The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients.

Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ±â€¯3.41 g/m2/year in males and 1.69 ±â€¯2.73 g/m2/year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height2.7/year) of patients who received long-term ERT (male, 4.07 ±â€¯1.03 to 1.25 ±â€¯1.39; female, 2.31 ±â€¯0.81 to 0.78 ±â€¯1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT.

Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy.

BACKGROUND: Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition. METHODS: We investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆K210 knock-in mouse) (B6;129-Tnnt2tm2Mmto) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting. RESULTS: The immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆K210 knock-in mice. CONCLUSION: Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts.

Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-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 cardiac function during ischemia-reperfusion injury (IRI). 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 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone 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. Notably, the MR 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 the results for 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 MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

The role of successful catheter ablation in patients with paroxysmal atrial fibrillation and prolonged sinus pauses: outcome during a 5-year follow-up.

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.

Corticosteroids increase intracellular free sodium ion concentration via glucocorticoid receptor pathway in cultured neonatal rat cardiomyocytes.

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. CONCLUSIONS: 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.

A technique for quantifying intracellular free sodium ion using a microplate reader in combination with sodium-binding benzofuran isophthalate and probenecid in cultured neonatal rat cardiomyocytes.

BACKGROUND: 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. FINDINGS: 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. CONCLUSIONS: 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.

Rapid induction of aldosterone synthesis in cultured neonatal rat cardiomyocytes under high glucose conditions.

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.

An immunohistochemical analysis of tissue thrombin expression in the human atria.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.

Cardiac tamponade as an independent condition affecting the relationship between the plasma B-type natriuretic peptide levels and cardiac function.

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.

Improvement of atrioventricular conduction following catheter ablation of atrioventricular nodal reentry tachycardia in a patient with a prolonged PR interval.

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.

Substrate modification by pulmonary vein isolation and left atrial linear ablation in patients with persistent atrial fibrillation: its impact on complex-fractionated atrial electrograms.

UNLABELLED: PV and Linear Ablation for CFAEs. INTRODUCTION: 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. METHODS AND RESULTS: 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). CONCLUSION: 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).

Contribution of extracardiac factors to the inconsistency between plasma B-type natriuretic peptide levels and the severity of pulmonary congestion on chest X-rays in the diagnosis of heart failure.

OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Identification of a conduction gap of the mitral isthmus by using a novel high-density mapping catheter.

Peri-mitral atrial flutter, which is a type of macroreentrant atrial tachycardia circulating around the mitral annulus, was terminated with the guidance of the high-density mapping catheter. A 72-year-old woman with atrial fibrillation and atrial tachycardia presented with symptoms of congestive heart failure. The recurrent peri-mitral atrial flutter following the initial catheter ablation for atrial tachycardia and atrial fibrillation was terminated by radiofrequency application on the gap that was identified using a novel high-density mapping catheter.

Impact of body mass index on clinical outcome in patients hospitalized with congestive heart failure.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: High BMI was associated with better clinical outcomes in Japanese CHF patients.

Adenosine-induced atrial tachycardia and multiple foci initiating atrial fibrillation eliminated by catheter ablation using a non-contact mapping system.

A 47-year-old male with both atrial tachycardia and atrial fibrillation underwent catheter ablation. During the procedure, rapid administration of adenosine triphosphate induced atrial tachycardia. A non-contact mapping system revealed a focal atrial tachycardia originating from the lateral right atrium, which was successfully ablated. Following the ablation of tachycardia, atrial fibrillation was induced by the injection of adenosine along with multiple extra pulmonary vein foci, which were eliminated by the application of radiofrequency under the guidance of a non-contact mapping system.

Serial measurements associated with an amelioration of acute heart failure: an analysis of repeated quantification of plasma BNP levels.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.