Effects of Rumen Fermentation Characteristics on Stress-Related Hormones and Behavior in Sheep.

This study investigated the relationship between rumen fermentation, stress-related hormones, and behavior in sheep with the aim of providing insights for improving animal welfare and feed management practices. Eight lambs were assigned to either a high concentration or control group. Blood samples were collected for hormone analysis, and an open field test was conducted to observe behavioral stress responses. The results showed that diet composition may affect the behavior of ruminants in response to stressors and novel situations, as evidenced by the higher number of escape attempts in the high-concentration group. In addition, analyses of individual volatile fatty acids (VFAs) showed a significant positive correlation between the acetic acid/propionic acid ratio and sniffing behavior of the novel object (p < 0.05, ρ = -0.414). These findings have important implications for animal welfare and feed management practices. Overall, this study provides insights into the potential impact of diet composition on the behavior of ruminants in response to stressors and novel situations, highlighting the importance of improving animal welfare through feed management practices. Further research is needed to fully elucidate the mechanisms underlying the complex relationship between rumen fermentation, stress-related hormones, and behavior in ruminant animals.

The impact of physical activity on cardiovascular mortality in the general population.

The beneficial effect of moderate physical activity (PA) on morbidity and mortality has been observed in the general population. However, the ideal intensity of PA for improving cardiovascular longevity in Japanese general population is uncertain. The aim of this study was to investigate the relationship between the PA and cardiovascular mortality in the general population. This longitudinal cohort study included 1,826 apparently healthy subjects who participated in a community-based health checkup. There were 31 cardiovascular deaths during 10-year follow-up. Subjects were divided into 4 groups based on the quartiles of PA (low, mild, moderate and high). Kaplan-Meier analysis and multivariate Cox proportional hazard analysis demonstrated that the most favorable cardiovascular prognosis was observed in subjects with moderate PA followed by those with mild PA. High PA as well as low PA were associated with higher cardiovascular mortality compared with mild and moderate PA. Noteworthy, in subjects with high PA, Cox hazard analysis revealed that previous cardiovascular disease, smoking, brain natriuretic peptide levels, and Framingham risk score were associated with cardiovascular mortality. The results suggest a U-shaped association between cardiovascular mortality and PA. Mild to moderate PA was associated with favorable cardiovascular outcomes in the Japanese general population. High PA might be associated with poor cardiovascular outcomes in subjects with a history of heart disease and high coronary risk factors.

Prognostic significance of the controlling nutritional (CONUT) score in patients with acute coronary syndrome.

BACKGROUND: Malnutrition is an independent predictor of adverse outcomes in patients with acute coronary syndrome. The controlling nutritional (CONUT) score has been applied to assess nutritional status, and has been reported to be associated with poor prognosis in patients with heart failure. However, the prognostic impact of the CONUT score in patients with acute coronary syndrome (ACS) remains to be elucidated. METHODS: We evaluated the CONUT score in 196 patients with ACS who underwent percutaneous coronary intervention. We divided the patients into four groups according to CONUT score (undernutrition degree: normal, CONUT 0-1 (reference); mild, CONUT 2-4; moderate, CONUT 5-8; severe, CONUT 9-12). The endpoint of the present study was composite events including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke. RESULTS: The median CONUT score was significantly higher in patients with composite events than in those without events (P = 0.0058). Kaplan-Meier analysis revealed that a significantly higher event rate in patients with severe malnutrition (log-rank test, P = 0.0222). In the multivariate Cox proportional hazards analysis, CONUT score was independently associated with composite events after adjustment for confounding factors (adjusted hazard ratio 1.284, 95% confidence interval 1.126-1.457, P = 0.0003). CONCLUSION: Higher CONUT scores were associated with unfavorable outcomes in patients with ACS. Malnutrition assessed by the CONUT score may provide valuable prognostic information in patients with ACS.

The effect of daily calf stroking frequency during the postnatal period on the establishment of the human-calf relationship.

OBJECTIVE: Stroking calves during the postnatal period could effectively improve humancalf relationships. The objective of this study is to examine how daily calf stroking frequency during the postnatal period affects the establishment of human-calf relationships. METHODS: Six calves were stroked by a trainer for 6 minutes once daily for 5 days after birth (D1). Six calves were stroked by a trainer for 3 minutes twice daily for 5 days after birth (D2). A further four calves were stared at but not stroked as the control group. The overall stroking or staring duration was the same for all groups, at 6 min/d and 30 min over 5 days. The tests for reactions to the stationary trainer in an unfamiliar environment and avoidance distance measurements for an approaching trainer were conducted at 1 month and 3 months after the treatment. RESULTS: Calves in both stroking groups approached significantly closer to the stationary trainer, vocalized less, and looked at the trainer shorter than the control group at 1 month. However, at 3 months, there was no significant difference between the D1 and the control group, whereas the D2 approached significantly closer to the trainer and vocalized less, and looked at the trainer for a shorter time than the control group. For the avoidance distance, the trainer could approach closer to both stroking groups than the control at 1 month, however, there was no difference among groups at 3 months. CONCLUSION: Our results suggested that the difference in the calf stroking procedure affected the established human-calf relationships, even though the total stroking duration was the same for all stroked calves. It is likely to be more effective to stroke more frequently than intensively when the aim is to establish better human-calf relationships within limited labor time.

Impact of pre-operative coronary artery disease on the clinical outcomes of patients with aortic aneurysms.

Aortic aneurysm is an increasingly important public health problem with high morbidity and mortality. It is associated with coronary artery disease (CAD), which is a comorbidity of high incidence that is reported to worsen perioperative complications and long-term clinical outcomes in patients with an aortic aneurysm. Patients with significant coronary artery stenosis may require coronary revascularization and/or optimal medical therapy in the perioperative period of aneurysm surgery. However, the prognostic impact of non-significant coronary artery stenosis not indicated for coronary revascularization on clinical outcomes of patients with aortic aneurysms remains unclear. We performed coronary angiography on 239 consecutive patients with thoracic and abdominal aortic aneurysms before endovascular aortic repair or surgical repair. The patients were divided into the following 3 groups according to the severity of stenosis of major coronary arteries: non-CAD group (with < 25% stenosis), non-significant CAD group (with ≥ 25% but < 75% stenosis), and significant CAD group (with ≥ 75% stenosis). CAD was diagnosed in 133 (56%) patients consisting of 48 (20%) patients with non-significant CAD and 85 (36%) patients with significant CAD. Thirty-nine major adverse cardiovascular and cerebrovascular events (MACCEs) occurred in a median follow-up period of 723 days. Kaplan-Meier analysis revealed that the risk of MACCEs was higher in the significant and non-significant CAD groups than in the non-CAD group. Multivariate Cox proportional hazard regression analysis showed that the risk of MACCEs was equally high in the non-significant CAD and significant CAD groups compared to that in the non-CAD group after adjustment for confounding factors. CAD is significantly associated with poor outcomes in patients with aortic aneurysms, irrespective of the significance of CAD.

Unmet needs for emergency care and prevention of prehospital death in acute myocardial infarction.

INTRODUCTION: Percutaneous coronary intervention (PCI) has successfully reduced the mortality of patients with acute myocardial infarction (AMI). However, patients with out-of-hospital cardiac arrest have high mortality, which is difficult to control by hospital staff. In this study, we investigated the prevalence of prehospital death (PHD) in patients with AMI. Furthermore, we investigated the risk factors associated with 30-day mortality in patients with AMI who survived PHD. METHODS: We investigated the prevalence of PHD using data from the Yamagata AMI registry and from death certification of the entire Yamagata Prefecture in Japan between 2010 and 2015. Furthermore, we investigated the risk factors for 30-day mortality in patients who survived PHD, using data from the Yamagata AMI registry from 1993 to 2015. AMI was identified by the International Classification of Diseases, 10th revision code I21. RESULTS: Out of the 6984 patients with AMI, 3771 patients had PHD. Patients with PHD were older and more likely to be women than those without PHD. More PHD occurred in winter and spring than in summer or autumn. Multivariate regression analysis showed that age, female sex, and winter onset were independently associated with PHD. We also investigated the risk factors associated with 30-day mortality in 9675 patients who survived PHD. The rate of PCI was remarkably lower in patients with acute death than in those without acute death. Multivariate regression analysis showed that age, anterior infarction, estimated glomerular filtration rate, Killip class, and PCI were independently associated with 30-day mortality after adjusting for confounding factors. CONCLUSION: Approximately half of the patients with AMI died before they could reach the destination hospital. Although emergency PCI is the most important factor in reducing 30-day mortality in patients with AMI, attempts to reduce patient delay and system delay are possibly needed to further reduce PHD.

HECT (Homologous to the E6-AP Carboxyl Terminus)-Type Ubiquitin E3 Ligase ITCH Attenuates Cardiac Hypertrophy by Suppressing the Wnt/ß-Catenin Signaling Pathway.

The HECT (homologous to the E6-AP carboxyl terminus)-type ubiquitin E3 ligase ITCH is an enzyme that plays an important role in ubiquitin-proteasomal protein degradation. Disheveled proteins (Dvl1 [disheveled protein 1], Dvl2, and Dvl3) are the main components of the Wnt/ß-catenin signaling pathway, which is involved in cardiac hypertrophy. The aim of this study was to examine the role of ITCH during development of cardiac hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type mice. Cardiac hypertrophy after TAC was attenuated in ITCH-Tg mice, and the survival rate was higher for ITCH-Tg mice than for wild-type mice. Protein interaction between ITCH and Dvls was confirmed with immunoprecipitation in vivo and in vitro. Expression of key molecules of the Wnt/ß-catenin signaling pathway (Dvl1, Dvl2, GSK3ß [glycogen synthase kinase 3ß], and ß-catenin) was inhibited in ITCH-Tg mice compared with wild-type mice. Notably, the ubiquitination level of Dvl proteins increased in ITCH-Tg mice. Protein and mRNA expression levels of ITCH increased in response to Wnt3a stimulation in neonatal rat cardiomyocytes. Knockdown of ITCH using small-interfering RNA increased cardiomyocyte size and augmented protein expression levels of Dvl proteins, phospho-GSK3ß, and ß-catenin after Wnt3a stimulation in cardiomyocytes. Conversely, overexpression of ITCH attenuated cardiomyocyte hypertrophy and decreased protein expression levels of Dvl proteins, phospho-GSK3ß and ß-catenin. In conclusion, ITCH targets Dvl proteins for ubiquitin-proteasome degradation in cardiomyocytes and attenuates cardiac hypertrophy by suppressing the Wnt/ß-catenin signaling pathway.

Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin.

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction.

AIMS: Reactive oxygen species are reportedly involved in the mechanism underlying heart failure with preserved ejection fraction (HFpEF); however, the disease pathophysiology remains poorly understood. Xanthine oxidoreductase (XOR), the rate-limiting enzyme of purine metabolism, plays an important role in uric acid production and generates reactive oxygen species. However, the impact of plasma XOR activity on the clinical outcomes of patients with HFpEF remains unclear. The aim of this study was to investigate whether plasma XOR activity is associated with major adverse cardiovascular events (MACEs) in patients with HFpEF. METHODS AND RESULTS: The plasma XOR activity was measured in 257 patients with HFpEF, who were then divided into three groups according to the activity levels: low XOR group (<33 pmol/h/mL, n = 45), normal XOR group (33-120 pmol/h/mL, n = 160), and high XOR group (>120 pmol/h/mL, n = 52). During the median follow-up period of 809 days, there were 74 MACEs. Kaplan-Meier analysis revealed that the high XOR group was at the highest risk for MACEs. Multivariate analysis by Cox's proportional hazard regression approach showed that high XOR activity was significantly associated with MACEs, after adjustment for confounding factors. The patients were also divided into four groups according to the absence/presence of high XOR activity and/or hyperuricaemia. According to the multivariate Cox regression analysis, high XOR activity was associated with MACEs, regardless of the hyperuricaemia status. CONCLUSIONS: Elevated plasma XOR activity is significantly associated with adverse clinical outcomes in patients with HFpEF.

The association between microRNA-21 and hypertension-induced cardiac remodeling.

Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-ß1 (TGF-ß1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-ß1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-ß1 signaling pathway.

The impact of kidney dysfunction categorized by urinary to serum creatinine ratio on clinical outcomes in patients with heart failure.

Kidney dysfunction (KD) is closely associated with poor clinical outcome in patients with heart failure (HF). KD is classified as intrinsic and pre-renal KD. However, the impact of each KD on the clinical outcome in patients with HF has not yet been fully elucidated. We measured the urinary to serum creatinine (UC/SC) ratio, a marker for intrinsic and pre-renal KD, in 1009 consecutive patients with HF at admission. There were 314 cardio-renal events including HF and advanced end-stage renal dysfunction during the median follow-up period of 1154 days. There were 63 (6%) patients with intrinsic KD (UC/SC ratio < 20), 118 (12%) patients with intermediate KD (UC/SC ratio 20-40), 607 (60%) patients with pre-renal KD (UC/SC ratio > 40), and 221 (22%) patients with no KD. Multivariate Cox's proportional hazard regression analysis demonstrated that intrinsic and intermediate KDs were significantly associated with poor clinical outcome. The prediction model for cardio-renal events was significantly improved by the addition of UC/SC ratio to the confounding risk factors. Subgroup analysis in patients with HF with severely reduced glomerular filtration rates showed that the prevalence rates of intrinsic, intermediate, and pre-renal KDs were 23%, 30%, and 47%, respectively. The cardio-renal event rate was the highest in the intrinsic KD group compared with that in the other groups. Intrinsic KD was closely associated with extremely poor clinical outcome in patients with HF. The UC/SC ratio could provide important clinical information for the treatment and management of KD in patients with HF.

Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling.

AIMS: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS. METHODS AND RESULTS: We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3' untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions. CONCLUSION: miR-34a plays an important role in the development of CAVS via Notch1-Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.

Endovascular Revascularization Improves the Central Hemodynamics and Augmentation Index in Patients with Peripheral Artery Disease.

Objective To evaluate the effect of endovascular therapy (EVT) on the central blood pressure (CBP) and augmentation index (AIx) in patients with peripheral artery disease (PAD). Methods The CBP and AIx were assessed by radial applanation tonometry the day before and the day after EVT. We compared the differences in the therapeutic effects between the stenotic and occlusive lesions and between the iliac and superficial femoral artery (SFA) lesions. Patients We enrolled 60 consecutive patients with PAD who underwent EVT for de novo lesions. Results Both the CBP and AIx were significantly decreased after EVT (125±22 mmHg to 112±22 mmHg; p=0.002 and 84%±16% to 73%±15%; p<0.001, respectively). The effects of EVT on the CBP and AIx were equivalent, regardless of whether the target lesion was the stenotic lesion or the occlusive lesion. There were no significant differences between the iliac and SFA lesions in the effects of EVT on the CBP and AIx. Conclusion EVT improved the CBP and AIx in patients with PAD, regardless of the morphology or site of the lesions.

Left atrial remodeling index is a feasible predictor of poor prognosis in patients with acute ischemic stroke.

Left atrial (LA) functional remodeling as well as LA structural remodeling are associated with incident LA appendage (LAA) thrombus formation. This study aimed to elucidate whether combined assessment of LA functional and structural remodeling can predict LAA dysfunction and recurrent cerebrovascular events in patients with acute ischemic stroke. We performed transthoracic and transesophageal echocardiography in 196 patients within 7 days after acute ischemic stroke. Peak systolic LA strain was evaluated using 2D speckle tracking imaging. We defined the ratio of LA peak systolic strain to LA volume index (LAVI) as the LA remodeling index (LARI). All patients were prospectively followed for recurrent cerebrovascular events. We divided patients into four groups according based on the LARI quartile. LAA dysfunction increased with decreasing LARI. In total, 52 recurrent cerebrovascular events were noted during the median follow-up period of 700 days. Patients with recurrent cerebrovascular events had lower LARI than those without recurrent events (0.50 ± 0.45 vs. 1.10 ± 0.95, P < 0.001). Kaplan-Meier analysis showed that patients with lower LARI were more susceptible to recurrent cerebrovascular events than those with higher LARI. Multivariate Cox proportional hazard regression analysis showed that LARI was an independent predictor of recurrent cerebrovascular events after adjustment for confounding factors. Net reclassification index improved with the addition of LARI to basic predictors. LARI is a novel feasible parameter for LAA dysfunction and can predict recurrent cerebrovascular events in patients with acute ischemic stroke.

Cardiac Nuclear High-Mobility Group Box 1 Ameliorates Pathological Cardiac Hypertrophy by Inhibiting DNA Damage Response.

High-mobility group box 1 (HMGB1) is a deoxyribonucleic acid (DNA)-binding protein associated with DNA repair. Decreased nuclear HMGB1 expression and increased DNA damage response (DDR) were observed in human failing hearts. DNA damage and DDR as well as cardiac remodeling were suppressed in cardiac-specific HMGB1 overexpression transgenic mice after angiotensin II stimulation as compared with wild-type mice. In vitro, inhibition of HMGB1 increased phosphorylation of extracellular signal-related kinase 1/2 and nuclear factor kappa B, which was rescued by DDR inhibitor treatment. DDR inhibitor treatment provided a cardioprotective effect on angiotensin II-induced cardiac remodeling in mice.

Prolonged total atrial conduction time evaluated with tissue Doppler imaging predicts poor cardiac prognosis in patients with heart failure.

Prolonged total atrial conduction time is caused by atrial remodeling. Left atrial remodeling is associated with poor outcome in patients with heart failure (HF). This study aimed to investigate whether prolonged total atrial conduction time predicts poor prognosis in patients with HF. We performed transthoracic echocardiography in 100 patients (65 men; mean age 68 ± 13 years) who were hospitalized for HF. Total atrial conduction time was defined as the duration from P wave onset on electrocardiography to peak A' wave on tissue Doppler imaging (TDI) echocardiography (PA-TDI duration). There were 37 cardiac events (37%) during a median follow-up period of 414 days. The PATDI duration was significantly longer in patients with cardiac events than in those without (150 ± 18 ms vs 133 ± 19 ms; P < 0.05). There were no significant differences in left ventricular end-diastolic dimensions and ejection fractions between patients with and without cardiac events. Patients with HF were divided into 3 groups according to tertiles of the PA-TDI duration. Kaplan-Meier analysis showed that the highest tertile of PA-TDI duration was associated with the greatest risk among patients with HF. Multivariate Cox proportional hazard analysis showed that the PA-TDI duration was an independent predictor of cardiac events, leading to the conclusion that prolonged PA-TDI duration was a feasible predictor of cardiac prognosis in patients with HF.

Direct comparison of prognostic ability of cardiac biomarkers for cardiogenic stroke and clinical outcome in patients with stroke.

Despite many recent advances in medicine, cardiogenic stroke is still a health problem with a high mortality rate. Cardiac biomarkers have been reported to be useful indicators for cardiogenic stroke and subsequent cerebrovascular events. However, there are no data directly comparing the cardiac biomarkers in stroke patients. We measured atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) levels and performed transthoracic and transesophageal echocardiography in 282 stroke patients. There were 108 cases of cardiogenic stroke and 47 cases of major adverse cardiovascular and cerebrovascular events (MACCE) during the follow-up period. Association with left atrial function and left atrial appendage function appeared somewhat stronger for BNP and NT-proBNP than ANP and hsTnT. Multivariate logistic analysis demonstrated that cardiac biomarkers excluding ANP were significantly associated with cardiogenic stroke in stroke patients, multivariate Cox's proportional hazards regression analysis demonstrated that all biomarkers were significantly associated with MACCE after adjustment for confounding risk factors. Receiver operating characteristic curve analysis showed that the C indices of BNP and NT-proBNP for cardiogenic stroke and MACCE were almost equal, but significantly greater than those of ANP and hsTnT. Both BNP and NT-proBNP levels are useful predictors of cardiogenic stroke and subsequent MACCE superior to ANP and hsTnT in stroke patients.

Brain Natriuretic Peptide (BNP) and N-Terminal-proBNP in Cardio-Renal Anemia Syndrome　- Difference in Prognostic Ability.

Background: Cardio-renal anemia syndrome (CRAS) is a growing health problem, with a high mortality rate. Brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are well-established diagnostic and prognostic biomarkers of heart failure (HF). The difference in the clinical significance of these biomarkers, however, has not yet been completely elucidated in HF. The aim of the present study was to compare the prognostic ability of BNP and NT-proBNP in HF patients with CRAS. Methods and Results: We measured BNP and NT-proBNP in 492 consecutive HF patients and in 17 control subjects. All patients were prospectively followed up during a median follow-up period of 1,034 days. NT-proBNP/BNP ratio was elevated in HF patients with CRAS compared with those without CRAS and the control subjects. There was no significant difference in the prognostic abilities of BNP and NT-proBNP in all HF patients. The C-index for NT-proBNP for predicting cardiovascular events and mortality, however, was significantly higher than that for BNP in HF patients with CRAS. On multivariate Cox proportional hazards-regression analysis, NT-proBNP, but not BNP, was an independent predictor for clinical outcome in HF with CRAS. Conclusions: The difference in the prognostic abilities of BNP and NT-proBNP was high in HF patients with CRAS. NT-proBNP had a superior prognostic ability to BNP in HF patients with CRAS.

Impact of Iron Deficiency on Peripheral Artery Disease After Endovascular Therapy.

Background: Despite advances in endovascular therapy (EVT), peripheral artery disease (PAD) is a public health problem associated with high cardiovascular mortality. Iron deficiency (ID) is associated with poor clinical outcome in patients with heart disease, but whether ID is associated with the severity and clinical outcome of PAD remains unclear. Methods and Results: A total of 449 patients with PAD who received EVT and who had iron and red blood cell measurement were enrolled. ID was defined as transferrin saturation (TSAT) <20%, based on a previous report. TSAT and hemoglobin decreased with deteriorating Fontaine class. During a median follow-up period of 1,064 days, 71 major adverse cardiovascular and leg events (MACLE) and 47 major adverse cardiovascular events (MACE) were noted. All patients were divided into 2 groups based on the presence of ID. On Kaplan-Meier analysis, patients with ID had higher rates of MACE and MACLE than those without. On multivariate Cox proportional hazard regression analysis, TSAT and hemoglobin were independently associated with MACLE. Addition of TSAT to the known risk factors significantly improved the net reclassification index and integrated discrimination improvement. Conclusions: ID, as assessed by TSAT, was associated with the severity and clinical outcome of PAD, indicating that it could be a therapeutic target.

Impact of Impaired Pancreatic ß-Cell Function on Cardiovascular Prognosis in Heart Failure Patients Without Diabetes Mellitus.

Background: Insulin resistance as assessed using homeostasis model assessment ratio (HOMA-R) is associated with latent myocardial damage in apparently healthy subjects in health check. Meanwhile, diabetes mellitus (DM) is an unfavorable prognostic risk factor in patients with heart failure (HF). We examined the impact of pancreatic ß-cell dysfunction on clinical outcomes in HF patients without DM. Methods and Results: This study enrolled 312 HF patients without DM. Pancreatic ß-cell dysfunction was defined as HOMA-ß <30%. A total of 108 patients (35%) had ß-cell dysfunction. Plasma brain natriuretic peptide was higher in patients with pancreatic ß-cell dysfunction compared with those without (625.2 vs. 399.0 pg/mL, P<0.001). On Kaplan-Meier analysis, a significantly higher cardiovascular events rate was observed in patients with pancreatic ß-cell dysfunction (log-rank test, P=0.001), but there was no significant difference between patients with and without insulin resistance. On Cox hazard analysis, pancreatic ß-cell dysfunction was independently associated with cardiovascular events after adjustment for confounding factors (HR, 1.58; 95% CI: 1.02-2.45), whereas insulin resistance was not associated with cardiovascular events. Conclusions: Pancreatic ß-cell dysfunction, but not insulin resistance, was associated with unfavorable outcome in HF patients without DM.