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T Tsutamoto, A Wada,
M Hayashi,
T Tsutsui,
K Maeda,
M Ohnishi,
M Fujii,
T Matsumoto,
T Yamamoto,
T Takayama,
C Ishii,
M Kinoshita
[show abstract]
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ABSTRACT: 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.
European Heart Journal 03/2003; 24(4):346-55. · 10.48 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Fujii,
T Matsumoto,
T Yamamoto,
T Takayama,
M Kinoshita
[show abstract]
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ABSTRACT: 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).
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.
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.
Journal of Cardiac Failure 12/2001; 7(4):322-8. · 3.66 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Fujii,
T Matsumoto,
T Yamamoto,
X Wang,
S Asai,
T Tsuji,
H Tanaka,
Y Saito,
K Kuwahara,
K Nakao,
M Kinoshita
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ABSTRACT: 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).
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.
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.
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.
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.
Journal of the American College of Cardiology 11/2001; 38(5):1485-90. · 14.16 Impact Factor
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M Hayashi,
T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
T Tsutsui,
T Matsui,
M Fujii,
T Matsumoto,
T Yamamoto,
H Horie,
M Ohnishi,
M Kinoshita
[show abstract]
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ABSTRACT: 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.
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.
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.
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.
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.
Journal of the American College of Cardiology 11/2001; 38(5):1375-82. · 14.16 Impact Factor
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X Wang,
M Ohnishi, A Wada,
T Tsutamoto,
M Sawaki,
M Fujii,
T Matsumoto,
T Yamamoto,
K Kurokawa,
H Yamada,
M Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: 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.
Life Sciences 10/2001; 69(21):2477-88. · 2.53 Impact Factor
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T Tsutamoto, A Wada,
T Matsumoto,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Yamamoto,
H Horie,
Y Sugimoto,
M Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: This study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM).
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.
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.
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.
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.
Journal of the American College of Cardiology 07/2001; 37(8):2086-92. · 14.16 Impact Factor
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ABSTRACT: 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).
Compared with GTN, ANP suppresses the renin-angiotensin-aldosterone system and endothelin-1 (ET-1), which stimulate LV remodeling.
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.
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.
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.
Journal of the American College of Cardiology 06/2001; 37(7):1820-6. · 14.16 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Matsumoto,
T Matsui,
M Kinoshita
[show abstract]
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ABSTRACT: We sought to evaluate the effects of spironolactone on neurohumoral factors and left ventricular remodeling in patients with congestive heart failure (CHF).
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.
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.
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.
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.
Journal of the American College of Cardiology 05/2001; 37(5):1228-33. · 14.16 Impact Factor
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ABSTRACT: 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.
Journal of Cardiovascular Pharmacology 12/2000; 36(5 Suppl 1):S140-3. · 2.29 Impact Factor
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ABSTRACT: 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.
Journal of Cardiovascular Pharmacology 12/2000; 36(5 Suppl 1):S323-6. · 2.29 Impact Factor
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K Maeda,
T Tsutamoto, A Wada,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Matsumoto,
M Kinoshita
[show abstract]
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ABSTRACT: 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).
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.
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.
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.
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.
Journal of the American College of Cardiology 12/2000; 36(5):1587-93. · 14.16 Impact Factor
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ABSTRACT: 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.
Journal of Applied Physiology 09/2000; 89(2):458-64. · 3.75 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Matsumoto,
H Horie,
Y Sugimoto,
M Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: The study evaluated the transcardiac extraction or spillover of aldosterone (ALDO) in normal subjects and in patients with congestive heart failure (CHF).
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.
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.
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).
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.
Journal of the American College of Cardiology 09/2000; 36(3):838-44. · 14.16 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Matsumoto,
H Horie,
Y Sugimoto,
M Kinoshita
[show abstract]
[hide abstract]
ABSTRACT: 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.
The American Journal of Cardiology 09/2000; 86(5):524-8. · 3.37 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
N Mabuchi,
M Hayashi,
T Tsutsui,
M Ohnishi,
M Sawaki,
M Fujii,
T Matsumoto,
M Kinoshita
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[hide abstract]
ABSTRACT: To evaluate the effects of an angiotensin (Ang II) type 1 receptor antagonist on immune markers in patients with congestive heart failure (CHF).
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.
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.
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.
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.
Journal of the American College of Cardiology 04/2000; 35(3):714-21. · 14.16 Impact Factor
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T Tsutamoto, A Wada,
K Maeda,
T Hisanaga,
N Mabuchi,
M Hayashi,
M Ohnishi,
M Sawaki,
M Fujii,
H Horie,
Y Sugimoto,
M Kinoshita
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ABSTRACT: To evaluate the level of plasma brain natriuretic peptide as a predictor of morbidity and mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.
We measured plasma levels of atrial natriuretic peptide, brain natriuretic peptide, norepinephrine, angiotensin II, and endothelin-1 and monitored haemodynamic parameters in 290 consecutive patients with asymptomatic or minimally and newly symptomatic left ventricular dysfunction (functional classes I-II, mean left ventricular ejection fraction=37%). All patients were followed up for a median period of 812 days. The Cox proportional hazards model was used to assess the association of variables with mortality and morbidity.
At the end of the follow-up, 24 patients had suffered cardiac death and 25 had been hospitalized for worsening heart failure during the follow-up period. Among 21 variables such as clinical characteristics, treatment, haemodynamics, and neurohumoral factors, high levels of plasma brain natriuretic peptide (P<0.0001), norepinephrine (P=0.042), left ventricular end-diastolic volume index (P=0.0035), and left ventricular end-diastolic pressure (P=0.033) were shown to be independent predictors of mortality and morbidity by stepwise multivariate analysis. Moreover, only a high level of plasma brain natriuretic peptide (P<0.0001) was shown to be an independent predictor of mortality in these patients.
These results indicate that a high plasma brain natriuretic peptide level provides information about mortality and morbidity in patients with asymptomatic or minimally symptomatic left ventricular dysfunction.
European Heart Journal 12/1999; 20(24):1799-807. · 10.48 Impact Factor
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ABSTRACT: The present report concerns a case of very low plasma levels of atrial natriuretic peptide (ANP) accompanying severe pulmonary hypertension due to mitral stenosis. There was remarkable fibrosis in the atrium and ANP secretion may have been insufficient. Low-dose infusion (0.025 microg kg(-1) min(-1)) of synthetic human alpha-ANP infusion was very effective in improving the pulmonary hypertension.
Japanese Circulation Journal 11/1999; 63(10):816-8.
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ABSTRACT: Natriuretic peptide (NP) receptor has been postulated to be downregulated under a high concentration of atrial NP (ANP) in congestive heart failure (CHF), but limited information is available on how the vascular functional responsiveness to NPs is altered in coronary circulation during CHF. We assessed the relaxant effects of ANP, brain NP (BNP), and other vasodilators in isolated coronary arteries obtained from dogs with and without severe CHF induced by rapid right ventricular pacing. In CHF dogs, plasma ANP and cGMP concentrations were elevated compared with control dogs. In CHF arteries the relaxant effects of ANP and BNP (10(-8) and 10(-7) mol/l) were suppressed compared with control arteries. Nitroglycerin, nitric oxide, 8-bromo-cGMP, and beraprost sodium produced similar concentration-response curves in both arteries. The addition of 10(-7) mol/l ANP increased the level of tissue cGMP in control arteries, but not in CHF arteries. We conclude that there was a specific reduction in the relaxant effects of ANP and BNP in isolated coronary arteries in severe CHF dogs, which suggests the possibility of the downregulation of NP receptors coupled to guanylate cyclase.
The American journal of physiology 07/1999; 276(6 Pt 2):H1935-42.
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ABSTRACT: This study was done to determine the spillover and extraction of endothelin-1 (ET-1) in the peripheral circulation, and to evaluate the factors that regulate local ET-1 extraction in the peripheral circulation in patients with congestive heart failure (CHF).
The relationship between the spillover and extraction of the ET-1 in the peripheral circulation and systemic vascular resistance (SVR) has not been fully clarified.
We measured plasma levels of ET-1 both in femoral artery (FA) and femoral vein (FV) in 93 patients with CHF.
Plasma ET-1 was significantly higher in FV than in FA in New York Heart Association (NYHA) functional class II patients, but there was no difference of ET-1 between FA and FV in functional class III patients. In patients with functional class IV, plasma ET-1 was significantly lower in FV than in FA, and SVR was significantly higher than in patients with NYHA class II or class III. Moreover, a significant positive correlation existed between plasma ET-1 extraction across the lower leg and SVR in these patients. Among the various neurohumoral factors and hemodynamics, plasma levels of ET-1, angiotensin II in the FA showed an independent and significant relationship with the plasma arteriovenous difference of ET-1 in the lower limb.
Circulating ET-1 is extracted in peripheral circulation in patients with severe CHF, suggesting the possibility of upregulation of ET receptors of vascular beds in the lower limb in these patients. The peripheral extraction of ET-1 correlates with SVR in severe CHF patients and is mainly regulated by the local ET-1 and renin angiotensin systems.
Journal of the American College of Cardiology 03/1999; 33(2):530-7. · 14.16 Impact Factor
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ABSTRACT: BACKGROUND--Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist. METHODS AND RESULTS--CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05). CONCLUSIONS--An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.
Circulation 03/1999; 99(4):570-7. · 14.74 Impact Factor
