Yasuki Nakada

Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction.

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120-1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes.

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.

Major Non-Cardiac Surgery Is a Risk Factor for Rapid Hemodynamic Progression of Non-Rheumatic Aortic Stenosis

BACKGROUND Inflammatory processes are suggested to play a pathogenic role in the development and progression of non-rheumatic aortic stenosis (AS). Major surgery causes an inflammatory reaction. With the increasing prevalence of non-rheumatic AS, the number of affected patients undergoing major surgery increases. We hypothesized that major non-cardiac surgery (MNCS) could accelerate the progression of non-rheumatic AS. METHODS AND RESULTS We enrolled 218 consecutive patients with non-rheumatic AS who underwent transthoracic echocardiography (TTE) at least twice more than 6 months apart. Study patients were divided into the MNCS group and the non-MNCS group. The MNCS group consisted of patients who underwent MNCS during the TTE follow-up interval. At baseline, peak pressure gradient across the aortic valve (AVG) was similar between the groups. Also baseline clinical characteristics and TTE follow-up interval were similar. The annual rate of peak AVG increase was much higher in the MNCS group than in the non-MNCS group. The proportion of patients with rapid hemodynamic progression was much higher in the MNCS group than in the non-MNCS group. Multiple logistic regression analysis showed that MNCS was an independent predictor of rapid hemodynamic progression of non-rheumatic AS. CONCLUSIONS The present study indicates for the first time that MNCS is associated with the rapid progression of non-rheumatic AS.

Prognostic Value of Urinary Neutrophil Gelatinase‐Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure

Background Urinary neutrophil gelatinase‐associated lipocalin (U‐NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U‐NGAL on the first day of admission for the occurrence of acute kidney injury and long‐term outcomes in acute decompensated heart failure patients. Methods and Results We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U‐NGAL in 24‐hour urine samples collected on the first day of admission. Primary end points were all‐cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U‐NGAL levels (32.5 μg/gCr). The high‐U‐NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low‐U‐NGAL group (P=0.0012). Kaplan‐Meier analysis revealed that the high‐U‐NGAL group exhibited a worse prognosis than the low‐U‐NGAL group in all‐cause death (hazard ratio 2.07; 95%CI 1.38‐3.12, P=0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28‐4.24, P=0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13‐2.77, P=0.0119). The addition of U‐NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all‐cause mortality (P=0.0083). Conclusions In acute decompensated heart failure patients, an elevated U‐NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis.

Alteration of β-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study

Accumulating evidence indicates alteration of the β-adrenoceptor (AR), such as desensitization and subtype switching of its coupling G protein, plays a role in the protection against catecholamine toxicity in heart failure. However, in human takotsubo syndrome (TTS), which is associated with a surge of circulating catecholamine in the acute phase, there is no histologic evidence of β-AR alteration. The purpose of this study was to investigate the involvement of alteration of β-AR signaling in the mechanism of TTS development. Left ventricular (LV) biopsied samples from 26 patients with TTS, 19 with normal LV function, and 26 with dilated cardiomyopathy (DCM) were studied. G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, which initiate the alteration of β-AR signaling, were more abundantly expressed in the myocardium in acute-phase TTS than in those of DCM and normal control as indicated by immunohistochemistry. The percentage of cardiomyocytes that showed positive membrane staining for GRK2 and β-arrestin2 was also significantly higher in acute-phase TTS. Sequential biopsies in the recovery-phase for two patients with TTS revealed that membrane expression of GRK2 and β-arrestin2 faded over time. This study provided the first histologic evidence of the involvement of alteration of β-ARs in the development of TTS.

Salt accelerates aldosterone-induced cardiac remodeling in the absence of guanylyl cyclase-A signaling.

AIMS Excess sodium causes the development of cardiovascular diseases in conjunction with enhancing renin-angiotensin-aldosterone system (RAAS). Natriuretic peptides are sodium regulators and prevent pathological cardiac alterations by counteracting RAAS. However, it is unknown whether natriuretic peptides inhibit the sodium effect in adverse cardiac alterations. Here, we investigated whether excess salt intake could exacerbate cardiac remodeling in mice with impaired natriuretic peptide signaling. MATERIALS AND METHODS Mice lacking the gene encoding the natriuretic peptide receptor, guanylyl cyclase-A (GC-A), and wild-type mice were administered with either a vehicle substance or a subpressor dose of aldosterone (100ng/kg/min), alongside low salt (0.001% NaCl), normal salt (0.6% NaCl), or high salt diets (6.0% NaCl) for four weeks. Mice were then sacrificed and the hearts were evaluated by histology and RT-PCR. KEY FINDINGS Salt load did not induce cardiac changes in vehicle and aldosterone groups in wild-type mice. On the other hand, cardiac hypertrophy and interstitial fibrosis were significantly exacerbated in a salt dependent manner in GC-A knockout (KO) mice administered aldosterone, and were associated with enhanced gene expression relevant to hypertrophy, fibrosis, and oxidative stress conditions. Of note, excess salt intake increased the expression of Sgk1, serum and glucocorticoid responsive kinase-1, in aldosterone-administered GC-A KO mice. These molecular changes were not observed in wild-type mice. SIGNIFICANCE The results of the present study demonstrate that excess salt intake induced cardiac remodeling in conjunction with aldosterone administration in GC-A KO mice, indicating that GC-A signaling attenuated the deleterious salt effect in aldosterone-induced cardiac remodeling.

Natriuretic peptides regulate sympathetic nervous activity independent of mineralocorticoid receptor

Background Natriuretic peptides (ANP/BNP) increase cGMP and exert cardiovascular protective effects via guanylyl cyclase A (GC-A) receptor, which is distributed in many organs such as the heart, the vasculature and the brain [1]. Sympathetic nervous system (SNS) as well as reninangiotensin-aldosterone-system contributes to cardiovascular disease. However, the endogenous effect of GC-A signaling on SNS is not investigated. Recent study shows that activated mineralocorticoid receptor (MR) in the hypothalamus induces systemic SNS activation [2], whereas ANP infusion in human inhibited SNS activity in the heart [3]. Notably, it is reported that ANP counteracts the deleterious effects of MR in the heart [4]. Therefore, we hypothesized that ANP suppresses MR activation in the brain and leads to the inhibition of SNS activity. Purpose To investigate whether ANP/GC-A signaling inhibits SNS activity through the suppression of the brain MR, we examined urinary catecholamine secretion in global GC-A receptor KO mice and the effect of intracerebroventricular (ICV) infusion of MR blocker. Methods and results We measured blood pressure (BP) and urinary norepinephrine (U-NE) secretion in wild type and global GC-A KO mice. Both BP and U-NE is significantly higher in GC-A KO than in wild type mice, indicating SNS is activated in GC-A KO mice. To study whether SNS activation is caused by the brain MR, we infused Eplerenone (MR blocker) into the ICV with osmotic mini pump for 2 weeks. Contrary to our hypothesis, both BP and U-NE did not change after 2 weeks ICV infusion, suggesting that activated SNS in GC-A KO is independent of MR. Furthermore, high sodium diet (NaCl 6%) for 2 weeks did not increase BP and U-NE in GC-A KO mice. MR protein expression in the hypothalamus was almost similar between GC-A KO and Wild type mice. These data suggest that SNS activity in GC-A KO mice is independent of MR and insensitive to sodium load. Unexpectedly, the most of GC-A KO mice died after ICV infusion of Losartan (AT1 receptor blocker), whereas wild type mice survived. Conclusion Natriuretic peptides/GC-A signaling regulates SNS activity independent of both brain MR and sodium load. Brain AT1 receptor might be important in the regulation of cardiovascular system in global GC-A KO mice.

Three Different Morphologies of Inferior Vena Cava Thrombosis: Case Reports

Inferior vena cava (IVC) thrombosis is a rare but significant complication in hospitalized patients. However, relevant information regarding IVC thrombosis, especially on its morphology, remains scarce. We present three cases of IVC thrombosis, with each showing a different morphology: mural, floating, and small polyp-like thrombus.

Worsening of Renal Function after Discharge is Lined to the Re-Hospitalization in Patients with ADHF

Background: Worsening of renal function (WRF) during the hospitalization of acute decompensated heart failure (ADHF) is associated with in-hospital mortality, however the influence of WRF after discharge on the re-hospitalization is not well known in patients with ADHF.Methods:We investigated the National CardiovAScular Center Acute DEcompensated Heart Failure (nCASCADE) database, a unicenter registry designed to prospectively collect data on each episode of hospitalization for ADHF(n5545). The sample consisted of 78 patients who had at least two hospitalizations during our observation period (2006-2009). We compared the clinical characteristics between the first (1st) and second (2nd) hospitalization. Results: In our study population, the age at the 1st hospitalization was 75612 years old, and the ratio of male was 54%. The period to the rehospitalization was 2106182 days. In the 2nd hospitalization, systolic blood pressure at admissions decreased (138mmHg vs 129mmHg, p!0.05), serum Cre level elevated (1.27mg/dl vs 1.48mg/dl, p!0.05), and anemia worsened (11.7g/dl vs 11.1g/dl, p!0.005) compared with the 1st hospitalization. However, there were no significant differences in left ventricle fractional shortening (20.8% vs 21.6%, NS) and serum brain natriuretic peptide levels (1107pg/ml vs 1241pg/ml, NS) between the two groups. The in-hospital mortality of the 2nd hospitalization was 9%. Conclusion: In patients with ADHF, decline of renal function by the rehospitalization may be associated with prognosis aggravation.