparison with pretreatment values, left ventricular ejection fraction had decreased substantially (−9.1%) in patients with plasma norepinephrine ≥600 pg/ml, but not in those with lower values of norepinephrine. With dopamine, plasma norepinephrine decreased from 516 ± 241 to 391 ± 208 pg/ml (n = 8; p <0.025 vs placebo), whereas it increased with placebo. In conclusion, the neurohormonal control provided by an angotensin-converting enzyme inhibitor is reduced in a large subset of patients during prolonged therapy; ibopamine appears to be a potentially useful drug to improve neurohormonal control in this setting.

Renal functional alterations induced by angiotensin-converting enzyme inhibitors in heart failure.

To review the effects of angiotensin-converting enzyme (ACE) inhibitors on renal pathophysiology and the compensatory mechanisms involved in heart failure. A clinical application of the use of these agents in the setting of concomitant heart failure and renal insufficiency also is presented. A MEDLINE search was conducted using the terms heart failure, congestive; renal insufficiency; and angiotensin-converting enzyme inhibitors. All applicable animal and human trials were reviewed. Advances in the management of heart failure have led to new insights into the complex pathophysiology of this condition, particularly the favorable clinical effects noted with the ACE inhibitors. The net effect of ACE inhibitors on the renin-angiotensin system in patients with heart failure is to augment renal blood flow to a greater extent than cardiac output. Glomerular filtration rate is either unchanged or decreased by ACE inhibition. Sodium excretion is augmented primarily by alterations in glomerular hemodynamic parameters. ACE inhibitors may alter renal tubular function, both directly and indirectly, leading to increased diuresis and natriuresis. Although ACE inhibitors exert beneficial pharmacodynamic effects on the renal bed in patients with heart failure, clinical consideration of volume and neurohormonal status prior to institution of therapy is prudent.

Biochemical mechanism of organic nitrate action

Increasing evidence suggests that organic nitrate action derives from their metabolic conversion to nitric oxide (NO) in the vascular smooth muscle cell. The primary catalytic activity of this process appears to reside at the cellular plasma membrane. There is no concrete evidence to indicate that NO formation is preceded by the production of inorganic nitrite ion or that the NO produced needs to form S-nitrosothiols before it can activate guanylate cyclase to produce cyclic guanosine 3′,5′-monophosphate (cGMP). Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon (by itself) is not sufficient to implicate intracellular sulfhydryl depletion as an operating mechanism of clinical nitrate tolerance. This is because sulfhydryl donors can react with nitroglycerin extracellularly to form S-nitrosothiols, and nonsulfhydryl compounds, such as enalapril and hydralazine, can prevent the development of in vivo nitrate tolerance. In addition to the cellular biochemical reactions, organic nitrates also produce systemic biochemical effects through altering neurohormonal status. These systemic effects may contribute significantly to the development of nitrate tolerance in therapeutic situations.