Effects of long-term intravenous administration of adrenomedullin (AM) plus hANP therapy in acute decompensated heart failure: a pilot study.

BACKGROUND: It was reported previously that 30 min administration of adrenomedullin (AM) improves hemodynamics in chronic stable heart failure patients. The present study was designed to examine whether long-term AM + human atrial natriuretic peptide (hANP) administration can be used as a therapeutic drug in patients with acute decompensated heart failure (ADHF) in clinical setting. METHODS AND RESULTS: Seven acute heart failure patients (74 +/- 5 years) with dyspnea and pulmonary congestion were studied. AM (0.02 microg x kg(-1) x min(-1)) + hANP (0.05 microg x kg(-1) x min(-1)) was infused for 12 h and then hANP (0.05 microg x kg(-1) x min(-1)) was infused for 12 h. Hemodynamic, renal, hormonal and oxidative stress responses were evaluated. AM + hANP significantly reduced mean arterial pressure, pulmonary arterial pressure and systemic and pulmonary vascular resistance without changing heart rate, and increased cardiac output for most time-points compared with those at baseline. In addition, AM + hANP reduced aldosterone, brain natriuretic peptide and free-radical metabolites compared with those at baseline (all P<0.05). AM + hANP increased urine volume and U(Na)V compared with baseline data. CONCLUSIONS: In this small, pilot trial, AM + hANP therapy had beneficial hemodynamic and hormonal effects in ADHF. Intravenous infusion of AM with hANP could be used as a therapeutic drug in ADHF. These data are preliminary and require confirmation in a larger clinical study.

Implantable cardioverter defibrillator in maintenance hemodialysis patients with ventricular tachyarrhythmias: a single-center experience.

Patients with hemodialysis (HD) are at risk of death due to cardiac arrhythmias, worsening congestive heart failure (CHF), and noncardiac causes. This study reviews our experience with the use of implantable cardioverter defibrillators (ICDs) in patients with ventricular tachycardia who are under maintenance HD. We retrospectively reviewed 71 consecutive patients who underwent an ICD implantation in our hospital. There were 11 patients under maintenance HD and 60 patients without HD. The group of patients with HD (HD group) was compared with the patients without HD (control group). The mean follow-up period was 30+/-9 vs. 39+/-4 months in the HD group vs. the control group, respectively. Among these patients, 6 in the HD group and 26 in the control group received appropriate ICD therapies. There was no difference in appropriate ICD therapy, time to the first therapy, and electrical storm between the 2 groups. In the HD group, 1 patient underwent surgical removal of the ICD system due to infective endocarditis. There were 5 deaths in the HD group (4 from CHF) and 8 deaths in the control group (4 from CHF). There were no sudden cardiac deaths or arrhythmic deaths in both groups of patients during the follow-up period. However, the overall death rate was significantly higher in the HD group (P<0.01). In HD patients, ICD therapy prevented arrhythmic death, but their rate of nonarrhythmic adverse outcomes was high. This risk-benefit association should be considered before implantation of the device.

Natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system has inhibitory effects in renal fibrosis in mice.

OBJECT: This study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanism involved. METHODS: Three groups were studied: untreated UUO in wild-type mice; untreated UUO in NPR-A KO mice; and ANP treated (0.05 microg/kg/min) UUO in wild-type mice. We measured histological and immunohistochemical findings (alpha-SMA and F4/80), tissue cGMP levels, various mRNA expression levels by real-time PCR analysis, and transcription factor levels (AP-1 and NF-kappaB) in renal tissue. RESULTS: Compared with wild-type UUO mice, NPRA-KO UUO mice had abnormal morphological findings (fibrous area: +26%, alpha-SMA expression: +30%) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta, collagen I, collagen III, PAI-1, renin and angiotensinogen, whereas there were no differences in F4/80 positive cells or the mRNA expression levels of ICAM-1, osteopontin, or MCP-1 between the two groups. In contrast, ANP pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta, collagen I, collagen III, PAI-1, ICAM-1, osteopontin, MCP-1, renin, and angiotensinogen. NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and ANP pre-treatment reduced AP-1 and NF-kappaB activity. CONCLUSION: The endogenous natriuretic peptide/NPR-A system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous ANP pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways.

Right atrial abnormalities in a patient with arrhythmogenic right ventricular cardiomyopathy without ventricular tachycardia.

We describe a 59-year-old woman with sick sinus syndrome (SSS) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Diagnosis of SSS was made because she had frequent episodes of sinus arrest with prolonged ventricular asystole. Cardiac images showed a dilated right atrium (RA) and a right ventricle (RV). Electroanatomical mapping of the RA showed extensive scarring with no recordable electrical potentials. Although she had frequent premature ventricular contractions, neither spontaneous ventricular tachycardia (VT) nor induced VT was observed. Microscopic examination of the RV indicated fibrofatty myocardium. Atrial arrhythmias associated with SSS may be the cause of symptoms in some cases of ARVC.

Delayed pericarditis associated with an implantable cardioverter defibrillator implantation using an active-fixation atrial lead.

A 57-year-old man with nonischemic dilated cardiomyopathy and ventricular tachycardia underwent routine dual chamber implantable cardioverter defibrillator (ICD) implantation. An active-fixation atrial lead was positioned at the lateral wall of the right atrium. He subsequently developed chronic severe pericarditis. Histopathological findings of the pericardium showed mechanical stimulus localized pericarditis. This case demonstrates that contact of the screw of the active-fixation atrial lead with the pericardium may be a possible mechanism for pericarditis after pacemaker/ICD implantation.

Idiopathic ventricular arrhythmias arising from the pulmonary artery: prevalence, characteristics, and topography of the arrhythmia origin.

BACKGROUND: The characteristics of idiopathic ventricular tachycardias (VTs) or idiopathic premature ventricular contractions (PVCs) arising from the pulmonary artery (PA) have not been sufficiently clarified. OBJECTIVE: The purpose of this study was to clarify the prevalence, characteristics, and preferential sites of idiopathic VT/PVCs arising from the PA (PA-VT/PVCs). METHODS: Data obtained from 276 patients with idiopathic VT/PVCs who underwent radiofrequency (RF) catheter ablation were analyzed. RESULTS: Twelve VT/PVCs (4%) were PA-VT/PVCs, and their onset (34 +/- 14 years) was the youngest among all subgroups. Because those QRS morphologies were similar to VT/PVCs arising from the right ventricular outflow tract (RVOT-VT/PVC) and the earliest ventricular activation was from the RVOT, an initial ablation was performed in the RVOT in all patients. However, RF catheter ablation at the RVOT resulted in a QRS morphology change in all patients, so thereafter PA mapping and ablation was performed. A characteristic potential during sinus rhythm and/or the arrhythmia was recorded at the successful PA ablation site in all patients. A perfect or good pace map was obtained in 7 (70%) of 10 patients. The successful ablation site was the septal side of the PA close to the posterolateral attachment in 9 patients (75%) and the septal side close to the anterior attachment in the remaining 3 (25%). No PA-VT/PVCs recurred during follow-up of 27 +/- 13 months. CONCLUSION: PA-VT/PVCs should always be considered when the ECG suggests RVOT-VT/PVCs and RF catheter ablation in the RVOT results in both a failed ablation and a change in QRS morphology. PA-VT/PVCs often originate from the septal side of the PA.

Efficacy and safety of the additional bepridil treatment in patients with atrial fibrillation refractory to class I antiarrhythmic drugs.

BACKGROUND: Bepridil has multiple ion-channel blocking effects and is expected to be useful for managing atrial fibrillation (AF). The purpose of this study was to clarify the efficacy and safety of additional treatment with bepridil in patients with AF who had been treated with class I antiarrhythmic drugs (AADs). METHODS AND RESULTS: Bepridil (50-200 mg/day) was given to 76 patients with either paroxysmal (n=49) or persistent AF (n=27). All patients had been treated with class I AADs (1.9+/-0.9 drugs/patient) that failed to control the AF. With the addition of bepridil, the frequency of symptomatic AF episodes decreased to less than 10% in 38 (78%) patients with paroxysmal AF, and sinus rhythm was restored within 3 months and maintained during the follow-up in 20 (74%) patients with persistent AF. Efficacy was usually obtained with a small to moderate dose (50-150 mg/day) of bepridil. During a mean follow-up period of 27+/-22 months, no potential complications occurred in any of the patients. CONCLUSIONS: The addition of bepridil to class I AADs is effective and safe for AF, but careful observation using periodic ECG recordings is essential for avoiding torsades de pointes caused by QT prolongation.

Maximum ventricular dyssynchrony predicts clinical improvement and reverse remodeling during cardiac resynchronization therapy.

BACKGROUND: Tissue synchronization imaging (TSI) and tissue tracking imaging (TTI) might facilitate the evaluation of ventricular dyssynchrony. METHODS: In 22 patients, TSI and TTI were performed before and < 1 month after onset of cardiac resynchronization therapy (CRT). With TSI guidance, maximum left ventricular (LV) intraventricular conduction delay (IVCDmax) was the greatest difference in time-to-peak velocity between septum and lateral wall. IVCD between the basal septum and lateral wall (IVCDbase) was also measured. Using TTI, the mean peak myocardial displacement of the basal septal and lateral walls (PMDbase), and the temporal coefficient of variation of the PMD in six LV regions (CV-PMDLV) were measured. The patients were divided into responders (whose LV end-systolic volume decreased by >/= 15% during a 27 +/- 9 months follow-up) and nonresponders. RESULTS: Before CRT, IVCDbase was similar in both groups, and remained unchanged within the 1st month of CRT in both groups. However, before CRT, IVCDmax was greater in responders than in nonresponders (P < 0.05), and decreased only in the responders during CRT (P < 0.05). No significant difference was observed in PMDbase or CV-PMDLV between the two groups, before or during CRT. CONCLUSIONS: TSI was useful to measure IVCDmax. A greater IVCDmax before CRT that decreased shortly after onset of CRT may predict long-term clinical improvement in CRT recipients.

Ablation of idiopathic ventricular tachycardia in two separate regions of the outflow tract: prevalence and electrocardiographic characteristics.

Few studies have clarified the prevalence and characteristics of idiopathic outflow tachycardia (OT-VT) with an altered QRS morphology after radiofrequency catheter ablation (RFCA), requiring additional RFCA applications at a different portion of the outflow tract (OT) to abolish the OT-VT. Among 344 patients (97 VTs and 247 premature ventricular contractions), 12 (3.5%; VTs-7, PVCs-5; 6 women) had dynamic QRS morphology changes following the RFCA, requiring additional RFCA applications at a different portion to abolish the OT-VT. In 8 of 12 patients (67%), this phenomenon occurred following RFCA at right (RVOT; n = 7) or left ventricular (LVOT; n = 1) endocardial sites of the OT: The second OT-VT was consistently associated with an increase in the R-wave amplitude in the inferior leads, and in five it was finally abolished by RFCA at the left sinus of Valsalva (LSV). Conversely, in four patients (33%), the second OT-VT appeared after RFCA at the LSV: two required additional RFCA applications at the LVOT to abolish the second OT-VT, and one at the RVOT, and all were associated with a decrease in the R-wave amplitude in the inferior leads. This kind of dynamic QRS morphology change was often observed when RFCA was applied to either the first or second OT-VT at a right or left ventricular endocardial site, with the other site being the LSV. A detailed continuous observation of the QRS morphology, especially of the R-wave in the inferior leads, is important for identifying changes in the QRS morphology during RFCA.

Prevalence and characteristics of left atrial tachycardia following left atrial catheter ablation.

BACKGROUND: Left atrial tachycardia (AT) is a complication of left atrial catheter ablation (LACA) of atrial fibrillation (AF). However, its prevalence and characteristics have not been sufficiently clarified. METHODS: We divided 121 patients who underwent LACA into 2 groups based on the results of AT occurrence after LACA (follow-up period; 12 +/- 7 months): an AT+ group and AT- group. RESULTS: New-onset left AT occurred in 30 patients (25%) 31 +/- 51 days after LACA. Among the 26 patients with an early onset of AT, 4 underwent a second ablation for AT, and 21 became free of AT within 6 months without a repeat ablation procedure. Among the 4 patients with a late onset of AT (> 2 months after the LACA), the tachycardia remitted without a repeat ablation procedure in a single patient within 6 months. Among 71 patients who underwent LACA with additional ablation lines, 22 (31%) developed new-onset left AT. Among 50 patients who underwent LACA alone, 8 (16%) developed new-onset left AT (P = 0.02). CONCLUSIONS: New-onset left AT is a frequent complication of LACA for AF, especially in men and in patients with a low left ventricular ejection fraction. Early (< 2 months) onset AT does not require a repeat ablation because it often represents a transient phenomenon and disappears spontaneously.

Left atrial catheter ablation promotes vasoconstriction of the right coronary artery.

BACKGROUND: Multiple cardiac ganglia are present in the left atrial (LA) region, and marked changes in autonomic nervous activity can occur after left atrial catheter ablation (CA) for atrial fibrillation (AF). Vasospastic angina involving the inferior wall of the left ventricle has been reported as a complication shortly after LACA. METHODS: We studied 20 patients with drug-refractory AF who underwent LACA, performed to encircle the left- and right-sided pulmonary veins, 1 to 2 cm from their ostia under fluoroscopic guidance. Quantitative coronary angiography was performed before and after LACA, and we analyzed the minimal lesion diameter (MLD) of the proximal segment of the coronary arteries, and the basal tone, the baseline percent constriction versus maximal dilation after nitroglycerin administration. RESULTS: No significant difference was observed in MLD or basal tone of the left coronary arteries after LACA. However, in the right coronary artery (RCA), the basal MLD was smaller (P < 0.01) and the basal tone was greater (P < 0.05) after than before LACA. No correlation was found between the baseline MLD or tone of the RCA and total amount of radiofrequency energy delivered or procedure duration. In 75% of RCA, the baseline MLD was smaller after than before LACA, which was significantly higher (P < 0.01) than observed in the left coronary arteries (38%). CONCLUSION: Vasoconstriction was promoted in the RCA shortly after LACA, which may explain the variant angina reported after LACA.

Idiopathic ventricular arrhythmias originating from the tricuspid annulus: Prevalence, electrocardiographic characteristics, and results of radiofrequency catheter ablation.

BACKGROUND: Idiopathic ventricular tachycardias (VTs) and premature ventricular contractions (PVCs) arising from the tricuspid annulus have been reported. OBJECTIVE: The purpose of this study was to clarify the prevalence and characteristics of VT/PVCs originating from the tricuspid annulus. METHODS: The ECG characteristics and results of radiofrequency (RF) catheter ablation were analyzed in 454 patients with idiopathic VT/PVCs. RESULTS: Thirty-eight (8%) patients had VT/PVCs arising from the tricuspid annulus: 28 VT/PVCs (74%) originated from the septal portion of the tricuspid annulus and the remaining 10 (26%) from the free wall of the tricuspid annulus. QRS duration and Q-wave amplitude in each of leads V1-V3 were greater in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (all P < .01). "Notching" of the QRS complex was observed more often in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (P < .01). A Q wave in lead V1 was observed more often in VT/PVCs arising from the septum of the tricuspid annulus than those from the free wall of the tricuspid annulus (P < .005). R-wave transition occurred beyond lead V3 more often in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (P < .005). RF catheter ablation eliminated 90% of the VT/PVCs arising from the free wall of the tricuspid annulus but only 57% of the VT/PVCs arising from septum of the tricuspid annulus. CONCLUSION: Idiopathic VT/PVCs arising from tricuspid annulus are not rare, and the detailed origin can be determined by ECG analysis. The preferential site of origin was the septum but also could be the free wall of the tricuspid annulus.

Significance and utility of plasma brain natriuretic peptide concentrations in patients with idiopathic ventricular arrhythmias.

BACKGROUND: Secretion of B-type natriuretic peptide (BNP) appears to be regulated mainly by wall tension, and an increase in the plasma BNP concentration is considered to reflect ventricular structural and functional abnormalities. The aim of this study was to clarify the significance and utility of the measurement of the plasma BNP in the setting of idiopathic ventricular arrhythmias (I-VT/PVCs). METHODS: This study included 135 patients with symptomatic, monomorphic I-VT/PVCs (73 women; 53 +/- 17 years; 50 ventricular tachycardias [VTs], 85 premature ventricular contractions) who underwent radiofrequency catheter ablation. None had structural heart disease or renal dysfunction. RESULTS: The plasma BNP concentration exceeded the normal range (>18.4 pg/mL; high BNP concentration) in 79 patients (56%). The high BNP concentration was found more often in I-VT/PVCs originating from the left ventricle (LV; 74%) than the right ventricle (RV; 49%; P < 0.01). The plasma BNP concentration correlated with the age (P = 0.0001) and frequency of premature ventricular contractions (P < 0.0001), and left-sided I-VT/PVCs and the presence of controlled hypertension were independent predictors of a high BNP concentration (both P < 0.05). In patients with a successful ablation and high BNP concentration before the ablation, the BNP concentration decreased to the normal range in 61% of patients after ablation. In patients with a failed ablation, the BNP concentration did not decrease to the normal range after ablation in any of the patients (P < 0.0005). CONCLUSIONS: The plasma BNP concentration was elevated in about 60% of the patients with symptomatic I-VT/PVCs. Normalization of the high BNP concentration after ablation may indicate a successful ablation.

Response of adrenomedullin system to cytokine in cardiac fibroblasts-role of adrenomedullin as an antifibrotic factor.

OBJECTIVE: The adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function. However, several aspects of the local action of adrenomedullin remain unclear. We studied the effects of interleukin 1-beta (IL-1beta) on the adrenomedullin system in cardiac fibroblasts and also examined the pathophysiological significance of such effects. METHODS: We cultured rat neonatal cardiac fibroblasts with or without IL-1beta and measured (1) two molecular forms of adrenomedullin in culture medium by specific immunoradiometric assay; (2) gene expression of adrenomedullin, calcitonin receptor like receptor (CRLR), receptor activity modifying protein2 (RAMP2), and RAMP3, components of the adrenomedullin receptor, by Northern blot analysis or RT-PCR analysis; (3) intracellular cAMP levels in response to exogenously administered adrenomedullin; and (4) (3)H-proline incorporation with and without a specific adrenomedullin antisense oligodeoxynucleotide. RESULTS: (1) IL-1beta time-dependently increased the levels of two molecular forms of adrenomedullin, adrenomedullin-mature and adrenomedullin-glycine (P<0.01). In contrast to known levels in plasma (about 10%), adrenomedullin-mature was a major molecular form in the culture medium of cardiac fibroblasts and myocytes (65-80%). (2) IL-1beta significantly increased gene expression of adrenomedullin and its receptor components (adrenomedullin: +46%, CRLR: +460%, RAMP2: +32%, RAMP3: +350%, all P<0.01). (3) Preincubated IL-1beta elevated the intracellular cAMP response to exogenous adrenomedullin administered at a concentration of 10(-7) M (+26%, P<0.05). (4) Adrenomedullin antisense oligodeoxynucleotide treatment significantly lowered adrenomedullin-mature levels in culture medium (-50%). Adrenomedullin nonsense oligodeoxynucleotide treatment did not change (3)H-proline incorporation or mRNA levels of collagen I and III, whereas adrenomedullin antisense oligodeoxynucleotide treatment significantly increased (3)H-proline incorporation and mRNA levels of collagen I and III in IL-1beta-treated cardiac fibroblasts. CONCLUSION: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels. This may beneficially modulate the pathophysiology of certain cardiac diseases.

Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic.

OBJECTIVE: We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. METHOD: We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. RESULTS: SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. CONCLUSION: Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.

Different secretion patterns of two molecular forms of cardiac adrenomedullin in pressure- and volume-overloaded human heart failure.

BACKGROUND: In the final step of production of adrenomedullin (AM), an inactive intermediate form of glycine-extended AM (AM-glycine) is converted to the active mature form of adrenomedullin (AM-mature) by enzymatic amidation. Recent studies have revealed that AM-mature and AM-glycine circulate in human plasma. In this study, we investigated the differences of the concentrations of cardiac AM between pressure-overloaded (PO) heart failure (HF) and volume-overloaded (VO)-HF in humans. METHODS AND RESULTS: We measured AM-mature and AM-glycine by immunoradiometric assays in pericardial fluid and plasma in 38 patients who underwent valve replacement surgery (PO-HF: aortic stenosis, n=14; VO-HF: aortic or mitral regurgitation, n=24). Stable coronary artery disease with normal left ventricular function served as the control (n=24). Plasma AM-mature (VO-HF: +59%, PO-HF: +65%, P<.05) and AM-glycine (VO-HF: +43%, PO-HF: +50%, P<0.05) were similarly higher in the 2 HF groups than in the control group. Interestingly, pericardial fluid AM-mature was markedly higher than that in plasma (control: +789%, VO-HF: +1050%, PO-HF: +1745%, all P<.001). Pericardial fluid AM-mature was higher in VO-HF (+106%, P<.01) than in controls and they were further increased in PO-HF (+243%, P<.05). Pericardial fluid molecular forms of AM correlated with left ventricular systolic pressure, but not with left ventricular end-diastolic volume index in PO-HF. In contrast, they correlated with left ventricular end-diastolic volume index, but not with left ventricular systolic pressure in VO-HF. CONCLUSION: These results suggest that cardiac AM is differently regulated from plasma AM and that cardiac AM production is upregulated in both types of HF in response to each different stimulus.

Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats.

OBJECTIVE: The present study was designed to clarify whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor. METHOD AND RESULTS: Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide (ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinasealpha, Rho-kinasebeta, collagen I and collagen III, and transforming growth factor-beta (TGF-beta) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (-25%) and ANP (-49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-beta (-20%), collagen I (-23%), and collagen III (-24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS. CONCLUSION: These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.

Association of plasma atrial natriuretic peptide, N-terminal proatrial natriuretic peptide, and brain natriuretic peptide levels with coronary artery stenosis in patients with normal left ventricular systolic function.

PURPOSE: To examine whether coronary artery stenosis affects plasma levels of atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (proANP), and brain natriuretic peptide (BNP) in patients with normal left ventricular systolic function. METHODS: We studied 104 consecutive patients with normal left ventricular function and suspected coronary artery stenosis. Plasma natriuretic peptide levels were measured by immunoradiometric assays. RESULTS: Plasma levels of ANP, N-terminal proANP, and BNP were higher in patients with (n = 65) than in those without (n = 39) coronary artery stenosis, whereas hemodynamic variables were similar. Patients who had coronary artery stenosis with only distal lesions (n = 36) had higher levels of all three natriuretic peptides than did patients with no coronary artery stenosis. N-terminal proANP levels were significantly higher in patients who had coronary artery stenosis with proximal lesions (n = 29) than in patients who had coronary artery stenosis with only distal lesions and those with no coronary artery stenosis. Multiple logistic regression analysis revealed that N-terminal proANP, but not ANP or BNP, was independently associated with coronary artery stenosis after adjusting for clinical and demographic variables (odds ratio per 100 fmol/mL increase = 1.9; 95% confidence interval: 1.9 to 2.6; P = 0.01). However, the sensitivity, specificity, and positive and negative predictive values of each peptide were not sufficiently high to be used for prediction. CONCLUSION: N-terminal proANP may be associated with clinically important coronary artery stenosis in patients with normal left ventricular systolic function, but its clinical usefulness may be limited.

Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats.

Acute administration of adrenomedullin (AM) exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure (HF). However, chronic effects of AM administration on HF remain unknown. This study sought to examine the effect of chronic infusion of AM on progression of HF in rat. Human recombinant AM was administered by osmotic minipump for 7 weeks in the HF model of Dahl salt-sensitive rats. The effect was compared with vehicle and diuretic treatment group. Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight (P<0.01 for all). AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels (P<0.01 for all). AM also inhibited the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide (P<0.01 for all). These changes were associated with the improvement of cardiac output and systemic vascular resistance (both P<0.05). Furthermore, AM improved left ventricular end-systolic elastance (P<0.01). These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with diuretic (P<0.05) and vehicle (P<0.01) treatment groups. These results suggest that endogenous AM plays a compensatory role in HF and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.

Upregulation of ligand, receptor system, and amidating activity of adrenomedullin in left ventricular hypertrophy of severely hypertensive rats: effects of angiotensin-converting enzyme inhibitors and diuretic.

OBJECT: We investigated the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand, receptor and amidating activity in the hypertrophied heart in severe hypertension. METHOD: We studied the following four groups: control Wistar-Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), 8 weeks captopril-treated SHR-SP, and 8 weeks trichlormethiazide-treated SHR-SP. AM precursor is converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly is converted to active mature AM (AM-m) by enzymatic amidation. We measured AM-m, AM-total (AM-T; AM-T = AM-m + AM-Gly), and atrial natriuretic peptide (ANP) in the plasma and left ventricle (LV) by immunoradiometric assay. We also measured gene expression of AM and ANP was and gene expression and protein levels of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor-activity modifying protein (RAMP) 2 and RAMP3. RESULTS: At 7 weeks old, SHR-SP had higher blood pressure and ANP mRNA levels and lower plasma AM-T compared with WKY, however, there were no differences in other indices between the two groups. At 17 weeks old, SHR-SP had increased blood pressure, LV weight, plasma and LV ANP levels and mRNA levels of ANP compared with WKY. AM-m and AM-T levels in plasma (AM-m: + 31%; AM-T: + 56%) and the LV (AM-m: + 84%; AM-T: + 31%) were significantly higher in SHR-SP than in WKY. The LV tissue AM-m/AM-T ratio was significantly higher in SHR-SP (93.2%) than in WKY. The mRNA levels of AM, CRLR, and RAMP2 in the LV were significantly higher in SHR-SP than in WKY. Captopril and trichlormethiazide similarly decreased blood pressure and LV hypertrophy with the reduction of the LV AM-m and AM-T levels and mRNA abundance of AM and its receptor component. CONCLUSION: These results suggest that cardiac AM system is upregulated in the hypertrophied heart in this hypertension model. Considering that AM acts as an anti-remodeling autocrine and/or paracrine factor, upregulation of the AM system may modulate the pathophysiology in LV hypertrophy.