[Show abstract][Hide abstract] ABSTRACT: Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on the cardiac function during ischemia-reperfusion injury. In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10-9 mol/L of aldosterone for 10 minutes before ischemia, and the response to ischemia-reperfusion injury was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, aldosterone preconditioning significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure, associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia-reperfusion. Of note, mineralocorticoid receptor inhibitor, eplerenone, did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemia-reperfusion, compared with that observed in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia-reperfusion in a mineralocorticoid receptor-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.
Preview · Article · Jun 2014 · Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Background
Glucocorticoids as well as mineralocorticoid have been shown to play essential roles in the regulation of electrical and mechanical activities in cardiomyocytes. Excess of these hormones is an independent risk factor for cardiovascular disease. Intracellular sodium ([Na+]i) kinetics are involved in cardiac diseases, including ischemia, heart failure and hypertrophy. However, intrinsic mediators that regulate [Na+]i in cardiomyocytes have not been widely discussed. Moreover, the quantitative estimation of altered [Na+]i in cultured cardiomyocytes and the association between the level of [Na+]i and the severity of pathological conditions, such as hypertrophy, have not been precisely reported.
Methods and results
We herein demonstrate the quantitative estimation of [Na+]i in cultured neonatal rat cardiomyocytes following 24 h of treatment with corticosterone, aldosterone and dexamethasone. The physiological concentration of glucocorticoids increased [Na+]i up to approximately 2.5 mM (an almost 1.5-fold increase compared to the control) in a dose-dependent manner; this effect was blocked by a glucocorticoid receptor (GR) antagonist but not a mineralocorticoid receptor antagonist. Furthermore, glucocorticoids induced cardiac hypertrophy, and the hypertrophic gene expression was positively and significantly correlated with the level of [Na+]i. Dexamethasone induced the upregulation of Na+/Ca2 + exchanger 1 at the mRNA and protein levels.
The physiological concentration of glucocorticoids increases [Na+]i via GR. The dexamethasone-induced upregulation of NCX1 is partly involved in the glucocorticoid-induced alteration of [Na+]i in cardiomyocytes. These results provide new insight into the mechanisms by which glucocorticoid excess within a physiological concentration contributes to the development of cardiac pathology.
Full-text · Article · Jun 2014 · IJC Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Intracellular sodium ([Na+]i) kinetics are involved in cardiac diseases including ischemia, heart failure, and hypertrophy. Because [Na+]i plays a crucial role in modulating the electrical and contractile activity in the heart, quantifying [Na+]i is of great interest. Using fluorescent microscopy with sodium-binding benzofuran isophthalate (SBFI) is the most commonly used method for measuring [Na+]i. However, one limitation associated with this technique is that the test cannot simultaneously evaluate the effects of several types or various concentrations of compounds on [Na+]i. Moreover, there are few reports on the long-term effects of compounds on [Na+]i in cultured cells, although rapid changes in [Na+]i during a period of seconds or several minutes have been widely discussed.
We established a novel technique for quantifying [Na+]i in cultured neonatal rat cardiomyocytes attached to a 96-well plate using a microplate reader in combination with SBFI and probenecid. We showed that probenecid is indispensable for the accurate measurement because it prevents dye leakage from the cells. We further confirmed the reliability of this system by quantifying the effects of ouabain, which is known to transiently alter [Na+]i. To illustrate the utility of the new method, we also examined the chronic effects of aldosterone on [Na+]i in cultured cardiomyocytes.
Our technique can rapidly measure [Na+]i with accuracy and sensitivity comparable to the traditional microscopy based method. The results demonstrated that this 96-well plate based measurement has merits, especially for screening test of compounds regulating [Na+]i, and is useful to elucidate the mechanisms and consequences of altered [Na+]i handling in cardiomyocytes.
Full-text · Article · Dec 2013 · BMC Research Notes
[Show abstract][Hide abstract] ABSTRACT: In addition to classical adrenal cortical biosynthetic pathway, there is increasing evidence that aldosterone is produced in extra-adrenal tissues. Although we previously reported aldosterone production in the heart, the concept of cardiac aldosterone synthesis remains controversial. This is partly due to lack of established experimental models representing aldosterone synthase (CYP11B2) expression in robustly reproducible fashion. We herein investigated suitable conditions in neonatal rat cardiomyocytes (NRCMs) culture system producing CYP11B2 with considerable efficacy. NRCMs were cultured with various glucose doses for 2-24 hours. CYP11B2 mRNA expression and aldosterone concentrations secreted from NRCMs were determined using real-time PCR and enzyme immunoassay, respectively. We found that suitable conditions for CYP11B2 induction included four-hour incubation with high glucose conditions. Under these particular conditions, CYP11B2 expression, in accordance with aldosterone secretion, was significantly increased compared to those observed in the cells cultured under standard-glucose condition. Angiotensin II receptor blocker partially inhibited this CYP11B2 induction, suggesting that there is local renin-angiotensin-aldosterone system activation under high glucose conditions. The suitable conditions for CYP11B2 induction in NRCMs culture system are now clarified: high-glucose conditions with relatively brief period of culture promote CYP11B2 expression in cardiomyocytes. The current system will help to accelerate further progress in research on cardiac tissue aldosterone synthesis.
[Show abstract][Hide abstract] ABSTRACT: We present the case of a patient who developed regular, narrow QRS tachycardia after ablation for long-standing persistent atrial fibrillation. During the electrophysiological study, this tachycardia was diagnosed as macroreentrant atrial tachycardia circulating around the mitral annulus. Catheter ablation was performed to treat the tachycardia by targeting the linear region between the annulus and the left inferior pulmonary vein. Although linear radiofrequency application along the mitral isthmus (MI) line resulted in the termination of this tachycardia, a unidirectional conduction block was observed through the MI. Bidirectional conduction block was subsequently achieved by delivering supplemental radiofrequency energies at the gap on the MI.
No preview · Article · Oct 2013 · Journal of Arrhythmia
[Show abstract][Hide abstract] ABSTRACT: Thrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle.
We examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle.
The thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium.
The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.
[Show abstract][Hide abstract] ABSTRACT: AIMS: Although patients with paroxysmal atrial fibrillation (AF) and prolonged sinus pauses [tachycardia-bradycardia syndrome (TBS)] are generally treated by permanent pacemaker, catheter ablation has been reported to be a curative therapy for TBS without pacemaker implantation. The purpose of this study was to define the potential role of successful ablation in patients with TBS.METHODS AND RESULTS: Of 280 paroxysmal AF patients undergoing ablation, 37 TBS patients with both AF and symptomatic sinus pauses (age: 62 ± 8 years; mean maximum pauses: 6 ± 2 s) were analysed. During the 5.8 ± 1.2 years (range: 5-8.7 years) follow-up, both tachyarrhythmia and bradycardia were eliminated by a single procedure in 19 of 37 (51%) patients. Repeat procedures were performed in 14 of 18 patients with tachyarrhythmia recurrence (second: 12 and third: 2 patients). During the repeat procedure, 79% (45 of 57) of previously isolated pulmonary veins (PVs) were reconnected to the left atrium. Pulmonary vein tachycardia initiating the AF was found in 46% (17 of 37) and 43% (6 of 14) of patients during the initial and second procedure, respectively. Finally, 32 (86%) patients remained free from AF after the last procedure. Three patients (8%) required pacemaker implantation, one for the gradual progression of sinus dysfunction during a period of 6.5 years and the others for recurrence of TBS 3.5 and 5.5 years after ablation, respectively.CONCLUSION: Catheter ablation can eliminate both AF and prolonged sinus pauses in the majority of TBS patients. Nevertheless, such patients should be continuously followed-up, because gradual progression of sinus node dysfunction can occur after a long period of time.
[Show abstract][Hide abstract] ABSTRACT: The magnitude of improvement of acute heart failure achieved during treatment varies greatly among patients. We examined changes in the plasma B-type natriuretic peptide (BNP) levels of patients with acute heart failure and attempted to elucidate the clinical factors associated with amelioration of acute heart failure.
The study population consisted of 208 consecutive patients admitted to our institution with acute heart failure. We measured plasma BNP levels before and after treatment of acute heart failure and evaluated these levels based on median age, body mass index (BMI), creatinine (Cr) level, and left ventricular ejection fraction (EF). Plasma BNP levels before treatment were equivalent between the younger and older age groups; however, plasma BNP levels after treatment were higher in the older age group (p<0.01). Plasma BNP levels before treatment were significantly high in the lower BMI group (p<0.05) and the higher Cr group (p<0.01). Similarly, plasma BNP levels after treatment were high in both the lower BMI and higher Cr groups (p<0.01 for both). In the low EF group, plasma BNP levels before treatment were significantly high (p<0.01), while plasma BNP levels after treatment were equivalent to those in the high EF group. A multiple linear regression analysis revealed that Cr was positively correlated and BMI and EF were negatively correlated with plasma BNP levels before treatment; however, the contributions of age, BMI, and Cr in reducing plasma BNP levels were more significant after treatment.
The contributions of clinical factors working against amelioration of heart failure vary before and after treatment. Regarding plasma BNP levels, older age, very low BMI, and the presence of renal dysfunction eventually act to prevent amelioration of acute heart failure. Systolic dysfunction does not act against amelioration of acute heart failure.
Full-text · Article · Sep 2012 · European Heart Journal: Acute Cardiovascular Care
[Show abstract][Hide abstract] ABSTRACT: Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24-48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 ± 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 ± 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered.
No preview · Article · Aug 2012 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Both aldosterone and Akt signaling play pivotal roles in the pathogenesis of heart failure. However, little is known about the correlation between them. We herein investigated whether aldosterone interacts with Akt signaling in a coordinated manner in cardiomyocytes. Neonatal rat cardiomyocytes were stimulated with aldosterone for either a short (10-min) or long (24-h) time. The phosphorylation of Akt and its downstream effector, GSK3β, were transiently increased after short-term stimulation, which was blocked by either PI3K or Na+/H+ exchanger inhibitors, but not by the mineralocorticoid receptor antagonist, eplerenone. Long-term stimulation also significantly increased Akt-GSK3β phosphorylation and this effect was reduced by eplerenone. Thus, these results suggest that aldosterone activates Akt signaling via a biphasic reaction that occurs through different cascades. To understand the significance of the rapid action of aldosterone, cardiomyocytes were exposed to hydrogen peroxide for from 10 to 60 min. A short-term aldosterone stimulation (for up to 30 min) significantly protected cardiomyocytes from oxidative stress-induced cellular damage. Eplerenone did not abrogate this beneficial effect, while a PI3K inhibitor did. Therefore, during the early phase, aldosterone has favorable effects on cardiomyocytes, partly by acute activation of a mineralocorticoid receptor-independent cascade through the Na+/H+ exchanger, PI3K, and Akt. In contrast, its persistent activity produces pathological effects partly by chronic Akt activation in a mineralocorticoid receptor-dependent manner.
No preview · Article · Jul 2012 · Hormone and Metabolic Research
[Show abstract][Hide abstract] ABSTRACT: PV and Linear Ablation for CFAEs.
Linear ablations in the left atrium (LA), in addition to pulmonary vein (PV) isolation, have been demonstrated to be an effective ablation strategy in patients with persistent atrial fibrillation (PsAF). This study investigated the impact of LA linear ablation on the complex-fractionated atrial electrograms (CFAEs) of PsAF patients.
A total of 40 consecutive PsAF patients (age: 54 ± 10 years, 39 males) who underwent catheter ablation were enrolled in this study. Linear ablation of both roofline between the right and left superior PVs and the mitral isthmus line joining from the mitral annulus to the left inferior PV were performed following PV isolation during AF. High-density automated CFAE mapping was performed using the NAVX, and maps were obtained 3 times during the procedure (prior to ablation, after PV isolation, and after linear ablations) and were compared. PsAF was terminated by ablation in 13 of 40 patients. The mean total LA surface area and baseline CFAEs area were 120.8 ± 23.6 and 88.0 ± 23.5 cm(2) (74.2%), respectively. After PV isolation and linear ablations in the LA, the area of CFAEs area was reduced to 71.6 ± 22.6 cm(2) (58.7%) (P < 0.001) and 44.9 ± 23.0 cm(2) (39.2%) (P < 0.001), respectively. The LA linear ablations resulted in a significant reduction of the CFAEs area percentage in the region remote from ablation sites (from 56.3 ± 20.6 cm(2) (59.6%) to 40.4 ± 16.5 cm(2) (42.9%), P < 0.0001).
Both PV isolation and LA linear ablations diminished the CFAEs in PsAF patients, suggesting substrate modification by PV and linear ablations. (J Cardiovasc Electrophysiol, Vol. 23, pp. 962-970, September 2012).
No preview · Article · Apr 2012 · Journal of Cardiovascular Electrophysiology
[Show abstract][Hide abstract] ABSTRACT: We herein present the case of a 60-year-old male with narrow QRS tachycardia who had a remarkable PR prolongation during sinus rhythm. The tachycardia was diagnosed as a slow-fast atrioventricular nodal reentry tachycardia. Slow pathway ablation was performed after the confirmation of the presence of an antegrade fast pathway. Following the elimination of the slow pathway, the PR and atrio-His intervals became shortened from 470 and 420 to 170 and 120 ms, respectively. Moreover, the improvement of atrioventricular conduction after the slow pathway ablation lasted for at least 34 months.
No preview · Article · Feb 2012 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Chest X-rays and plasma B-type natriuretic peptide (BNP) levels are useful for diagnosing congestive heart failure. However, the relationship between plasma BNP levels and pulmonary congestion on chest X-rays often seems inconsistent. Extracardiac factors can directly alter plasma BNP levels, independent of cardiac function. In the present study, we examined the clinical factors that impact the diagnosis of heart failure by using chest X-rays and plasma BNP levels.
This study comprised 459 consecutive patients who were admitted to the cardiovascular division of our hospital for any reason and in whom chest X-rays and plasma BNP levels were measured within 12 hours after admission. The approximate BNP value associated with pulmonary congestion that was detectable by chest X-rays was 143 pg/mL, but this value was influenced by renal function, age, and body mass index (BMI). Furthermore, we examined the effect of these three extracardiac factors on plasma BNP levels in each stage of pulmonary congestion. We found that renal dysfunction and advanced age increased the plasma BNP levels, whereas a high BMI decreased the levels, and that the effect of BMI on plasma BNP levels was greater for severe heart failure.
Extracardiac factors should be considered when the relationship between the plasma BNP levels and the severity of pulmonary congestion on chest X-rays seems inconsistent. In particular, low levels of plasma BNP in patients with a high BMI should be carefully considered to avoid underestimating the degree of heart failure.
No preview · Article · Jan 2012 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: Obesity has recently been shown to have a favorable effect on the prognosis of patients with congestive heart failure (CHF), but only a few such studies are available in Japan. The purpose of the present study was to investigate whether the obesity paradox is still present after adjusting for CHF characteristics.
A total of 219 patients hospitalized with CHF were reviewed, and the impact of body mass index (BMI) on prognosis was examined. Patients were divided into 4 groups according to BMI quartiles. The endpoint was defined as all-cause death or unplanned CHF hospitalization. According to univariate analysis, a higher BMI was associated with better outcomes. High-BMI patients were younger, likely to be male, and had a higher prevalence of hypertension and diabetes. The plasma B-type natriuretic peptide (BNP) levels and blood urea nitrogen (BUN) levels were lower, while the serum hemoglobin and sodium levels were higher in high-BMI patients. The prevalence of atrial fibrillation was lower in high-BMI patients. Predictors for all-cause death or CHF hospitalization based on univariate analysis were age, prior CHF hospitalization, estimated glomerular filtration rate, plasma BNP levels, BUN levels, and serum hemoglobin and sodium levels. According to multivariate analysis, a high BMI was still associated with better outcomes.
High BMI was associated with better clinical outcomes in Japanese CHF patients.
No preview · Article · Nov 2011 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: We report a 48-year-old woman with manifest Wolff-Parkinson-White (WPW) syndrome and a long QT interval in her electrocardiogram, who represented the marked prolongation of QT interval after the successful catheter ablation for the accessory pathway. The increase in QT interval was completely restored to the baseline level 2 days after the procedure. Thus, the change in QT interval should be evaluated with particular caution after catheter ablation for WPW syndrome patients.