Objective Exercise therapy as part of cardiac rehabilitation is one of the most effective treatments for patients with chronic heart failure (HF). The anaerobic threshold (AT) determined by an exhaled gas analysis during cardiopulmonary exercise testing (CPX) is used to prescribe the appropriate level of exercise therapy. However, CPX using an exhaled gas analysis is not widely performed because of its cost, complexity, and the need for skilled staff. Therefore, a simpler and inexpensive method for determining AT without respiratory gas measurements is required in patients with HF. The present study elucidated the relationship between the AT determined by the CPX ventilatory method (CPX-AT) and the AT determined by cardiac acoustic biomarkers (CABs), which are measured by acoustic cardiography (CAB-AT), in HF patients. Methods Patients underwent symptom-limited ramp CPX twice using a cycle ergometer. The ATs determined from the exhaled gas analysis were identified by three independent physicians. CABs, including the first heart sound (S1) and the second heart sound intensities (peak-to-peak amplitudes), electromechanical activation time (EMAT) defined as the time interval from the Q wave onset on electrocardiography to S1, heart rate, and other parameters, were collected during CPX. Patients Forty patients with HF were included in this study. Results A significant correlation (R=0.70; p<0.001) was found between CPX-AT and CAB-AT, using the double product of S1 intensity and heart rate. CAB-AT using S1 intensity also showed a significant correlation with CPX-AT (R=0.71; p<0.001). Conclusion The present study suggests a possible new method for determining AT without respiratory gas measurements in patients with HF.

This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet–cold pattern), from the viewpoint of cardiorenal syndrome. Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria–Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups. Of the entire study cohort, 1073 patients (19

AbstractAimsEvidence on the association between ambient temperature and the onset of acute heart failure (AHF) is scarce and mixed. We sought to investigate the incidence of AHF admissions based on ambient temperature change, with particular interest in detecting the difference between AHF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF).Methods and resultsIndividualized AHF admission data from January 2015 to December 2016 were obtained from a multicentre registry (Tokyo CCU Network Database). The primary event was the daily number of admissions. A linear regression model, using the lowest ambient temperature as the explanatory variable, was selected for the best‐estimate model. We also applied the cubic spline model using five knots according to the percentiles of the distribution of the lowest ambient temperature. We divided the entire population into HFpEF + HFmrEF and HFrEF for comparison. In addition, the in‐hospital treatment and mortality rates were obtained according to the interquartile ranges (IQRs) of the lowest ambient temperature (IQR1 <5.5°C; IQR25.5–13.3°C; IQR3 13.3–19.7°C; and IQR4 >19.7°C). The number of admissions for HFpEF, HFmrEF and HFrEF were 2736 (36%), 1539 (20%), and 3354 (44%), respectively. The lowest ambient temperature on the admission day was inversely correlated with the admission frequency for both HFpEF + HFmrEF and HFrEF patients, with a stronger correlation in patients with HFpEF + HFmrEF (R2 = 0.25 vs. 0.05, P < 0.001). In the sensitivity analysis, the decrease in the ambient temperature was associated with the greatest incremental increases in HFpEF, followed by HFmrEF and HFrEF patients (3.5% vs. 2.8% vs. 1.5% per −1°C, P < 0.001), with marked increase in admissions of hypertensive patients (systolic blood pressure >140 mmHg vs. 140–100 mmHg vs. <100 mmHg, 3.0% vs. 2.0% vs. 0.8% per −1°C, P for interaction <0.001). A mediator analysis indicated the presence of the mediator effect of systolic blood pressure. The in‐hospital mortality rate (7.5%) did not significantly change according to ambient temperature (P = 0.62).ConclusionsLower ambient temperature was associated with higher frequency of AHF admissions, and the effect was more pronounced in HFpEF and HFmrEF patients than in those with HFrEF.

Risk stratification of patients with infective endocarditis (IE) is difficult. The Controlling Nutritional Status (CONUT) score is an index of immune function and nutritional status. We investigated the prognostic value of the CONUT score in IE and whether its prognostic value differed between IE patients with and without indications for surgery.Clinical records were retrospectively evaluated for 92 patients with IE treated at Nihon University Itabashi Hospital and Nihon University Hospital between January 2014 and May 2019. The CONUT score was determined upon admission, and patients were divided into two groups at the median score (≤ 7 [n = 50] and ≥ 8 [n = 42]). The primary outcome was all-cause mortality at 90 days after admission.The high CONUT group had significantly higher C-reactive protein and N-terminal pro-brain natriuretic peptide levels, as well as a significantly lower hemoglobin and estimated glomerular filtration rate (all P < 0.05), and considerably more valve perforation (26% versus 8%, P < 0.05). Kaplan-Meier analysis revealed that mortality was significantly higher in the high CONUT group (P < 0.001). Even after adjusting for the propensity score based on IE risk factors, a higher CONUT score was still associated with mortality. A receiver-operating characteristic analysis revealed that a CONUT score ≥ 8 had a sensitivity of 86% and specificity of 76% for predicting all-cause mortality. A CONUT score ≥ 8 was most strongly associated with mortality in patients with surgical indications (P < 0.001).In patients with IE, a higher CONUT score was significantly associated with inflammation, heart failure, renal dysfunction, anemia, valve dysfunction, and short-term mortality, especially in patients with surgical indications.

BACKGROUND:The absence of high quality, large-scale data that indicates definitive mortality benefits does not allow for firm conclusions on the role of intravenous vasodilators in acute heart failure. We aimed to investigate the associations between intravenous vasodilators and clinical outcomes in acute heart failure patients, with a specific focus on patient profiles and type of vasodilators.METHODS:Data of 26,212 consecutive patients urgently hospitalised for a primary diagnosis of acute heart failure between 2009 and 2015 were extracted from a government-funded multicentre data registration system. Propensity scores were calculated with multiple imputations and 1:1 matching performed between patients with and without vasodilator use. The primary endpoint was inhospital mortality.RESULTS:On direct comparison of the vasodilator and non-vasodilator groups after propensity score matching, there were no significant differences in the inhospital mortality rates (7.5% vs. 8.8%, respectively; P=0.098) or length of intensive/cardiovascular care unit stay and hospital stay between the two groups. However, there was a substantial difference in baseline systolic blood pressure by vasodilator type; favourable impacts of vasodilator use on inhospital mortality were observed among patients who had higher systolic blood pressures and those who had no atrial fibrillation on admission. Furthermore, when compared to nitrates, the use of carperitide (natriuretic peptide agent) was significantly associated with worse outcomes, especially in patients with intermediate systolic blood pressures.CONCLUSIONS:In acute heart failure patients, vasodilator use was not universally associated with improved inhospital outcomes; rather, its effect depended on individual clinical presentation: patients with higher systolic blood pressure and no atrial fibrillation seemed to benefit maximally from vasodilators.TRIAL REGISTRATION:UMIN-CTR identifier, UMIN000013128.

This letter comments on the letter by Asit Shil.

Abstract Background Despite recommendations from clinical practice guidelines, there is scant evidence confirming the effects of vasodilators on clinical outcomes in patients with acute heart failure (AHF). Purpose We sought to investigate the effects of intravenous vasodilators on clinical outcomes and to identify the potential patient populations that would benefit from its use. Methods Data of 26 212 consecutive patients urgently hospitalized for AHF between 2009 and 2015 were extracted from a multicenter data registration system (Tokyo Cardiovascular Care Unit Network Database, including 72 institutions within the Tokyo metropolitan area in Japan). Patients who did not present with typical AHF episodes, including those without pulmonary congestion on physical and/or chest X-ray and serum B-type natriuretic peptide level <500 pg/ml, as well as those who had hypotension and/or hypoperfusion (systolic blood pressure [SBP] <100 mmHg) as dominant presentation, were excluded. Propensity scores were calculated with multiple imputation and 1:1 matching performed between patients with and without vasodilators. The primary endpoint was in-hospital mortality and the secondary endpoints were length of intensive/cardiovascular care unit (ICU/CCU) stay and hospital stay. Results Overall, 8 863 patients were included in the present analysis; they were predominantly male (57%) with a median age of 79 (interquartile range: 70–86) years. Compared with the group without vasodilator use, the vasodilator group had higher SBPs and heart rates and higher frequency of assisted ventilation use, but lower frequency of intravenous diuretics use. After propensity score matching, there were no significant differences in in-hospital mortality rates (7.8% vs. 8.9% in patients without vasodilators, p=0.16) or in length of ICU/CCU stay (5.8 days vs. 5.4 days, p=0.44) and hospital stay (22.7 days vs. 23.8 days, p=0.22) between the groups. However, in subgroup analyses, favorable impacts of vasodilator use on in-hospital mortality were observed among patients who had higher SBPs and among those who had no atrial fibrillation upon admission (Figure). In addition, vasodilators were likely to be more effective in AHF patients with SBP increasing; while levels below 140 mmHg of SBP appeared to be associated with an increased risk for mortality among patients treated with vasodilators compared with those without vasodilators. Figure 1 Conclusions In patients with AHF, vasodilator use was not universally associated with improved in-hospital outcomes; however, its effect was dependent of individual clinical presentation. Detailed phenotyping might aid tailoring of treatment strategies for patients with AHF. Acknowledgement/Funding the Tokyo Metropolitan Government

OBJECTIVES Heart failure with preserved ejection fraction (HFpEF) is now recognized as a geriatric syndrome with multifactorial pathophysiology and clinical heterogeneity rather than a solely left ventricular diastolic dysfunction. Because the pathophysiology of HFpEF is suggested to differ by age, this study compared the clinical characteristics and prognostic factors between HFpEF patients aged 65 to 84 years and those aged 85 years or older. DESIGN Retrospective cohort study. SETTING The Tokyo CCU Network including 73 hospitals in Tokyo, Japan. PARTICIPANTS Individuals aged 65 years or older with HFpEF (N = 4305). MEASUREMENTS Very old patients were defined as those aged 85 years or older. Potential risk factors for in-hospital mortality were selected by univariate analyses, and those with a P value <.10 were used in multivariate Cox regression analysis with forward selection (likelihood ratio) to identify significant factors. RESULTS Prevalence of hypertension was significantly higher in very old patients, whereas prevalence of coronary artery disease, diabetes mellitus, hyperlipidemia, and smoking was significantly higher in patients aged 65 to 84 years. In very old patients, low systolic blood pressure (hazard ratio [HR] = .988), high serum creatinine level (HR = 1.34), and coexisting chronic obstructive pulmonary disease (COPD; HR = 2.01) were identified as independent risk factors for in-hospital mortality. In contrast, low systolic blood pressure (HR = .987) and low body mass index (HR = .935) were identified as independent risk factors in patients aged 65 to 84 years. CONCLUSION Significant differences were observed in the clinical characteristics and prognostic factors for in-hospital mortality between HFpEF patients aged 65 to 84 and those 85 years and older. Of note, coexisting COPD was associated with significantly lower survival rate only in patients aged 85 years and older, suggesting the prognostic impact of concomitant pulmonary disease in HFpEF may increase with age. These results have implications for future research and management of older HFpEF patients. J Am Geriatr Soc 00:1-6, 2019. J Am Geriatr Soc 67:2123-2128, 2019

Objective: No agents have been proven to improve survival in heart failure with preserved ejection fraction (HFpEF), but the phenotypic diversity of HFpEF suggests it may be possible to identify specific HFpEF phenotypes that will benefit from certain treatments. This study compared the risk factors for and prognostic impacts of treatments on in-hospital mortality between HFpEF patients with (+) and without (-) high blood pressure (HBP). Methods: Data on 2238 consecutive HFpEF patients were extracted from Tokyo CCU Network data registry and analysed. HFpEF was defined as an ejection fraction greater than or equal to 50%; HBP was defined as elevated systolic blood pressure (>140 mmHg) at admission. Potential risk factors for in-hospital mortality were selected by univariate analyses and those with P<0.10 were used in multivariate Cox regression analysis with forward selection (likelihood ratio) to identify significant factors. Results: In-hospital mortality was significantly lower for HFpEF + HBP than HFpEF - HBP patients (log-rank, P<0.001). Independent risk factors for in-hospital mortality in HFpEF + HBP patients were older age (hazard ratio 1.069) and in-hospital treatment without beta-blockers (hazard ratio 7.946), whereas older age (hazard ratio 1.035), higher C-reactive protein (hazard ratio 1.047), higher B-type natriuretic peptide (hazard ratio 1.000) and in-hospital treatment without diuretics (hazard ratio 4.201) were identified as independent risk factors in HFpEF - HBP patients. Conclusion: There were significant differences in prognostic factors, including beta-blocker and diuretic treatments, for in-hospital mortality between HFpEF patients with and without HBP. These findings suggest possible individualized therapies for patients with HFpEF.

The relationship between glycemic control and outcome in patients with heart failure (HF) remains contentious. A recent study showed that patients with HF with mid-range ejection fraction (HFmrEF) more frequently had comorbid diabetes relative to other patients. Herein, we examined the association between glycosylated hemoglobin (HbA1c) and in-hospital mortality in acute HF patients with reduced, mid-range, and preserved EF. A multicenter retrospective study was conducted on 5205 consecutive patients with acute HF. Potential risk factors for in-hospital mortality were selected by univariate analyses; then, multivariate Cox regression analysis with backward stepwise selection was performed to identify significant factors. Kaplan–Meier survival curves and log-rank testing were used to compare in-hospital mortality between groups. Across the study cohort, 44% (2288 patients) had reduced EF, 20% had mid-range EF, and 36% had preserved EF. The overall in-hospital mortality rate was 4.6%, with no significant differences among the HF patients with reduced, mid-range, and preserved EF groups. For patients with HFmrEF, higher HbA1c level was a significant risk factor for in-hospital mortality (hazard ratio 1.387; 95% confidence interval 1.014–1.899; P = 0.041). In contrast, HbA1c was not an independent risk factor for in-hospital mortality in HF patients with preserved or reduced EF. In conclusion, HbA1c is an independent risk factor for in-hospital mortality in acute HF patients with mid-range EF, but not in those with preserved or reduced EF. Elucidation of the pathophysiological mechanisms behind these findings could facilitate the development of more effective individualized therapies for acute HF.

BACKGROUND: The onset of acute heart failure is known to be associated with increased physical activity and other specific behaviors that can trigger hemodynamic deterioration. This analysis aimed to describe the distribution of triggers in patients hospitalized for acute heart failure, and investigate their effects on in-hospital outcomes. METHODS: Consecutive patients hospitalized for acute heart failure between 2010 and 2014 were registered in a multicenter data registration system (72 institutions within Tokyo, Japan). Baseline demographics and in-hospital mortality were extracted from 17,473 patients. Patients with a trigger were grouped based on their triggering event: those with onset during (a) physical activity; (b) sleeping; (c) eating or watching television; (d) bathing or excretion (use of restrooms); and (e) engaging in other activities. These patients were compared with patients without identifiable triggers. Multiple imputation was used for missing data. RESULTS: Patients were predominantly men (57.1%), with a mean age of 76.0 +/- 13.0 years; a triggering event was present in 49.1%. No significant difference in baseline characteristics was noted between groups except for younger age, higher blood pressure, and prevalence of signs of congestion in the trigger-positive group. In-hospital mortality rate was 7.9%. Presence of triggers was positively associated with a reduced risk of in-hospital mortality (adjusted odds ratio 0.79; 95% confidence interval, 0.70-0.90; P = .0003). In a delta-adjusted pattern mixture model, the effect of a triggering event on in-hospital mortality remained consistently significant. CONCLUSION: Triggering events for acute heart failure can provide additional information for risk prediction. Efforts to identify the triggers should be made to classify patients according to risk group. (c) 2018 Elsevier Inc. All rights reserved.

Background/Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetically heterogeneous disease with two inherited forms identified: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RYR2), and a recessive form associated with mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2).Mortality rate of CPVT reaches up to 50% by the age of 30 in untreated individuals; however the patients can be effectively treated by beta adrenergic blockers and/or implantable cardioverter defibrillator (ICD).Therefore, clinical genetic screening for early diagnosis is of great interest.Purpose: After arriving at our cardiology service a patient with a history of syncopes from childhood and recovered from a cardiorespiratory arrest, he was diagnosed with a possible CPVT and an ICD was implanted due to his family history of sudden death in two brothers of 8 and 14 years.With the intention of confirming the diagnosis and finding genetic factors involved, we send it to genetic testing.Methods: The patient's DNA was sequenced for a panel of 28 genes related to primary electrical diseases.Detected variants were prioritised based on the likelihood of causality, according to the recommendations.Raw sequencing data were reviewed through a genomic viewer.Genetic variants classified as pathogenic or possibly pathogenic were confirmed by alternative methods.First-degree relatives were also analysed for the prioritised variant.Results: Sequencing did not show any single nucleotide genetic variant with causality but the sequence review of the two main genes, RYR2 and CASQ2, allowed us to verify that the patient did not present sequencing data of the last three exons of the CASQ2 gene.The deletion was confirmed with alternative methods based on conventional sequencing.The family study allowed demonstrating the implication of the deletion in the development of CPVT and sudden death, when presented in homozygosis.Conclusions: For the first time, the development of CPVT and the risk of sudden cardiac death associated with the disease may be explained not only by small sequence variants but also by relatively large losses or gains of genetic material.Therefore, special care should be taken when applying massive sequencing technologies in genetic diagnosis, being also important to look for copy number variation.

CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from GC-B smcKO mice. Consistent with this finding, GC-B smcKO mice exhibited marked attenuation in acute hypotensive effects induced by intravenous administration of CNP. Conclusions: These results indicate that endothelium-derived CNP maintains endothelial function and then contributes to the chronic regulation of vascular tone and systemic blood pressure independently of vascular smooth muscle GC-B.

Both the obesity paradox and blood pressure (BP) paradox remain ill defined. Because both obesity and hypertension are well-known predictors of coronary artery disease (CAD) and acute heart failure (HF), in the present study, we compared the obesity paradox and the BP paradox between patients with acute HF with and without a history of CAD. A multicenter retrospective study was conducted on 3,204 consecutive patients with acute HF. Potential risk factors for in-hospital mortality were selected by univariate analyses; multivariate Cox regression analysis with backward stepwise selection was then used to identify significant factors. Kaplan-Meier survival curves and log-rank testing were used to compare in-hospital mortality between groups. Across the study cohort, 27% of patients had a history of CAD, and the all-cause in-hospital mortality rate was 5%. In-hospital mortality was significantly lower for patients with obesity than in those without obesity (log-rank, p = 0.033). However, this obesity paradox disappeared in the group with HF and CAD (log-rank, p = 0.740). In contrast, in-hospital mortality was significantly lower for patients with high BP at admission, regardless of the presence of a history of CAD (log-rank, p <0.001 for both groups). In conclusion, a history of CAD canceled the obesity paradox in patients with acute HF, whereas the BP paradox persisted regardless of a history of CAD.

BACKGROUND:We hypothesized that an increase in plasminogen activator inhibitor 1 (PAI-1) might reduce low-density lipoprotein (LDL) particle size in conjunction with triglyceride (TG) metabolism disorder, resulting in an increased risk of atherosclerotic cardiovascular disease (ASCVD). METHODS:This study was carried out as a hospital-based cross-sectional study in 537 consecutive outpatients (mean age: 64 years; men: 71%) with one or more risk factors for ASCVD from April 2014 to October 2014 at the Cardiovascular Center of Nihon University Surugadai Hospital. The estimated LDL-particle size was measured as relative LDL migration using polyacrylamide gel electrophoresis with the LipoPhor system.The plasma PAI-1 level, including the tissue PA/PAI-1 complex and the active and latent forms of PAI-1, was determined using a latex photometric immunoassay method. RESULTS:A multivariate regression analysis after adjustments for ASCVD risk factors showed that an elevated PAI-1 level was an independent predictor of smaller-sized LDL-particle in both the overall patients population (β=0.209, P<0.0001) and a subset of patients with a serum low-density lipoprotein cholesterol (LDL-C) level lower than 100 mg/dl (β=0.276, P<0.0001). Furthermore, an increased BMI and TG-rich lipoprotein related markers [TG, remnant-like particle cholesterol, apolipoprotein (apo) B, apo C-II, and apo C-III] were found to be independent variables associated with an increased PAI-1 level in multivariate regression models. A statistical analysis of data from nondiabetic patients with well-controlled serum LDL-C levels yielded similar findings. Furthermore, in the 310 patients followed up for at least 6 months, a multiple-logistic regression analysis after adjustments for ASCVD risk factors identified the percent changes of the plasma PAI-1 level in the third tertile compared with those in the first tertile as being independently predictive of decreased LDL-particle size [odds ratio (95% confidence interval): 2.11 (1.12/3.40), P=0.02]. CONCLUSION:The plasma PAI-1 levels may be determined by the degree of obesity and TG metabolic disorders. These factors were also shown to be correlated with a decreased LDL-particle size, increasing the risk of ASCVD, even in nondiabetic patients with well-controlled serum LDL-C levels.