Hisamitsu Onitsuka

Adrenomedullin Administration Immediately After Myocardial Infarction Ameliorates Progression of Heart Failure in Rats

Background—Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats. Methods and Results—Rats were infused with 1.0 &mgr;g/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%; P<0.05) and body weight gain (32%; P<0.01) and reduced heart weight (−28%; P<0.01), lung weight (−26%; P<0.01), left ventricular (LV) end-diastolic pressure (11.4±2.0 versus 4.0±0.6 mm Hg, mean± SEM; P<0.01), collagen volume fraction of noninfarcted LV (−39%; P<0.05), and plasma levels of endogenous rat AM (−38%; P<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (−61%; P<0.01) and noninfarcted LV mRNA levels of ACE (−31%; P<0.05) and p22-phox (−30%; P<0.05). Conclusions—AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.

Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats

Objective: We previously reported that plasma adrenomedullin (AM) levels increase in patients with acute myocardial infarction (MI) and AM inhibits growth of rat cardiac myocytes and fibroblasts. The aim of this study was to examine the effects of long-term administration of AM on left ventricular (LV) remodeling, hemodynamic and hormonal parameters in a rat model of MI. Methods: Rats with MI induced by left coronary ligation were intravenously infused with 1.0 μg/h of recombinant human AM or saline by osmotic mini-pump. After infusion for 4 weeks, hemodynamic and hormonal studies were performed, and the myocyte size and collagen volume in non-infarct LV area were quantified morphometrically. Results: When compared with the MI rats infused with saline, continuous infusion of AM reduced the heart weight/body weight (4.4±0.2 vs. 3.6±0.1 g/kg, P <0.01), myocyte size (922±23 vs. 868±10 μm2, P <0.05) and collagen volume fraction of non-infarct LV area (7.6±0.8 vs. 4.8±0.5%, P <0.05), without affecting the infarct size. The AM infusion had no significant effect on the arterial pressure, but decreased the LV end-diastolic pressure (8.8±1.8 vs. 4.4±0.5 mmHg, P <0.05) in the MI rats. The plasma level of endogenous rat AM in the MI rats infused with human AM was reduced by 27% ( P <0.05), with a slight reduction of plasma atrial natriuretic peptide, compared with the control. Conclusions: Continuous administration of AM had beneficial effects on LV remodeling and hemodynamics in MI rats, suggesting the possibility that this peptide could be a useful therapeutic tool for acute MI.

Chronic Salt Loading Upregulates Expression of Adrenomedullin and Its Receptors in Adrenal Glands and Kidneys of the Rat

Abstract—The vasodilator peptide adrenomedullin (AM) elicits diuresis and natriuresis and inhibits aldosterone secretion. The aim of this study was to better understand the role of AM in maintaining water and electrolyte balance during chronic salt loading. Male Wistar rats were divided into a high salt (HS) group that received a diet containing 8% sodium chloride (NaCl) and a normal salt group that received a diet containing 0.4% NaCl. Plasma AM concentrations as well as expression of AM mRNA in the adrenal gland and kidney were then measured after 3, 7, 14, and 28 days. After 28 days, sodium and water excretion were significantly higher in HS rats than in control, although blood pressure and fluid volume were not significantly affected. Moreover, although plasma AM remained unchanged for up to 14 days, it was increased 2.5-fold in HS rats after 28 days on a high salt diet, and there were corresponding 3-fold and 1.5-fold increases in the levels of AM mRNA in the adrenal gland and kidney, respectively. At the same time, expression of calcitonin receptor-like receptor mRNA was significantly upregulated in both kidney and adrenal gland, as was expression of receptor activity-modify protein 1 (RAMP1) and RAMP2 mRNA in the adrenals and expression of RAMP3 in kidneys. Taken together, these results suggest that AM plays a role in the regulation of water and electrolyte balance in animals chronically ingesting high levels of salt.

Rat RAMP domains involved in adrenomedullin binding specificity

When coexpressed with receptor activity‐modifying protein (RAMP)2 or ‐3, calcitonin receptor‐like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2 or ‐3). Coexpression of rat (r)CRLR with rRAMP deletion mutants in HEK293T cells revealed that deletion of residues 93–99 from rRAMP2 or residues 58–64 from rRAMP3 significantly inhibits high‐affinity [125I]AM binding and AM‐evoked cAMP production, despite full cell surface expression of the receptor heterodimer. Apparently, these two seven‐residue segments are key determinants of high‐affinity agonist binding to rAM receptors and of receptor functionality. Consequently, their deletion yields peptides that are able to serve as negative regulators of AM receptor function.

Assessment of diastolic function using 16-frame 201Tl gated myocardial perfusion SPECT: a comparative study of QGS2 and pFAST2

ObjectiveThe objective of the present study is to investigate the correlations across various types of interface software for 201Tl gated myocardial perfusion SPECT (MPS) in calculating two common diastolic function parameters (DFx), peak-filling rates (PFR), and time-to-peak filling (TTPF).MethodsA total of 109 patients (66 men and 43 women; age 35–78 years) were studied. All patients were classi-fied into three groups (i.e., ND, no-defect group; SD, small-defect group; LD, large-defect group) to clarify the influence of perfusion defects possibly affecting the analysis. Two kinds of available software, namely, quantitative gated SPECT (QGS2) and perfusion and functional analysis for gated SPECT (pFAST2) with cardioGRAF were used to obtain PFR and TTPF. Finally, we analyzed the correlation between DFx obtained with the two different kinds of software.ResultsThe values of LVEF, PFR, and TTPF were assessed in all patients. In both the ND (correlation coefficients were 0.92, 0.79, and 0.99, respectively) and SD groups (correlation coefficients were 0.74, 0.88, and 0.98, respectively), a strong correlation was observed. In contrast, PFR did not show a significant correlation in the LD group.ConclusionsWith the two different kinds of software, QGS2 and pFAST2, the calculated PFR was almost equal and showed good correlations in both ND and SD groups. In contrast, the numerical value varied between the two methods, and its correlation was poor in the LD group. However, TTPF showed a good correlation regardless of the presence of perfusion defects, and the values were equal. TTPF was confirmed to be a stable diastolic index across the two kinds of software, QGS2 and pFAST2, in 201Tl gated MPS.

Differential gene expression of adrenomedullin receptors in pressure- and volume-overloaded heart--role of angiotensin II.

Left ventricular (LV) adrenomedullin (AM) gene expression differs between pressure overload (POL) and volume overload (VOL) and angiotensin II could be a critical stimulator of AM gene expression in POL and VOL models. Calcitonin receptor-like receptor (CRLR) co-expressed with receptor activity modifying protein 2 (RAMP2) or RAMP3 functions as an AM receptor. Levels of CRLR, RAMP2 and RAMP3 mRNA that were significantly increased within 24 h returned to the basal level at 5 days after the imposition of POL in the present study. In contrast, mRNA levels of CRLR and RAMP2 gradually increased over 6 weeks after the imposition of VOL. Continuous infusion of angiotensin II stimulated LV AM gene and AM receptor gene expression independently of LV peak-systolic and LV end-diastolic pressure. The gene expression of LV AM receptors increased in different types of cardiac overload. The present study revealed an intimate association between the AM signaling system and angiotensin II.

Osteoprotegerin is Secreted Into the Coronary Circulation: A Possible Association with the Renin-Angiotensin System and Cardiac Hypertrophy

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

Reciprocal Production of Adiponectin and C-reactive Protein in Coronary Circulation of Patients with and without Coronary Artery Disease

Introduction & The adipocyte-specifi c plasma protein adi ponectin was originally isolated from human adipose tissues. Adiponectin has anti-atherosclerotic properties such as the suppression of adhesion molecule expression on endothelial cells, the proliferation of vascular smooth muscle cells, and the transformation of macrophages to foam cells. Systemic clinical hypoadiponectinemia is closely associated with obesity, type 2 diabetes, and coronary artery disease (CAD) [1] . These data suggest that adiponectin contributes to suppressing the initiation and progression of atherosclerosis. We already reported that adiponectin is locally produced in the coronary circulation and might participate in modulating the coronary circulation [2] . Iacobellis et al. recently showed that epicardial adipose tissue expresses adiponectin protein and that the level is signifi cantly lower in patients with, than in those without, CAD [3] . Locally produced adiponectin might exert local anti-atherosclerotic action on the adjacent coronary artery [3] . These fi ndings together indicate that the locally produced adiponectin in the coronary circulation might be at least partly attributable to its production and secretion from epicardial adipose tissue and affect coronary atherosclerosis. However, whether the plasma level of adiponectin in the coronary circulation varies with the presence of CAD remains unknown. We therefore investigated the relationship between the presence of CAD and the amount of adiponectin production in the coronary circulation and compared with the amount of C-reactive protein (CRP) in the coronary circulation of patients with and without CAD.

SIGNIFICANCE OF CARDIAC TROPONIN T LEVELS IN SUPRAVENTRICULAR TACHYCARDIA

Background: Cardiac troponin T is sensitive and specific markers of myocardial injury and is used routinely for the diagnosis of acute coronary syndrome. Recently, the magunitude of troponin T levels in heart failure patients has been reported to correlate with severity of the disease and with adverse outcomes. They may suggest ongoing myocardial damage. In supraventricular tachycardia, common atrial flutter (AFL) and atrial tachycardia (AT) often produce changes in cardiac function and structure, but atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) do not. To our knowledge, there are no reports about the relationship between the levels of troponin T and the types of supraventricular tachycardia. We examined the clinical usefulness of previously unmeasurable levels of troponin T (hs-TnT) by using highly sensitive assay for the differential diagnosis of supraventricular tachycardia.