Improved cerebral blood flow and hippocampal blood flow in stroke-free patients after catheter ablation of atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is a risk factor for reduced cerebral blood flow (CBF) and cognitive dysfunction, even in stroke-free patients. We aimed to test the hypothesis that CBF and hippocampal blood flow (HBF), measured with arterial spin labeling magnetic resonance imaging (MRI), improve after catheter ablation of AF to achieve sinus rhythm (SR). METHODS: A total of 84 stroke-free patients (63.1 ± 9.1 years; paroxysmal AF, n = 50; non-paroxysmal AF, n = 34) undergoing AF catheter ablation were included. MRI studies were done before, 3 months, and 12 months after the procedure with CBF and HBF measurements. RESULTS: Baseline CBF and HBF values in 50 paroxysmal AF patients were used as controls. Baseline CBF was higher in patients with paroxysmal AF than with non-paroxysmal AF (100 ± 32% vs. 86 ± 28%, p = .04). Patients with non-paroxysmal AF had increased CBF 3 months after AF ablation (86 ± 28% to 99 ± 34%, p = .03). Differences in CBF and HBF were greater in the group with AF restored to SR (p < .01). Both CBF and HBF levels at 12 months were unchanged from the 3 months level. Successful rhythm control by catheter ablation was an independent predictor of an increase in CBF > 17.5%. The Mini-Mental State Examination score improved after ablation (p = .02). CONCLUSION: SR restoration with catheter ablation was associated with improved CBF and HBF at 3 months, maintenance of blood flow, and improved cognitive function at 12 months.

Growth Differentiation Factor-15 and Clinical Outcomes in Japanese Patients With Ischemic Heart Disease.

Background: Despite a reduction in the rate of thrombotic events, ischemic heart disease (IHD) remains a key medical problem associated with high major bleeding and mortality in Asian patients with IHD. Growth differentiation factor (GDF)-15, a stress-response cytokine belonging to the transforming growth factor beta superfamily, is reportedly associated with poor clinical outcomes in Western patients with IHD. However, the clinical significance of GDF-15 in Asian patients with IHD has not yet been fully elucidated. Objectives: The aim of the present study was to examine the impact of serum GDF-15 on clinical outcomes in Japanese patients with IHD. Methods: Serum GDF-15 levels were evaluated in 632 consecutive patients with IHD. All patients were followed up for a median period of 2.8 years. The primary endpoint was the all-cause mortality rate. Secondary endpoints were major adverse cardiovascular events (MACE), heart failure (HF)-related rehospitalization, bleeding, and thrombotic events. Results: Serum GDF-15 levels were elevated in acute coronary syndrome, severe coronary artery disease, and the major Japanese version of the high bleeding risk criteria. Multivariate Cox proportional hazards regression analysis demonstrated that GDF-15 was an independent predictor of all-cause mortality, MACE, HF-related rehospitalizations, and bleeding events after adjusting for confounding risk factors but not for thrombotic events. Adding GDF-15 to risk factors significantly improved the net reclassification index and integrated discrimination improvement for all-cause deaths, MACE, HF-related rehospitalization, and bleeding events. Conclusions: Serum GDF-15 could be a feasible marker for major bleeding and adverse clinical outcomes in Japanese patients with IHD.

Renal tubular damage and clinical outcome in heart failure with preserved ejection fraction and chronic kidney disease.

AIMS: Despite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD. METHODS AND RESULTS: We measured RTD markers, such as urinary ß2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-ß-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76 ± 12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300 µg/gCr and NAG >14.2 U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2 years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P = 0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P = 0.0244). CONCLUSION: RTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.

Growth Differentiation Factor 15 and Clinical Outcomes in Japanese Patients With Heart Failure.

BACKGROUND: Heart failure (HF) is an increasing health problem associated with a high mortality rate. Growth differentiation factor (GDF) 15, a stress response cytokine belonging to the transforming growth factor-ß superfamily, is associated with poor clinical outcomes in a broad spectrum of cardiovascular diseases. However, the prognostic usefulness of GDF15 in Japanese patients with HF remains unclear.Methods and Results: We measured serum concentrations of GDF15 and B-type natriuretic peptide (BNP) in 1,201 patients with HF. All patients were prospectively followed for a median period of 1,309 days. In all, 319 HF-related events and 187 all-cause deaths occurred during the follow-up period. Kaplan-Meier analysis demonstrated that, among GDF15 tertiles, the highest tertile group had the greatest risk of HF-related events and all-cause mortality. Multivariate Cox proportional hazard regression analysis demonstrated that the serum GDF15 concentration was an independent predictor of HF-related events and all-cause deaths after adjusting for confounding risk factors. Serum GDF15 improved the prediction capacity for all-cause deaths and HF-related events with a significant net reclassification index and integrated discrimination improvement. Subgroup analysis in patients with HF with preserved ejection fraction also showed the prognostic usefulness of GDF15. CONCLUSIONS: Serum GDF15 concentrations were associated with HF severity and clinical outcomes, indicating that GDF15 could provide additional clinical information to track the health status of patients with HF.

Prognostic impact of plasma xanthine oxidoreductase activity in patients with heart failure with atrial fibrillation.

BACKGROUND: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme for uric acid (UA) production and plays an important role in generating reactive oxygen species (ROS). Overproduction of ROS is reported to contribute to the pathophysiology of atrial fibrillation (AF), however, the prognostic impact of plasma XOR activity in patients with heart failure (HF) with AF is undetermined. METHODS: We measured plasma XOR activity in 475 HF patients, including those with sinus rhythm (HF-SR, n = 211), and those with AF (HF-AF, n = 264). The type of AF included paroxysmal (n = 128) and persistent (n = 136) AF. All patients were prospectively followed up for a median period of 804 days. RESULTS: HF-AF patients had significantly higher plasma XOR activity and serum UA levels compared with HF-SR patients. Both plasma XOR activity and serum UA levels were higher in patients with persistent AF than in those with SR and with paroxysmal AF. Multivariate linear regression analysis showed that persistent AF was independently associated with increased XOR activity. During the follow-up period, there were 79 major adverse cardiovascular events (MACEs). HF-AF patients with MACEs had higher plasma XOR activity compared with those without MACEs, while there were no significant differences in serum UA levels. Multivariate Cox proportional analysis showed that high XOR activity was an independent risk factor for MACEs after adjustment for confounding factors. Kaplan-Meier analysis revealed that the high XOR activity group had a higher risk of MACEs than the low XOR activity group. The prediction model was significantly improved by the addition of XOR activity to the basic predictors. CONCLUSIONS: HF-AF patients had significantly higher plasma XOR activity compared with HF-SR patients. Plasma XOR activity proved to be a reliable indicator for MACEs in HF-AF patients.

Prognostic Impact of Renal Dysfunction at 1-Year Follow-Up on Clinical Outcomes After Percutaneous Coronary Intervention.

AIMS: Renal dysfunction is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). However, the prognostic impact of mid-term changes in renal dysfunction status remains unclear. This study aimed to investigate the impact of mid-term changes in renal dysfunction status on long-term clinical outcomes in CAD patients who underwent percutaneous coronary intervention (PCI). METHODS: We enrolled 382 consecutive patients with CAD who underwent PCI. Renal dysfunction was defined as a reduced estimated glomerular filtration rate (eGFR) of ＜60 mL/min/1.73m2. Renal dysfunction status was evaluated at baseline and 1-year follow-up after PCI. We divided the study population into three groups: persistent renal dysfunction, new-onset renal dysfunction, and no or improved renal dysfunction at 1-year follow-up as compared with on baseline. The endpoints of this study were composite events, including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke. RESULTS: At baseline, renal dysfunction was observed in 77 patients (20%). At the 1-year follow-up, new-onset renal dysfunction was observed in 46 patients (12%), and 59 patients (15%) had persistent renal dysfunction. Kaplan-Meier analysis revealed a significantly higher event rate in patients with persistent renal dysfunction and new-onset renal dysfunction (log-rank test, P=0.0003). In the multivariate Cox proportional hazards analysis, persistent renal dysfunction and new-onset renal dysfunction were independently associated with composite events after adjusting for confounding factors (adjusted hazard ratios 4.08 and 2.64, 95% confidence intervals 1.72-9.57 and 1.03-6.31, P=0.0016, P=0.0045, respectively). CONCLUSION: Persistent and new-onset renal dysfunction at 1-year follow-up were associated with unfavorable outcomes in patients with CAD who underwent PCI.

Association of malnutrition with renal dysfunction and clinical outcome in patients with heart failure.

Malnutrition, glomerular damage (GD), and renal tubular damage (RTD) are common morbidities associated with poor clinical outcomes in heart failure (HF) patients. However, the association between malnutrition and renal dysfunction and its impact on clinical outcomes in HF patients have not yet been fully elucidated. We assessed the nutritional status and renal function of 1061 consecutive HF patients. Malnutrition, GD, and RTD were defined as a controlling nutritional status (CONUT) score of ≥ 5, reduced eGFR or microalbuminuria, and levels of N-acetyl-beta-D-glucosamidase of > 14.2 U/gCr according to previous reports, respectively. Patients with RTD had a higher CONUT score and a lower prognostic nutritional index and geriatric nutritional risk index than those without. Multivariate logistic analysis demonstrated that RTD, but not GD, was significantly associated with malnutrition. There were 360 cardiac events during the median follow-up period of 688 days. Multivariate Cox proportional hazard regression analysis demonstrated that comorbid malnutrition and renal dysfunction, rather than simple malnutrition, were significantly associated with cardiac events in HF patients. We found a close relationship between malnutrition and renal dysfunction in HF patients. Comorbid malnutrition and renal dysfunction were risk factors for cardiac events in HF patients, suggesting the importance of managing and treating these.

Albumin-to-globulin ratio predicts clinical outcomes of heart failure with preserved ejection fraction in women.

Despite advances in medicine, heart failure with preserved ejection fraction (HFpEF) remains an increasing health concern associated with a high mortality rate. Research has shown sex-based differences in the clinical characteristics of patients with HF; however, definitive biomarkers for poor clinical outcomes of HFpEF in women are unavailable. We focused on the albumin-to-globulin ratio (AGR), a biomarker for malnutrition and inflammation and investigated its usefulness as a predictor of clinical outcomes of HFpEF in women. We measured the AGR in consecutive 224 women with HFpEF and 249 men with HFpEF. There were 69 cardiac events in women with HFpEF and 69 cardiac events in men with HFpEF during the follow-up period. The AGR decreased with advancing New York Heart Association functional class in women with HFpEF. Patients were categorized into three groups based on AGR tertiles. Kaplan-Meier analysis showed that among the three groups, the risk for cardiac events and HF-associated rehospitalizations was the highest in the lowest tertile in women with HFpEF. Univariate and multivariate Cox proportional hazard regression analyses showed that after adjustment for confounding risk factors, the AGR was an independent predictor of cardiac events and HF-associated rehospitalizations in women with HFpEF, but not in men with HFpEF. The addition of AGR to the risk factors significantly improved the net reclassification and integrated discrimination indices in women with HFpEF. This is the first study that highlights the significant association between the AGR and the severity and clinical outcomes of HFpEF in women. Addition of AGR to the risk factors improved its prognostic value for clinical outcomes, which indicates that this variable may serve as a useful clinical biomarker for HFpEF in women.

Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study.

BACKGROUND: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. METHODS AND RESULTS: This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. CONCLUSION: Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.

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.

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.

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.