Serum carvedilol concentration and its relation to change in plasma brain natriuretic peptide level in the treatment of heart failure: a preliminary study.

OBJECTIVE: To examine the influence of carvedilol dose and concentration in serum on plasma brain natriuretic peptide (BNP), a measure of heart failure progression. METHODS: 12 patients with New York Heart Association (NYHA) functional class II-III chronic heart failure were enrolled in the study. They received carvedilol at daily doses of 1-20 mg with a 1-2 weekly adjustment. Serum carvedilol trough concentrations were measured in steady-state using a specific fluorescence HPLC method. The degree of improvement in heart failure was assessed from the ratio of change in the plasma BNP concentration, 2 weeks, 1 month and 3 months after the commencement of carvedilol administration. RESULTS: From the pharmacokinetic aspect, there was no valid correlation between the trough serum carvedilol concentration (Cmin) and daily dose per body weight (Dd/BW), indicating that there was a wide difference in the carvedilol elimination capacity among individuals. A significant decrease in the BNP was observed at the 3rd month in patients treated with the high dose (> 750 mg/3 months). On the other hand, in patients with a mean serum carvedilol level (Cmin) of less than 2.5 nmol/l up to 2 weeks after the start ofcarvedilol therapy, the degree of reduction in the BNP value after the 3rd month was significantly larger, relative to the patient group with Cmin over 2.5 nmol/l. CONCLUSIONS: The total carvedilol dose was confirmed to be one of the determinants for improvement in heart failure, and it was suggested that the initial serum level also plays an important role in therapeutic outcome. Therefore, it may be important to monitor the serum carvedilol level at the introductory period to determine the daily dose requirements because of the wide inter-individual variability in its metabolic clearance.

Relationship between transcardiac gradient of endothelin-1 and left ventricular remodelling in patients with first anterior myocardial infarction.

Aims To evaluate whether plasma endothelin-1 (ET-1) is extracted or produced through the heart in patients with acute myocardial infarction (AMI), and the relationship between transcardiac extraction of plasma ET-1 and left ventricular (LV) remodelling. Methods and results We measured the plasma level of ET-1 in the aortic root (Ao) and coronary sinus (CS) in 48 consecutive patients, who received successful revascularization and enalapril, for a first anterior AMI. In the acute phase the plasma ET-1 level was significantly higher both in the Ao and the CS compared to the control subjects. However, the plasma ET-1 level was significantly lower in the CS than in the Ao in the acute phase and after 1 month. There were significant correlations between transcardiac extraction of ET-1 in the acute phase and LV ejection fraction and LV end-diastolic volume index (LVEDVI) after 1 month. Stepwise multivariate analysis showed that maximal creatine phosphokinase and transcardiac extraction of plasma ET-1 during the acute phase were independently and positively correlated with the absolute change in LVEDVI after 1 month. Conclusions These results indicate that elevated circulating ET-1 is extracted through the heart in patients with a first anterior AMI and that the extracted ET-1 plays a significant role in modulating post-infarct LV remodelling.

Relationship between transcardiac extraction of aldosterone and left ventricular remodeling in patients with first acute myocardial infarction: extracting aldosterone through the heart promotes ventricular remodeling after acute myocardial infarction.

OBJECTIVES: The purpose of this study was to evaluate whether plasma aldosterone (ALD) is extracted or produced through the heart in patients with acute myocardial infarction (AMI) and to determine the relationship between transcardiac extraction of plasma ALD and left ventricular (LV) remodeling. BACKGROUND: Although we demonstrated that circulating ALD was extracted through the failing heart and that transcardiac extraction of ALD correlated with LV end-diastolic volume index (LVEDVI) in patients with congestive heart failure, the existence and increase of ALD synthase in the hearts of infarct rats were reported, suggesting cardiac production of ALD in patients with AMI. METHODS: We measured plasma ALD in the aortic root (Ao) and coronary sinus (CS) in 57 consecutive patients who received successful revascularization and enalapril, with first AMI at acute phase and after one month. We also measured plasma procollagen type III aminoterminal peptide (PIIINP) in the CS. RESULTS: Plasma ALD was significantly lower in the CS than it was in the Ao at the acute phase (84.7 +/- 6.3 pg/ml vs. 105.5 +/- 8.0 pg/ml, p < 0.0001). Significant positive correlations exist between the transcardiac gradient of ALD at the acute phase and the LVEDVI at one month. Moreover, the transcardiac gradient of plasma ALD at the acute phase has a significant correlation with plasma PIIINP, a biochemical marker of fibrosis, after one month. Stepwise multivariate analysis showed that transcardiac extraction of plasma ALD at the acute phase had an independent and significant positive relationship with a large LVEDVI after one month. CONCLUSIONS: These results indicate that plasma ALD is extracted through the heart in patients with AMI at the acute phase and that the extracted ALD plays an important role in modulating post-infarct LV remodeling.

Relationship between plasma level of cardiotrophin-1 and left ventricular mass index in patients with dilated cardiomyopathy.

OBJECTIVES: The study evaluated the relationship between plasma cardiotrophin-1 (CT-1) concentration and left ventricular (LV) mass in dilated cardiomyopathy (DCM) patients with congestive heart failure (CHF). BACKGROUND: Cardiotrophin-1 is a newly identified member of the interleukin-6 (IL-6) family of cytokines and one of the endogenous ligands for gp130 signaling pathways in the heart, and it has potent hypertrophic and survival effects on cardiac myocytes. However, the clinical significance of CT-1 is poorly understood. METHODS: We measured the plasma CT-1 level in 51 consecutive patients with DCM. Patients were classified into two groups: small LV mass index group and large LV mass index group, based on the median level of LV mass index. RESULTS: The plasma CT-1 level was increased in DCM patients with the severity of CHF and was significantly higher in the large LV mass group than in the small LV mass group, despite the absence of a difference in LV ejection fraction between the two groups. In addition, there was a significant positive correlation between the plasma CT-1 level and the LV mass index (r = 0.627, p < 0.0001). According to stepwise multivariate analyses among hemodynamic and neurohumoral factors, a high plasma CT-1 level showed an independent and significant positive relationship with a large LV mass index in patients with DCM. CONCLUSIONS: These results indicate that the plasma CT-1 level is increased in patients with DCM and is significantly correlated with the LV mass index, suggesting that CT-1 plays an important role in structural LV remodeling in patients with DCM.

Endothelin-1 promotes vascular structural remodeling during the progression of heart failure prevention of vascular remodeling using a specific endothelin-converting enzyme inhibitor.

To evaluate the effects of endothelin (ET)-converting enzyme (ECE) inhibitor on vascular remodeling in dogs with congestive heart failure (CHF), we chronically administered an ECE inhibitor, FR901533 (FR, iv. 0.3mg/kg/hr, n=6), to dogs with CHF induced by rapid ventricular pacing. Vehicle CHF dogs were given saline (n=7). In the vehicle CHF group after 3 weeks of pacing, the ET system was activated in the plasma and vasculature (3 and 5 times higher than normal, respectively). Inward remodeling occurred in the femoral artery; medial thickness (MT, 225+/-5 vs 193+/-4 microm, P<0.05) and deposition of collagen (DC, 22+/-2 vs 17+/-1%, P<0.01) significantly increased, while lumen diameter (LD, 1173+/-39 vs 1481+/-44 microm, P<0.05) decreased in the femoral artery with CHF compared with the normal femoral artery. There were significant correlations between the number of ET-1 positive cells and MT, DC, LD and systemic vascular resistance. FR significantly suppressed the changes in these vascular parameters compared with the changes in the vehicle CHF group despite the lack of an effect on blood pressure, and moreover FR caused decreases in ET-1 levels in both the plasma and femoral artery (reduced to 43% and 54%, respectively, of the levels in the vehicle CHF group, P<0.05). In conclusion, ET-1 plays a critical role in the structural deterioration of the vasculature during the progression of CHF, and ECE inhibitors can prevent the development of vascular remodeling.

Intravenous atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction.

OBJECTIVES: The study evaluates the effect of atrial natriuretic peptide (ANP) compared with nitroglycerin (GTN) on left ventricular (LV) remodeling after first anterior acute myocardial infarction (AMI). BACKGROUND: Compared with GTN, ANP suppresses the renin-angiotensin-aldosterone system and endothelin-1 (ET-1), which stimulate LV remodeling. METHODS: Sixty patients with a first anterior AMI were randomly divided into the ANP (n = 30) or GTN (n = 30) groups after direct percutaneous transluminal coronary angioplasty. We evaluated LV ejection fraction (LVEF), end-diastolic volume index (LVEDVI) and end-systolic volume index (LVESVI) at the acute phase and after one month. We also measured neurohumoral factors during study drug infusion. RESULTS: There was no difference in the baseline characteristics or LVEF (46.9+/-1.0 vs. 46.8+/-1.3%) between the two groups. Although there was no difference in hemodynamics during the infusion periods, the LVEF was significantly improved after one month compared with the baseline value in both groups, but it was improved more in the ANP group than in the GTN group (54.6+/-1.1%, 50.8+/-1.3%, p < 0.05). Left ventricular enlargement was prevented in the ANP group (LVEDVI, 85.8+/-3.1 ml/m2 to 87.3+/-2.7 ml/m2; p = ns, LVESVI, 45.6+/-1.8 ml/m2 to 41.0+/-2.1 ml/m2, p < 0.05) but not in the GTN group (LVEDVI, 86.2+/-4.1 to 100.2+/-3.7, p < 0.01; LVESVI, 46.3+/-2.8 ml/m2 to 51.1+/-3.0 ml/m2, p = ns). During the infusion, ANP suppressed plasma levels of aldosterone, angiotensin II and ET-1 compared with GTN. CONCLUSIONS: These findings indicate that in patients with a first anterior AMI, an ANP infusion can prevent LV remodeling better than can GTN, and effectively suppresses aldosterone, angiotensin II and ET-1.

Relationship between tumor necrosis factor-alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy.

OBJECTIVES: This study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM). BACKGROUND: Oxidative stress appears to increase in the failing myocardium and may contribute to ventricular dysfunction in patients with DCM. Tumor necrosis factor-alpha (TNF-alpha), which is expressed in the failing heart, may stimulate oxidative stress. METHODS: We measured plasma oxidized low density lipoprotein (oxLDL) by sandwich enzyme-linked immunosorbent assay using specific antibodies against oxLDL in the aortic root (AO) and the coronary sinus (CS) in control subjects (n = 8) and in 22 patients with DCM and mild congestive heart failure. We also measured the plasma levels of TNF-alpha and angiotensin II. RESULTS: There was no difference in oxLDL between the AO and CS in control subjects. In contrast, plasma oxLDL was significantly higher in the CS than the AO in patients with DCM, suggesting that the transcardiac gradient ofoxLDL reflects oxidative stress in the failing heart in these patients. Plasma TNF-alpha levels were significantly higher in the CS than the AO with a significant positive correlation of the transcardiac gradient of TNF-alpha and the transcardiac gradient of oxLDL. Moreover, a significant negative correlation existed between the transcardiac gradient of oxLDL and left ventricular ejection fraction. The transcardiac gradient of plasma oxLDL was significantly lower in 6 patients who received carvedilol than in 16 patients who did not receive carvedilol. CONCLUSIONS: These findings indicate that the transcardiac gradient of oxLDL may be a marker of oxidative stress in the heart and that left ventricular dysfunction may be partly due to the oxidative stress in patients with DCM. In addition, TNF-alpha may stimulate oxidative stress in the failing heart in patients with DCM.

Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure.

OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohumoral factors and left ventricular remodeling in patients with congestive heart failure (CHF). BACKGROUND: Aldosterone (ALD) promotes collagen synthesis and structural remodeling of the heart. Spironolactone, an ALD receptor antagonist, is reported to reduce mortality in patients with CHF, but its influence on left ventricular remodeling has not been clarified. METHODS: Thirty-seven patients with mild-to-moderate nonischemic CHF were randomly divided into two groups that received treatment with spironolactone (n = 20) or placebo (n = 17). We measured left ventricular volume and mass before treatment and after four months of treatment. We also measured the plasma levels of neurohumoral factors, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), as well as plasma procollagen type III aminoterminal peptide (PIIINP), a marker of myocardial fibrosis. RESULTS: Left ventricular volume and mass were significantly decreased and ejection fraction was significantly increased in the spironolactone group, while there were no changes in the placebo group. Plasma levels of ANP, BNP and PIIINP were significantly decreased after spironolactone treatment, but were unchanged in the placebo group. There was a significant positive correlation between the changes of PIIINP and changes of the left ventricular volume index (r = 0.45, p = 0.045) as well as the left ventricular mass index (r = 0.65, p = 0.0019) with spironolactone treatment. CONCLUSIONS: These findings indicate that four months of treatment with spironolactone improved the left ventricular volume and mass, as well as decreased plasma level of BNP, a biochemical marker of prognosis and/or ventricular hypertrophy, suggesting that endogenous aldosterone has an important role in the process of left ventricular remodeling in nonischemic patients with CHF.

Comparison of neurohumoral effects of short-acting and long-acting loop diuretics in patients with chronic congestive heart failure.

We evaluated the comparative effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting loop diuretic, on neurohumoral factors and quality of life (QOL) in patients with congestive heart failure (CHF). Twenty-five stable patients with mild chronic CHF who had been administered furosemide (n = 14) or azosemide (n = 11) orally for more than 3 months were studied. We changed furosemide to azosemide or azosemide to furosemide and followed for 3 months. Echocardiography was performed, and we also measured neurohumoral factors and assessed QOL by questionnaire. Blood pressure, body weight, renal function and echocardiographic findings were the same during the furosemide and azosemide treatments. Plasma levels of atrial natriuretic peptide and brain natriuretic peptide were not different between the two treatments. However, plasma concentrations of active renin and norepinephrine were significantly higher with furosemide treatment than with azosemide treatment. QOL score was significantly lower with azosemide than with furosemide. These findings suggest that long-acting loop diuretics may have fewer adverse effects on the neuroendocrine system and QOL than short-acting loop diuretics in patients with mild CHF.

Relationship between cardiac 123I-metaiodobenzylguanidine imaging and the transcardiac gradient of neurohumoral factors in patients with dilated cardiomyopathy.

Cardiac sympathetic nervous function is altered in congestive heart failure (CHF) and the uptake and washout rate of cardiac 123I-metaiodobenzylguanidine (MIBG) are useful markers for evaluating the severity of it. To assess what parameters predict decreased uptake or increased washout rate of MIBG, the concentrations of neurohumoral factor in both the aorta (Ao) and coronary sinus (CS) were measured, as well as hemodynamic parameters by catheterization, in patients with dilated cardiomyopathy (DCM). MIBG imaging was performed within 1 week of cardiac catheterization. Regarding MIBG parameters, the correlation with the transcardiac gradient of norepinephrine (NE), brain natriuretic peptide (BNP) and hemodynamics was investigated. Stepwise multivariate regression analysis was used to determine which variables closely correlated with cardiac MIBG parameters. There was a significant increase in the NE level between the Ao (446 pg/ml) and the CS (727 pg/ml). According to stepwise multivariate regression analysis, the heart/mediastinum (H/M) ratio independently correlated with the transcardiac gradient of BNP (r=-0.480, p<0.01), and the washout rate independently correlated with the transcardiac gradient of NE (r=0.481, p<0.01). These findings indicate that the H/M ratio may reflect the transcardiac gradient of BNP, which implies the degree of left ventricular dysfunction and/or damage and the washout rate may reflect altered cardiac sympathetic nerve terminal in DCM patients with CHF, suggesting that both the H/M ratio and washout rate provide important information about the failing ventricle.

Relationship between plasma levels of cardiac natriuretic peptides and soluble Fas: plasma soluble Fas as a prognostic predictor in patients with congestive heart failure.

BACKGROUND: Cardiac natriuretic peptides may induce apoptosis in myocytes; however, the relationship between plasma levels of cardiac natriuretic peptides and those of soluble Fas (sFas) and tumor necrosis factor (TNF)-alpha remains unknown in patients with congestive heart failure (CHF). METHODS AND RESULTS: We measured plasma levels of sFas and TNF-alpha and those of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, and endothelin 1 in 96 patients with CHF (ejection fraction < 45%). The patients were monitored for 3 years. Plasma levels of sFas and TNF-alpha increased with the severity of CHF. There was no significant correlation between sFas plasma levels and those of ANP and BNP. Cox proportional hazard analysis showed that high levels of sFas (P = .009) and BNP (P < .0001) and a low ejection fraction (P = .019) were independent significant prognostic predictors. CONCLUSIONS: There is no significant correlation between cardiac natriuretic peptide and sFas levels in plasma. Plasma sFas is a useful prognostic marker independent of neurohumoral factors, suggesting that immune activation and/or apoptosis play a significant role in the pathogenesis of CHF.

Significant roles of endothelin-A- and -B-receptors in renal function in congestive heart failure.

Endothelin-1 (ET-1) not only causes potent vasoconstriction but also leads to fluid retention, both actions mediated by ET(A)- and/or ET(B)-receptors. Selective ET(A)- and combined ET(A)/ET(B)-receptor antagonists improve hemodynamics in heart failure; however, it is also important to evaluate the effects of these antagonists on urine output in heart failure. We administered an acute dose of either the selective ET(A)-receptor antagonist FR139317 (FR, n=5, 1 and 3 mg/kg) or the mixed ET(A)/ET(B)-receptor antagonist TAK-044 (TAK, n = 5, 1 and 3 mg/kg) to dogs with heart failure induced by rapid ventricular pacing. Renal hemodynamic and tubular functions were subsequently investigated. FR increased urinary excretion in association with increased renal plasma flow (RPF) and glomerular filtration rate (GFR) with no significant changes in the fractional reabsorption of water distally (FRWD). In contrast, despite increased GFR, TAK did not alter urine volume or RPF with significantly increased FRWD. The increase of GFR and RPF induced by FR was significantly larger than that of TAK. These findings indicate that ET(B)-receptor activation may result in diuresis by renal vasodilatation and reduction of water reabsorption in the distal tubules and collecting ducts. Acute ET(A)-receptor antagonism may therefore be more beneficial to diuresis than dual ET(A)/ET(B)-receptor inhibition in heart failure.

Chronic effects of an orally active selective endothelin-B-receptor antagonist in experimental congestive heart failure.

Endothelin-B- (ETB) receptors located in vascular beds mainly mediate vasorelaxation, however, long-term treatment with a mixed ETA/ETB receptor antagonist has been shown to improve the survival rate of rats with heart failure in a similar way to ETA-receptor inhibitors. The inhibition of ETB-receptor-mediated action should therefore be beneficial in preventing the deterioration seen in heart failure, despite various adverse hemodynamic effects. We administered K-8794 (Kowa Co. Ltd, Japan, 2mg/kg/day, n = 6), an orally active selective ETB-receptor antagonist, to dogs with heart failure induced by rapid right ventricular pacing for 14 days, commencing 8 days after pacing. Control dogs were given a placebo (n = 6). Mean arterial pressure decreased and systemic vascular resistance increased in both groups at the end of the protocol. In the K-8794 group, however, those values were higher than in the control group. Cardiac output decreased in both groups, but there were no significant differences observed between the two groups. Plasma renin activity and aldosterone increased in both groups at the end of the protocol, however levels in the K-8794 group were significantly lower than those in the control group. In the K-8794 group, it was quite interesting to note that Na excretion and urine flow rate were higher than in the control group. Our findings thus suggest that, although ETB-receptor antagonism produces some hemodynamic disadvantages, it can successfully prevent body fluid retention through the suppression the activation the renin-angiotensin-aldosterone system in dogs with heart failure.

Plasma cardiac natriuretic peptides as biochemical markers of recurrence of atrial fibrillation in patients with mild congestive heart failure.

To determine changes in plasma brain natriuretic peptide (BNP) after direct current cardioversion (DC) and to evaluate the relationship between plasma atrial natriuretic peptide (ANP) and BNP and the recurrence of atrial fibrillation (AF) after DC in patients with mild congestive heart failure (CHF), plasma ANP and BNP were measured before and after DC in 71 patients with mild CHF and then followed. In 65 patients with successful DC, both ANP and BNP decreased 15 min after DC. Cox stepwise multivariate analysis among 14 variables such as age, history of AF, echocardiographic parameters, medication and ANP and BNP revealed that only low ANP (p=0.005) and high BNP before DC (p=0.0002) were independent predictors of recurrent AF. A ratio of ANP to BNP less than 0.44 was a significant risk factor for AF recurrence by Kaplan-Meier analysis (p=0.02). BNP began to decrease immediately after successful DC. High BNP and relatively low ANP compared with BNP were independent risk factors of AF recurrence in patients with mild CHF.

High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure.

OBJECTIVES: The aim of this study was to evaluate whether repetitive measurements of plasma levels of neurohumoral factors and cytokines before and after additional treatment are useful for predicting mortality in patients with congestive heart failure (CHF). BACKGROUND: Neurohumoral and immune activation play an important role in the pathophysiology of CHF. However, the effects of serial changes in these factors on the prognostic value remain unknown. METHODS: We measured plasma levels of neurohumoral factors and cytokines and left ventricular ejection fraction (LVEF) before and three months after optimized treatment for CHF in 102 consecutive patients with severe CHF (New York Heart Association class III to IV) on admission to our hospital. Physicians who were blind to the plasma neurohumoral factors until study completion treated patients using standard drugs. Patients were monitored for a mean follow-up period of 807 days. RESULTS: Plasma levels of neurohumoral factors, cytokines and LVEF were significantly improved three months after optimized treatment. Cardiac death occurred in 26 patients. Among 19 variables including LVEF, only a high level of brain natriuretic peptide (BNP) and interleukin-6 (IL-6) at three months after optimized treatment showed significant independent relationships by Cox proportional hazard analysis with a high mortality for patients with CHF. CONCLUSIONS: These findings indicate that high plasma BNP and IL-6 levels three months after optimized treatment are independent risk factors for mortality in patients with CHF, suggesting that sustained high plasma levels of BNP and IL-6 after additional standard treatment were independent risk factors for mortality in patients with CHF despite improvements in LVEF and symptoms.

[Plasma cardiac natriuretic peptide as a biological marker of recurrence of atrial fibrillation in elderly people].

We designed this study to evaluate the relationship between plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels and recurrence of atrial fibrillation (AF) after direct current cardioversion (DC) and the differences with aging. Fifty patients with mild congestive heart failure (CHF) undergoing elective DC of AF were included in this study (New York Heart Association (NYHA) functional class II: n = 42, III = 8). Patients who failed to show restoration of sinus rhythm or those with mitral valve stenosis were excluded. Before successful DC, we measured plasma levels of ANP and BNP and evaluated left atrial dimension (LAD), left ventricular end-diastolic dimension (LVDd), and left ventricular ejection fraction (EF) by echocardiography. Twenty-one patients had recurrence of AF within 2 months after DC (average 9.05 days). We followed up the other 29 patients for 580.5 days. By Cox stepwise multivariate analysis, history of AF (p = 0.007), low plasma levels of ANP (p = 0.003), and high plasma levels of BNP (p = 0.0003) were found to be independent predictors of recurrent AF. High plasma BNP levels indicating ventricular dysfunction and low plasma ANP levels may be due to atrial histological change such as fibrosis. In these patients, plasma ratios of ANP and BNP (ANP/BNP) less than 0.43 were predictive factors for AF recurrence (sensitivity 70%, specificity 62%), especially in patients who were older than 70 years (sensitivity 100%, specificity 80%). Relatively low plasma ANP level compared to BNP is an independent risk factor of AF recurrence in patients with CHF, especially in elderly patients, suggesting that plasma cardiac natriuretic peptides are important biochemical markers of AF recurrence in elderly patients with CHF.

Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure.

OBJECTIVES: The study evaluated the transcardiac extraction or spillover of aldosterone (ALDO) in normal subjects and in patients with congestive heart failure (CHF). BACKGROUND: Aldosterone promotes collagen synthesis and structural remodeling of target organs such as the heart. Spironolactone, an ALDO receptor antagonist, has recently been reported to reduce the mortality of patients with CHF; however, the effects of spironolactone on the transcardiac gradient of ALDO have not been clarified. METHODS: We measured plasma ALDO in the aortic root (AO) and coronary sinus (CS) in normal subjects and 113 consecutive CHF patients and also measured plasma procollagen type III aminoterminal peptide (PIIINP) in CS, a biochemical marker of myocardial fibrosis. RESULTS: Plasma ALDO was significantly lower in the CS than in the AO in normal subjects (n = 15; 61.2 +/- 9.3 vs. 83.1 +/- 11.8 pg/ml, p < 0.0001). In 96 CHF patients who did not receive spironolactone, plasma ALDO was significantly lower in the CS than in the AO (59.3 +/- 3.9 vs. 73.8 +/- 4.9 pg/ml, p < 0.0001). In contrast to the difference in these 96 patients, there was no significant difference in ALDO between the AO and CS in 17 patients who received spironolactone (127.4 +/- 20 vs. 124.0 +/- 19 pg/ml, p = 0.50). Stepwise multivariate analyses showed that spironolactone therapy had an independent and significant negative relationship with the transcardiac gradient of plasma ALDO in patients with CHF. In addition, significant positive correlations were seen between the transcardiac gradient of plasma ALDO and PIIINP (r = 0.565, p < 0.0001) and the left ventricular end-diastolic volume index (r = 0.484, p < 0.0001). CONCLUSIONS: These results indicate that plasma ALDO is extracted through the heart in normal subjects and in CHF patients who do not receive spironolactone and that spironolactone inhibits the transcardiac extraction of ALDO in CHF patients, suggesting that spironolactone blocks the effects of ALDO on the failing heart in patients with CHF.

Transcardiac extraction of circulating endothelin-1 across the failing heart.

To determine the transcardiac gradient of plasma endothelin-1 (ET-1) in patients with congestive heart failure (CHF), we measured plasma levels of ET-1 in both the aortic root and the coronary sinus in 14 normal subjects and 79 consecutive patients with CHF. In normal subjects, plasma ET-1 was significantly higher in the coronary sinus than in the aortic root; these findings were also shown in patients with mild CHF, suggesting that there was ET-1 spillover across the heart. In contrast, plasma ET-1 was significantly lower in the coronary sinus than in the aortic root in patients with severe CHF, suggesting there was ET-1 extraction across the heart in patients with severe CHF. The transcardiac gradient of plasma ET-1 was correlated with the left ventricular end-diastolic volume index (r = 0.501, p <0.0001) and plasma level of procollagen type III amino terminal peptide in the coronary sinus (r = 0.54, p = 0.0008), a marker of myocardial fibrosis. Stepwise multivariate analysis showed that the transcardiac gradient of plasma ET-1 was an independent and significant relation with the left ventricular end-diastolic volume index in patients with CHF (r = 0.665, p <0.0001). These findings suggest that elevated circulating ET-1 is extracted across the failing heart with a significant correlation between the transcardiac gradient of plasma ET-1 and the left ventricular end-diastolic volume index, suggesting that ET receptors are upregulated in the failing ventricle and that the elevated circulating ET-1 might stimulate the process of left ventricular remodeling in patients with severe CHF.

Insufficient secretion of atrial natriuretic peptide at acute phase of myocardial infarction.

To investigate the secretion of the plasma levels of atrial natriuretic peptide (ANP) in patients with acute myocardial infarction (AMI), we evaluated the relationship between plasma levels of ANP and pulmonary capillary wedge pressure (PCWP) in 45 consecutive patients during the acute phase of AMI ( approximately 12 h after the attack) (group 1) and compared data with those obtained after 1 mo (group 2). In both groups 1 and 2, plasma ANP levels significantly correlated with PCWP. The slope of the linear regression line between the PCWP and ANP in group 1 was significantly lower, by about one-third, than that in group 2. In addition, we examined changes in ANP levels and left ventricular end-diastolic pressure (LVEDP) over 180 min after AMI induced by injection of microspheres into the left coronary arteries of three dogs. The LVEDP and ANP levels 30 min after AMI were significantly higher than those before; however, despite the persistent high LVEDP during the 180 min after AMI, ANP levels decreased gradually and significantly to 63% of the peak level at 150 min. These findings suggest that the secretion of ANP during the acute phase of myocardial infarction may be insufficient relative to the chronic phase.

Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure.

OBJECTIVES: To evaluate the effects of an angiotensin (Ang II) type 1 receptor antagonist on immune markers in patients with congestive heart failure (CHF). BACKGROUND: Ang II stimulates production of immune factors via the Ang II type 1 receptor in vitro, and the long-term effects of Ang II type 1 receptor antagonists on plasma markers of immune activation are unknown in patients with CHF. METHODS: Twenty-three patients with mild to moderate CHF with left ventricular dysfunction were randomly divided into two groups: treatment with Ang II type 1 receptor (candesartan cilexetil) (n = 14) or placebo (n = 9). We measured plasma levels of immune factors such as tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). We also measured plasma levels of the neurohumoral factors such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP), a biological marker of ANP and BNP. RESULTS: Plasma levels of TNFalpha, IL-6, sICAM-1 and sVCAM-1 were increased in the 23 CHF patients compared with normal subjects and significantly decreased after 14 weeks of candesartan cilexetil treatment, but did not change in the placebo group. Plasma levels of BNP, which is a marker of ventricular injury, significantly decreased, and the molar ratio of plasma cGMP to cardiac natriuretic peptides (ANP + BNP) was significantly increased after candesartan cilexetil treatment, but did not change in the placebo group. CONCLUSIONS: These findings suggest that 14 weeks of treatment with an Ang II type 1 receptor antagonist (candesartan cilexetil) decreased plasma levels of the immune markers such as TNFalpha, IL-6, sICAM-1 and sVCAM-1 and that it improved the biological compensatory action of endogenous cardiac natriuretic peptides in patients with mild to moderate CHF.