Impact of Left Ventricular Chamber Size on Outcome in Heart Failure with Preserved Ejection Fraction.

Although heart failure with preserved ejection fraction (HFpEF) has a highly variable phenotype, heterogeneity in left ventricular chamber size (LVCS) and its association with long-term outcome have not been thoroughly investigated. The present study sought to determine the impact of LVCS on clinical outcome in HFpEF.A total of 1505 consecutive HFpEF patients admitted to hospitals in the multicenter WET-HF Registry for acute decompensated HF (ADHF) between 2006 and 2017 were analyzed. The patients (age: 80 [73-86], male: 48%) were divided into larger (L) or smaller (S) LV end-diastolic diameter (LVEDD) groups by the median value 45 mm.Younger age, male sex, higher body mass index, more favorable nutritional status, valvular etiology, and lower LVEF were associated with larger LVEDD. After propensity matching (399 pairs), the L group showed a larger left atrial diameter, E/e', and tricuspid regurgitation pressure gradient and greater severity of mitral regurgitation. The L group had a higher rate of composite endpoint of all-cause death and ADHF re-admission (P = 0.021) and was an independent predictor. On the other hand, in the pre-matched cohort, the S group rather showed higher in-hospital (4% versus 2%. P = 0.004) and post-discharge mortality (P = 0.009).In HFpEF, LVCS was affected by demographic and cardiac parameters. After adjustment for demographic parameters, larger LVCS was associated with worse clinical outcome. Higher mortality in the S group in the pre-matched cohort might be related to the demographic factors suggesting frailty and/or sarcopenia.

Association between Plasma Follistatin-like Protein 1 Levels and the Presence and Severity of Coronary Artery Disease.

Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein known for its role in inflammation. However, plasma FSTL1 levels in patients with coronary artery disease (CAD) have not been fully elucidated. Thus, in this study, we investigated the plasma FSTL1 levels of 350 patients who underwent elective coronary angiography. The severity of CAD was represented as the numbers of > 50% stenotic vessels and segments and the severity score. CAD was detected in 196 patients, of whom 84 had 1-vessel disease (1-VD), 62 had 2-VD, and 50 had 3-VD. Plasma high-sensitivity C-reactive protein (hsCRP) levels were higher in patients with CAD than in those without CAD (median 0.56 versus 0.44 mg/L, P < 0.01). Notably, plasma FSTL1 levels were higher in patients with CAD than in those without CAD (median 4.05 versus 3.47 ng/mL, P < 0.02). A stepwise increase in FSTL1 levels was found depending on the number of > 50% stenotic vessels: 3.47 in CAD (-), 3.74 in 1-VD, 4.42 in 2-VD, and 4.65 ng/mL in 3-VD (P < 0.05). FSTL1 levels also correlated with the number of > 50% stenotic segments and the severity score (r = 0.14 and r = 0.15, respectively, P < 0.005) and hsCRP levels (r = 0.10, P < 0.05). In the multivariate analysis, FSTL1 levels were an independent factor associated with CAD. The odds ratio for CAD was 1.61 (95% CI = 1.01-2.58) for high FSTL1 level of > 3.6 ng/mL (P < 0.05). In conclusion, plasma FSTL1 levels in patients with CAD were found to be high and associated with the presence and severity of CAD, thus, suggesting that FSTL1 may play a role in the progression of coronary atherosclerosis.

Associations between plasma nesfatin-1 levels and the presence and severity of coronary artery disease.

Nesfatin-1 is a recently identified anorexigenic peptide mainly secreted from the brain and adipose tissue. Although nesfatin-1 may have pro-inflammatory and apoptotic properties, the association between plasma nesfatin-1 levels and coronary artery disease (CAD) has not been clarified yet. We investigated plasma nesfatin-1 levels in 302 patients undergoing elective coronary angiography. Of the 302 study patients, CAD was present in 172 (57%), of whom 67 had 1-vessel, 49 had 2-vessel, and 56 had 3-vessel disease. Compared with 130 patients without CAD, 172 with CAD had higher plasma nesfatin-1 levels (median 0.21 vs. 0.17 ng/mL, P < 0.01). A stepwise increase in nesfatin-1 levels was found depending on the number of > 50% stenotic coronary vessels: 0.17 in CAD(-), 0.20 in 1-vessel, 0.21 in 2-vessel, and 0.22 ng/mL in 3-vessel disease (P < 0.05). A high nesfatin-1 level (> 0.19 ng/mL) was found in 43% of patients with CAD(-), 55% of those with 1-vessel, 55% of those with 2-vessel, and 68% of those with 3-vessel disease (P < 0.05). Nesfatin-1 levels significantly correlated with the number of > 50% stenotic coronary segments (r = 0.14, P < 0.02). In multivariate analysis, plasma nesfatin-1 levels were a significant factor for CAD independent of atherosclerotic risk factors. The odds ratio for CAD was 1.71 (95% CI 1.01-2.91) for high nesfatin-1 level of > 0.19 ng/mL (P < 0.05). Thus, plasma nesfatin-1 levels were found to be high in patients with CAD and were associated with CAD independent of atherosclerotic risk factors, suggesting that high nesfatin-1 levels in patients with CAD may play a role in the development of coronary atherosclerosis.

Plasma Soluble Endoglin Levels Are Inversely Associated With the Severity of Coronary Atherosclerosis-Brief Report.

OBJECTIVE: Transforming growth factor-ß inhibits migration and proliferation of endothelial and smooth muscle cells. Endoglin is a transmembrane receptor for transforming growth factor-ß1 and transforming growth factor-ß3. Endoglin is released into blood as a soluble form (soluble endoglin [sEng]), but plasma sEng levels in patients with coronary artery disease (CAD) have not been elucidated. APPROACH AND RESULTS: We measured plasma sEng levels in 244 patients undergoing coronary angiography. The severity of coronary atherosclerosis was evaluated as the numbers of >50% stenotic vessels and segments. CAD was found in 147 patients, of whom 55 had 1-vessel, 42 had 2-vessel, and 50 had 3-vessel disease. Compared with 97 patients without CAD, 147 with CAD had lower sEng levels (median 4.04 versus 4.37 ng/mL; P<0.005). A stepwise decrease in sEng levels was found based on the number of stenotic vessels: 4.37 in CAD(-), 4.23 in 1-vessel, 4.13 in 2-vessel, and 3.74 ng/mL in 3-vessel disease (P<0.005). sEng levels inversely correlated with the number of stenotic segments (r=-0.25; P<0.001). In multivariate analysis, sEng was an independent factor for 3-vessel disease and CAD. Odds ratios for CAD and 3-vessel disease were 0.97 (95% confidence interval, 0.95-0.99; P<0.02) and 0.96 (95% confidence interval, 0.93-0.99; P<0.01) for a 0.1 ng/mL increase in sEng levels, respectively. CONCLUSIONS: Plasma sEng levels were low in patients with CAD, especially 3-vessel disease, and were inversely associated with the severity of coronary atherosclerosis.

Identification of Left Atrial Appendage Thrombi in Patients With Persistent and Long-Standing Persistent Atrial Fibrillation Using Intra-Cardiac Echocardiography and Cardiac Computed Tomography.

BACKGROUND: Intracardiac echocardiography (ICE) and cardiac computed tomography (CCT), in addition to standard transesophageal echocardiography (TEE), have been used to identify left atrial (LA) thrombi prior to ablation for atrial fibrillation (AF). The clinical advantages of this, however, remain unclear. This study therefore investigated the advantages of additional pre-procedural LA appendage (LAA) thrombus evaluation using ICE and the clinical value of CCT in persistent and long-standing persistent AF.Methods and Results:We analyzed data from 108 consecutive patients with persistent and long-standing persistent AF who were scheduled to undergo AF ablation. TEE was performed within 24 h prior to ablation. ICE was performed for 97 patients in whom a thrombus was not detected on TEE. CCT was performed in 95 patients. Thrombus or sludge was detected on TEE in 11 patients (10.3%), for whom ablation was cancelled. Four additional patients were diagnosed with LAA thrombus on ICE. When TEE and ICE were used as the reference for thrombus detection, the sensitivity, specificity, positive predictive value, and negative predictive value of CCT for identifying contrast defects in the LAA were 100%, 81.0%, 40.7%, and 100%, respectively. CONCLUSIONS: ICE combined with TEE increased the detection rate of LAA thrombi in patients with persistent and long-standing persistent AF. Moreover, CCT had high sensitivity and negative predictive value for LAA thrombus detection.

Outcomes of Percutaneous Coronary Intervention Performed With or Without Preprocedural Dual Antiplatelet Therapy.

BACKGROUND: Preprocedural dual antiplatelet therapy (DAPT) in percutaneous coronary interventions (PCI) has been shown to improve outcomes; however, the efficacy of the procedure and its complications in Japanese patients remain largely unexplored, so we examined the risks and benefits of DAPT before PCI and its association with in-hospital outcomes. METHODS AND RESULTS: We analyzed data from patients who had undergone PCI at 12 centers within the metropolitan Tokyo area between September 2008 and September 2013.Our study group comprised 6,528 patients, of whom 2,079 (31.8%) were not administered preprocedural DAPT. Non-use of preprocedural DAPT was associated with death, postprocedural shock, or heart failure (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.10-1.96, P=0.009), and postprocedural myocardial infarction (OR: 1.41, 95% CI: 1.18-1.69, P<0.001) after adjusting propensity scores for known predictors of in-hospital complications. Non-use of DAPT was not associated with procedure-related bleeding complications (OR: 0.98, 95% CI: 0.71-1.59, P=0.764). CONCLUSIONS: Approximately one-third of the patients who underwent PCI did not receive preprocedural DAPT despite guideline recommendations. Our results indicate that patients undergoing PCI with DAPT have a lower risk of postprocedural cardiac events without any increased bleeding risk. Further studies are needed to implement the use of DAPT in real-world PCI.

Sex Differences in Cardiac and Clinical Phenotypes and Their Relation to Outcomes in Patients with Heart Failure.

Biological sex is one of the major factors characterizing the heart failure (HF) patient phenotype. Understanding sex-related differences in HF is crucial to implement personalized care for HF patients with various phenotypes. There are sex differences in left ventricular (LV) remodeling patterns in the HF setting, namely, more likely concentric remodeling and diastolic dysfunction in women and eccentric remodeling and systolic dysfunction in men. Recently supra-normal EF (snLVEF) has been recognized as a risk of worse outcome. This pathology might be more relevant in female patients. The possible mechanism may be through coronary microvascular dysfunction and sympathetic nerve overactivation from the findings of previous studies. Further, estrogen deficit might play a significant role in this pathophysiology. The sex difference in body composition may also be related to the difference in LV remodeling and outcome. Lower implementation in guideline-directed medical therapy (GDMT) in female HFrEF patients might also be one of the factors related to sex differences in relation to outcomes. In this review, we will discuss the sex differences in cardiac and clinical phenotypes and their relation to outcomes in HF patients and further discuss how to provide appropriate treatment strategies for female patients.

Supra-normal and mildly reduced ejection fraction in women -An overlooked vulnerable subpopulation in heart failure.

BACKGROUND: Recently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. METHODS: The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. RESULTS: In HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and ß-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). CONCLUSIONS: In women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword?

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) show cardiovascular protective effects, regardless of the patient's history of diabetes mellitus (DM). SGLT2is suppressed cardiovascular adverse events in patients with type 2 DM, and furthermore, SGLT-2is reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF. Along with these research findings, SGLT-2is are recommended for patients with HF in the latest guidelines. Despite these benefits, the concern surrounding the increasing risk of body weight loss and other adverse events has not yet been resolved, especially for patients with sarcopenia or frailty. The DAPA-HF and DELIVER trials consistently showed the efficacy and safety of SGLT-2i for HF patients with frailty. However, the Rockwood frailty index that derived from a cumulative deficit model was employed for frailty assessment in these trials, which might not be suitable for the evaluation of physical frailty or sarcopenia alone. There is no fixed consensus on which evaluation tool to use or its cutoff value for the diagnosis and assessment of frailty in HF patients, or which patients can receive SGLT-2i safely. In this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2i for HF patients with sarcopenia or frailty.

Coronary microvascular dysfunction in heart failure patients.

Coronary microcirculation has multiple layers of autoregulatory function to maintain resting flow and augment hyperemic flow in response to myocardial demands. Functional or structural alterations in the coronary microvascular function are frequently observed in patients with heart failure with preserved or reduced ejection fraction, which may lead to myocardial ischemic injury and resultant worsening of clinical outcomes. In this review, we describe our current understanding of coronary microvascular dysfunction in the pathogenesis of heart failure with preserved and reduced ejection fraction.

A Low Arginine/Ornithine Ratio is Associated with Long-Term Cardiovascular Mortality.

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p＜0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.

D-Dimer beyond Diagnosis of Pulmonary Embolism: Its Implication for Long-Term Prognosis in Cardio-Oncology Era.

Venous thromboembolism (VTE) is a common comorbidity of cancer, often referred to as cancer-associated thrombosis (CAT). Even though its prevalence has been increasing, its clinical picture has not been thoroughly investigated. In this single-center retrospective observational study, 259 patients who were treated for pulmonary embolism (PE) between January 2015 and December 2020 were available for analysis. The patients were divided by the presence or absence of concomitant malignancy, and those with malignancy (N = 120, 46%) were further classified into active (N = 40, 15%) and inactive groups according to the treatment status of malignancy. In patients with malignancy, PE was more often diagnosed incidentally by computed tomography or D-dimer testing, and the proportion of massive PE was lower. Although D-dimer levels overall decreased after the initiation of anticoagulation therapy, concomitant malignancy was independently associated with higher D-dimer at discharge despite the lower severity of PE at onset. The patients with malignancy had a poor prognosis during post-discharge follow-up. Active malignancy was independently associated with major adverse cardiovascular events (MACE) and major bleeding. D-dimer at discharge was an independent predictor of mortality even after adjustment for malignancy. This study's findings suggest that CAT-PE patients might have hypercoagulable states, which can potentially lead to a poorer prognosis.

ß1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues.

A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the ß1-adrenergic receptor (ß1AR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). Β1AR-Aabs have agonist effects inducing desensitization of ß1AR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. Β1AR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including ß1AR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of ß1AR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with ß1AR-AAb better responded to ß-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of ß1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.

Xenografted human amniotic membrane-derived mesenchymal stem cells are immunologically tolerated and transdifferentiated into cardiomyocytes.

RATIONALE: Amniotic membrane is known to have the ability to transdifferentiate into multiple organs and is expected to stimulate a reduced immunologic reaction. OBJECTIVE: Determine whether human amniotic membrane-derived mesenchymal cells (hAMCs) can be an ideal allograftable stem cell source for cardiac regenerative medicine. METHODS AND RESULTS: We established hAMCs. After cardiomyogenic induction in vitro, hAMCs beat spontaneously, and the calculated cardiomyogenic transdifferentiation efficiency was 33%. Transplantation of hAMCs 2 weeks after myocardial infarction improved impaired left ventricular fractional shortening measured by echocardiogram (34+/-2% [n=8] to 39+/-2% [n=11]; P<0.05) and decreased myocardial fibrosis area (18+/-1% [n=9] to 13+/-1% [n=10]; P<0.05), significantly. Furthermore hAMCs transplanted into the infarcted myocardium of Wistar rats were transdifferentiated into cardiomyocytes in situ and survived for more than 4 weeks after the transplantation without using any immunosuppressant. Immunologic tolerance was caused by the hAMC-derived HLA-G expression, lack of MHC expression of hAMCs, and activation of FOXP3-positive regulatory T cells. Administration of IL-10 or progesterone, which is known to play an important role in feto-maternal tolerance during pregnancy, markedly increased HLA-G expression in hAMCs in vitro and, surprisingly, also increased cardiomyogenic transdifferentiation efficiency in vitro and in vivo. CONCLUSIONS: Because hAMCs have a high ability to transdifferentiate into cardiomyocytes and to acquire immunologic tolerance in vivo, they can be a promising cellular source for allograftable stem cells for cardiac regenerative medicine.

Potential association with malnutrition and allocation of combination medical therapies in hospitalized heart failure patients with reduced ejection fraction.

Malnutrition is common in patients with heart failure with reduced ejection fraction (HFrEF) and may influence the long-term prognosis and allocation of combination medical therapy. We reviewed 1231 consecutive patient-level records from a multicenter Japanese registry of hospitalized HFrEF patients. Nutritional status was assessed using geriatric nutritional risk index (GNRI). Combination medical therapy were categorized based on the use of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists. The composite outcome of all-cause death and HF rehospitalization was assessed. The mean age was 72.0 ± 14.2 years and 42.6% patients were malnourished (GNRI < 92). At discharge, 43.6% and 33.4% of patients were receiving two and three agents, respectively. Malnourished patients had lower rates of combination medical therapy use. The standardized GNRI score was independently associated with the occurrence of adverse events (hazard ratio [HR]: 0.88, 95% confidence interval [CI] 0.79-0.98). Regardless of the GNRI score, referenced to patients receiving single agent, risk of adverse events were lower with those receiving three (HR: 0.70, 95% CI 0.55-0.91) or two agents (HR: 0.70, 95% CI 0.56-0.89). Malnutrition assessed by GNRI score predicts long-term adverse outcomes among hospitalized HFrEF patients. However, its prognosis may be modified with combination medical therapy.

Personalized Target Heart Rate for Patients with Heart Failure and Reduced Ejection Fraction.

The optimal heart rate (HR) in patients with heart failure with reduced ejection fraction (HFrEF) has been ill-defined. Recently, a formula was proposed for estimating the target heart rate (THR), which eliminates the overlap between the E and A wave (E-A overlap). We aim to validate its prognostic significance in the multicenter WET-HF registry. This study used data from 647 patients with HFrEF hospitalized for acute decompensated HF (ADHF). The patients were divided into the 2 groups by THR. The primary endpoint was defined as the composite of all-cause death and ADHF readmission. The THR successfully discriminated the incidence of the primary endpoint, whereas no significant difference was observed in the primary endpoint when dividing the patients by uniform cutoff 70 bpm. HR at discharge ≤ THR was inversely associated with the primary endpoint. Restricted cubic spline analysis demonstrated the difference between HR at discharge, and THR (ΔHR) from -10 to ±0 was associated with a lower risk of primary endpoint and ΔHR from ±0 to +15 was associated with a higher risk. THR discriminated long-term outcomes in patients with HFrEF more efficiently than the uniform cutoff, suggesting that it may aid in tailored HR reduction strategies.

Effectiveness of the d-ROMs oxidative stress test to predict long-term cardiovascular mortality.

BACKGROUND: The long-term prognostic value of the derivatives of reactive oxidative metabolites (d-ROMs) oxidative stress test, which measures hydroperoxide in blood, has not been fully investigated. METHODS AND RESULTS: We administered the d-ROMs test to 265 patients with cardiovascular disease (204 men, 61 women; age, 65 ± 13 years) and followed these patients for up to 10 years. During the observational period of 5.82 (2.47-8.34) years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, and 33 (12%) had major adverse cardiovascular events (MACEs). Cox regression analysis revealed that patients with a d-ROMs value ≥395 U.CARR had a greater risk for all-cause mortality [unadjusted hazard ratio (95% confidence interval), 3.586 (1.772-7.257)], cardiovascular death [7.034 (2.805-17.640)], and MACEs [4.440 (2.237-8.814)] (p < 0.001 for all). In a model adjusted for age, sex, estimated glomerular filtration rate, C-reactive protein, diabetes, hypertension, hyperlipidemia, coronary artery diseases, current smoking, and log-transformed brain natriuretic peptide, all-cause death [2.311 (1.059-5.135), p = 0.036], cardiovascular death [4.398 (1.599-12.099), p = 0.004], MACEs [2.696 (1.266-5.739), p = 0.010] were still significant in patients with high d-ROMS values. CONCLUSION: A high d-ROMs value is an independent predictor of the long-term risk of cardiovascular mortality. A d-ROMs value of 395 U.CARR was considered to be an appropriate threshold for distinguishing prognosis.

Association of serum nitric oxide metabolite level with mortality in patients undergoing coronary angiography.

BACKGROUND: Nitric oxide (NO) is a relevant molecule for vascular homeostasis. The level of serum NO metabolites (NOx), which consist of nitrite and nitrate, has been investigated as an alternative biomarker of NO production, but its clinical value has not yet been determined. METHODS AND RESULTS: 143 patients (66 ±â€¯12 years old) were followed up after coronary catheterization. During a median (inter-quartile range) observation period of 6.13 (3.32-9.21) years, there were 20 (14 %) all-cause deaths, including 11 (8 %) cardiovascular deaths, 17 (12 %) major adverse cardiovascular events, and 17 (12 %) hospital admissions for heart failure. Median NOx level was 34.5 µmol/L (23.9-54.3). NOx was a risk factor for all-cause death [hazard ratio (HR) by unit increase, 1.010, 95 % confidence interval (CI) 1.001-1.018; p = 0.021] and heart failure (HR 1.010, CI 1.001-1.019; p = 0.029). Even after adjustment for age, sex, coronary risk factors, C-reactive protein, log-transformed brain natriuretic peptide, estimated glomerular filtration rate, and nitrate treatment, NOx was a risk factor for all-cause death (HR 1.015, CI 1.004-1.027; p = 0.008) and admission with heart failure (HR 1.018, CI 1.005-1.018, p = 0.007). CONCLUSIONS: An increase in serum NOx level does not herald a benign clinical course but is an independent predictor of high risk of any-cause mortality and heart failure.

Divergent effect of blood glucose dysregulation on long-term clinical outcome in acute decompensated heart failure: A reappraisal in contemporary practice.

BACKGROUND: The prognostic implication of elevated or decreased blood glucose (BG) level in acute decompensated heart failure (ADHF) has been still controversial. Indices of stress hyperglycemia, expressed by the ratio of BG and chronic BG control, has been reported to be associated with poor outcome in different disease population. We sought to assess BG at admission and %ΔBG, an index of BG deviation from estimated average BG calculated from glycated hemoglobin (HbA1c), on the long-term outcome in ADHF patients. METHODS AND RESULTS: The West Tokyo Heart Failure (WET-HF) Registry is a prospective multicenter registry enrolling consecutive hospitalized ADHF patients. Among the patients (N = 3078, 77 [67-84] years, male 59%), BG at admission discriminated the long-term (1000 days) incidence of ADHF rehospitalization, but not cardiac death. BG at admission showed a U-shape relationship with the long-term incidence of ADHF rehospitalization after adjustment for covariates. Especially, in patients with HbA1c ≥ 6.5%, the lowest quartile showed the highest risk of ADHF rehospitalization. On the contrary, %ΔBG showed U-shape relationship with the long-term incidence of cardiac death after discharge, rather than ADHF rehospitalization after adjustment for covariates. In addition, elevated %ΔBG was associated with the long-term risk of sudden cardiac death (SCD) even after adjustment for covariates. CONCLUSIONS: For ADHF patients, BG at admission and %ΔBG might be a simple, useful tool for predicting and stratifying long-term risk of cardiac events. Especially, elevated %ΔBG might be an important in predicting hard events such as cardiac death or SCD.

Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.

Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.