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A 47-year-old man was complaining of consciousness disorder. He had acute kidney injury, hypokalemia, and severe metabolic alkalosis. Initial treatment using intravenous infusion of 0.9% saline and potassium chloride improved his consciousness. It was clarified that he was a severe alcohol abuser who habitually self-vomited. We diagnosed him with volume depletion and pseudo-Bartter's syndrome due to loss of chloride by habitual vomiting. Gastrointestinal endoscopy demonstrated pyloric stenosis, which was ameliorated by Helicobacter pylori eradication therapy. We should consider volume depletion and pseudo-Bartter's syndrome as differential diagnoses when we encounter patients with acute kidney injury and severe metabolic alkalosis.

Metabolic syndrome, including diabetes mellitus, obesity, and dyslipidemia, is associated with the development and progression of metabolic dysfunction-associated fatty liver disease. Therapeutic strategies, particularly optimal medical therapies, for treating metabolic dysfunction-associated fatty liver disease remain unestablished. We encountered a 37-year-old man with obesity (body mass index 39.0), metabolic dysfunction-associated fatty liver disease, and nephrotic syndrome due to obesity-related focal segmental glomerulosclerosis. Combination therapy using pemafibrate and dapagliflozin, together with body weight reduction, ameliorated his hypertriglyceridemia, hyperglycemia, hepatic injury, and proteinuria. Combination therapy using selective peroxisome proliferator-activated receptor α modulator and sodium-glucose cotransporter 2 inhibitor, together with body weight reduction, might be a promising dual-medical strategy for ameliorating metabolic dysfunction-associated fatty liver disease.

Plasma B-type natriuretic peptide (BNP) is a practical tool with which to estimate hemodynamic status including intra-cardiac pressure in patients with heart failure (HF). However, plasma BNP levels cannot be measured immediately in an outpatient private clinic. We investigated the value of remote dielectric sensing (ReDS), a novel non-invasive electromagnetic energy-based tool to quantify lung fluid amount immediately, to predict plasma BNP levels.Successive measurements of ReDS values and plasma BNP levels were performed in patients hospitalized to treat HF in a prospective manner. Correlations between ReDS values and plasma BNP levels were assessed.A total of 117 datasets for HF patients were obtained in this prospective study. The median ReDS value was 28% (interquartile range: 25%, 34%) and the median plasma BNP level was 205 (86, 469) pg/mL, both of which had a slight correlation (r = 0.234, P = 0.011). Their correlation improved when those with a body mass index less than 18.5 (n = 23) were excluded (r = 0.278, P = 0.007).ReDS might be a practical tool for estimating plasma BNP levels, particularly in outpatient private clinics where the immediate measurement of plasma BNP levels is not available.

We investigated the agreement between remote dielectric sensing (ReDS) system, which is a recently introduced non-invasive technology to quantify the degree of pulmonary congestion, and lung ultrasound (LUS), which is a gold standard to assess the existence of severe pulmonary congestion. Consecutive patients who were hospitalized to examine the cause of heart failure and treat their heart failure in our institute were prospectively included. They received LUS and simultaneous ReDS measurements. Three or more B-lines at each LUS zone was assigned to B-profile positive, indicating the existence of significant pulmonary congestion. ReDS values ≥ 35% were defined as significant pulmonary congestion. A total of 19 heart failure patients were included (77 years, 13 men). Plasma B-type natriuretic peptide level was 131 (36, 416) pg/ml. Three patients had B-profile, indicating significant pulmonary congestion, and two of them had ≥ 35% of ReDS (sensitivity 66.7%, specificity 87.5%, and negative predictive value 93.3%). Most of the patients (79%) had lower B-lines below 3 and did not satisfy the criteria of B-profile, irrespective of wide ranges of ReDS values. ReDS system had as acceptable predictability as LUS in assessing the existence of significant pulmonary congestion. ReDS would be recommended to rule out significant pulmonary congestion or quantify the degree of less significant pulmonary congestion.

The association between respirophasic variation and lung fluid levels is unknown. Remote dielectric sensing (ReDS™) is a novel non-invasive technology to quantify lung fluid levels. We investigated the change in ReDS values over the course of the respiratory cycle. Patients with clinically stable chronic heart failure at outpatient clinics were prospectively included. ReDS values were measured at three respiratory statuses and compared: (1) at rest with normal breathing, (2) at inspiration, and (3) at expiration. A total of 11 patients were included. Median age was 73 (58, 78) years and 9 were men. ReDS value was 28% (25%, 32%) at rest and decreased significantly with inspiration down to 26% (24%, 30%) (p = 0.004). ReDS value were significantly higher on expiration as 30% (27%, 34%) as compared with rest (p = 0.003). Lung fluid levels in chronic heart failure patients can vary with changes in the respiratory cycle-attention should be paid to what point in the respiratory cycle measurements are taken when interpreting results in each modality, such as chest X-ray (measured at inspiratory status) and right heart catheterization (measured at expiratory status). ReDS system might be a physiologically ideal modality to assess lung fluid amount under natural breathing.

Even a slight increase in plasma N-terminal-pro B-type natriuretic peptide (NT-pro BNP) levels is associated with an incremental cardiovascular risk in a healthy cohort. Sacubitril/valsartan has recently been reimbursed in Japan for hypertension. Its impact on reducing plasma NT-pro BNP levels in hypertensive patients remains unknown.Patients who received 3-month sacubitril/valsartan treatment for their hypertension were retrospectively included. Changes in plasma NT-pro BNP levels during 3-month sacubitril/valsartan therapy (on-treatment period) were compared with those during pre-treatment 3-month period without sacubitril/valsartan (pre-treatment period).A total of 33 hypertensive patients {73 [64, 77] years old and systolic blood pressure 138 [134, 149] mmHg on median} were included. During a pre-treatment period, systolic blood pressure tended to decrease (P=0.091) whereas plasma NT-pro BNP levels remained unchanged {from 204 [132, 412] to 207 [107, 386] pg/mL, P=0.84}. During on-treatment period, both systolic pressure and plasma NT-pro BNP levels decreased significantly {P0.001 and P=0.001, respectively, from 207 [107, 386] to 119 [64, 355] pg/mL in NT-pro BNP}. The amount of changes in plasma NT-pro BNP levels during on-treatment period was significantly higher than those during pre-treatment period {-51 [-158, -17] versus -12 [-28, 33] mmHg, P=0.001}.Plasma NT-pro BNP levels decreased significantly following 3-month sacubitril/valsartan therapy. Its clinical implication requires further long-term studies.

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy, and Kampo Goreisan is receiving great concern to mediate body water balance particularly for such a cohort. However, its detailed biological mechanism remains uncertain. We had two hospitalized patients with congestive heart failure receiving tolvaptan. Following the administration of Goreisan, both urine cyclic adenosine monophosphate concentration and urine aquaporin-2 concentration decreased, accompanied by incremental diluted urine volume. Although further studies are warranted to establish therapeutic strategy, Goreisan might be a promising therapeutic tool for those with congestive heart failure refractory to conventional diuretics including tolvaptan, via pleiotropic effects including suppression of aquaporin-incorporated water reabsorption system.

The purpose of this study was to evaluate the advantage of heart rate (HR) modulation using ivabradine referring Doppler echocardiography over the conventional ivabradine therapy without echocardiography guide in patients with systolic heart failure.From October 2020, our institute updated the protocol of ivabradine therapy, in which HR was optimized to minimize the overlap between the two left ventricular inflow waves using Doppler echocardiography (echo-guided group). The degree of cardiac reverse remodeling at 3-month follow-up was compared between the echo-guided group and the conventional ivabradine therapy group treated before October 2020.A total of 28 patients (62 years old, 17 men) were included, and 18 patients were from echo-guided group. Left ventricular ejection fraction increased significantly in the echo-guided group (from 41% [28%, 49%] to 55% [37%, 66%], p = 0.007), whereas it remained unchanged in the conventional group (p = 0.333). Systolic blood pressure and the daily dose of carvedilol increased significantly only in the echo-guided group (p = 0.009 and p = 0.001, respectively).Among those with systolic heart failure, a Doppler echocardiography guide might be a promising therapeutic tool in modulating HR by ivabradine in facilitating reverse remodeling.

Background and Objectives: Sex-specific outcome in patients with acute myocardial infarction-related cardiogenic shock (AMI-CS) receiving temporary mechanical circulatory support remains controversial. Materials and Methods: Patients with AMI-CS who received Impella support were prospectively enrolled in the Japanese registry for Percutaneous Ventricular Assist Device. Patients enrolled between January 2021 and December 2022 were considered to be eligible. Patients with out-of-hospital cardiac arrest and those without revascularization were excluded. The sex disparity in the 30-day survival after the initiation of Impella support was evaluated. Results: A total of 924 patients (median age 73 years; 21% female) were included. Female patients were older and had a smaller physiques than male patients (p < 0.05 for both). Female sex was significantly associated with a higher 30-day mortality after adjustment for four other potential confounders with a hazard ratio of 1.365 (95% confidence interval 1.026–1.816, p = 0.0324). In the female cohort, patients who received Impella prior to revascularization (N = 138) had a greater survival rate compared to those who received Impella after revascularization (68.1% versus 44.8%, p = 0.0015). Conclusions: Among the patients with AMI-CS who received Impella support and underwent revascularization, female sex was independently associated with a lower 30-day survival. For female patients, early initiation of Impella support prior to revascularization may improve their clinical outcomes.

Background: Morbidity and mortality following trans-catheter aortic valve replacement (TAVR) remain high. Renin-angiotensin system inhibitors improve clinical outcomes in the cohort studied in this work. However, post-TAVR prognostic impact of mineralocorticoid receptor antagonist (MRA), another neuro-hormonal blocker, remains uncertain. Here, we hypothesized that MRA was associated with improved clinical outcomes in elderly patients with severe aortic stenosis receiving TAVR. Methods: Consecutive patients who received TAVR at our institute between 2015 and 2022 were considered for inclusion. Propensity score matching analysis was performed to match pre-procedural baseline characteristics between those with and without MRA. The prognostic impact of MRA use on the composite primary endpoint consisting of all-cause death and heart failure during the 2-year observational period following index discharge was evaluated. Results: Among 352 patients who received TAVR, 112 patients (median 86 years, 31 men) were included, consisting of baseline-matched 56 patients with MRA and 56 patients without MRA. Following TAVR, patients with MRA had more impaired renal function compared with no MRA group. Following index discharge, serum potassium tended to increase, and renal function tended to decline in patients with MRA. Patients with MRA had a higher cumulative incidence of the primary endpoints during a two-year observational period (30% versus 8%, p = 0.022). Conclusions: Routine prescription of MRA might not be recommended in elderly patients with severe aortic stenosis receiving TAVR, given its negative prognostic impact. Optimal patient selection for MRA administration in this cohort needs further study.

OPC-61815, a prodrug of tolvaptan, is an injectable aquaretic drug. This study evaluated the tolerability of OPC-61815 in patients with congestive heart failure (CHF) who had difficulty with, or were incapable of, oral intake in a multicenter, uncontrolled, open-label Phase III study.Methods and Results: Forty-five patients were enrolled at 30 Japanese sites. OPC-61815 infusion was administered once daily; the 8 mg initial dose could be increased to 16 mg if the dose escalation criteria were met. Patients were treated for up to 5 days. Thirty-eight patients maintained the 8-mg dose and 7 had a dose increase to 16 mg; 41 completed the trial (34 completed early). One patient had mild hypernatremia. No significant safety concerns were observed with OPC-61815 administration at a starting dose of 8 mg and with dose escalation in accordance with the protocol-specified criteria. Treatment resulted in weight decrease (-3.01 kg); improvement or disappearance rates for other CHF symptoms (including edema, dyspnea, orthopnea, pulmonary congestion, and rales) indicated that treatment was effective. Urine excretion was increased 0-1 h after OPC-61815 administration and reached a maximum level at 1-2 h.The tolerability of once daily (up to 5 days) intravenous OPC-61815 (8 mg or 16 mg) was confirmed in patients with CHF who had difficulty with, or were incapable of, oral intake.

In some cases with idiopathic ventricular fibrillation, short-coupled premature ventricular contractions (PVCs) initiate fatal arrhythmia, which has recently been proposed as short-coupled ventricular fibrillation (SCVF). In the present case of SCVF, catheter ablation for trigger PVCs originating from the His-Purkinje system in both ventricles caused transient complete atrioventricular block, and a combination of quinidine and verapamil suppressed ventricular tachyarrhythmia.

Biomarkers that can predict cardiac resynchronization therapy (CRT) response have not yet been identified. The purpose of this study was to assess whether individual measurements of four brain/B-type natriuretic peptide (BNP) forms, coupled with cyclic guanosine monophosphate (cGMP) might contribute to the prediction of echocardiographic CRT responders.A BNP precursor (proBNP) and total BNP (= proBNP + mature BNP) were measured with newly developed kits, while an N-terminal fragment of proBNP (NT-proBNP) and cGMP were measured with commercial kits on the day before CRT implantation. Estimated mature BNP (emBNP = total BNP-proBNP), and the ratio of cGMP to each BNP form, as well as the concentrations of three other BNP forms, were prospectively investigated for their capability in predicting a response to CRT. A CRT responder was defined as an improvement in left ventricular ejection fraction10% and/or a reduction in left ventricular end-systolic volume15% at 6-month follow-up.Out of 77 patients, 46 (60%) were categorized as CRT responders. Among the measurement parameters, only the highest quartile of the cGMP to emBNP ratio was an independent predictor of CRT responders (odds ratio 4.87, 95% confidence interval 1.25-18.89, p = 0.02). The cGMP to emBNP ratio was associated with the cumulative events of heart failure hospitalization within one year following CRT implantation (log-rank p = 0.029).The cGMP to emBNP ratio could be utilized as a predictive biomarker of CRT responders. (Clinical Study on Responder Prediction in Cardiac Resynchronization Therapy Using Individual Molecular Measurement of Natriuretic Peptide: UMIN R000038927).

A de novo cardiac malignant tumor is rare and sometimes challenging to diagnose. We encountered a 67-year-old man without any medical history complaining of dyspnea on effort. On admission, his hemodynamics were deteriorated due to cardiac tamponade, which was improved by percutaneous drainage of 1,200 mL pericardial effusion, showing 11.0 g/dL of hemoglobin. We suspected primary cardiac malignancy following multidisciplinary tests, and a cardiac biopsy via sternotomy demonstrated the definitive diagnosis of primary malignant tumor (angiosarcoma) infiltrating the right atrial myocardium. We initiated weekly paclitaxel therapy. Further studies are warranted to establish the optimal diagnostic and therapeutic strategy for de novo cardiac malignancy.

Background Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients.Methods In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged >= 40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033.Findings Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1.0 [95% CI 0.8-1.2]; p=0.85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (p(interaction)=0.002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (p(interaction)=0.012 [>= 29.7 mL/m(2), worse outcomes]), and sex (p(interaction=)0.02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0.11).Interpretation Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Diastolic cardiac dysfunction in type 2 diabetes (DD2D) is a critical risk of heart failure with preserved ejection fraction. However, there is no established biomarker to detect DD2D. We aimed to investigate the predictive impact of fragmented QRS (fQRS) on electrocardiography on the existence of DD2D.We included in-hospital patients with type 2 diabetes without heart failure symptoms who were admitted to our institution for glycemic management between November 2017 and April 2021. An fQRS was defined as an additional R' wave or notching/splitting of the S wave in two contiguous electrocardiography leads. DD2D was diagnosed according to the latest guidelines of the American Society of Echocardiography.Of 320 participants, 122 patients (38.1%) had fQRS. DD2D was diagnosed in 82 (25.6%). An fQRS was significantly associated with the existence of DD2D (odds ratio 4.37, 95% confidence interval 2.33-8.20; p 0.0001) adjusted for seven potential confounders. The correlation between DD2D and diabetic microvascular disease was significant only among those with fQRS. Classification and regression tree analysis showed that fQRS was the most relevant optimum split for DD2D.An fQRS might be a simple and promising predictor of the existence of DD2D. The findings should be validated in a larger-scale cohort.

Background Baseline and post-procedural elevations in serum troponin-T levels are associated with increased morbidity and mortality following transcatheter aortic valve replacement (TAVR). However, the prognostic impact of change in serum troponin-T level following TAVR remains unknown. Methods Among the patients with severe aortic stenosis who underwent TAVR, those with baseline serum troponin-T level ≥51.5 ng/L were excluded. The impact of increases in serum troponin-T level to an abnormally high range (≥51.5 ng/L) following TAVR on 2-year cardiovascular death or heart failure readmissions was investigated. Results Among 189 included patients (median 86 years old, 28% men), serum troponin-T level increased in 79 patients following TAVR. An increase in serum troponin-T was associated with a higher rate of 30-day adverse events, predominantly due to pacemaker implantation for complete atrio-ventricular block, and a higher 2-year cumulative incidence of the primary endpoint (hazard ratio 5.24, 95% confidence interval 1.64-16.8, p = 0.005) adjusted for the potential confounders. Conclusion Post-procedural increase in serum troponin-T level was associated with adverse clinical outcomes following TAVR.

The prognostic impact of mitral inflow wave overlap during ivabradine therapy in patients with heart failure with reduced ejection fraction (HFrEF) remains to be unknown. Thus, in this study, we have retrospectively examined consecutive inpatients with HFrEF admitted with decompensated heart failure who continued ivabradine following the index discharge. Ideal heart rate (HR), at which echocardiographic mitral inflow wave overlap is theoretically 0, was retrospectively calculated as follows: 96 - 0.13 × (deceleration time [msec]). HR difference was then calculated as follows: actual HR - ideal HR. The association between the HR difference at index discharge and a composite outcome of cardiovascular death and heart failure readmissions was investigated. In total, 16 patients (68 [47, 75] years old, 11 men, median left ventricular ejection fraction 28% [22%, 35%]) were included in this study for analysis. Baseline actual HR was determined to be 88 (81, 93) bpm, whereas the ideal HR was calculated as 75 (73, 76) bpm. Following the initiation of ivabradine, actual HR at index discharge was 75 (64, 84) bpm. Patients with optimal HR (actual HR - ideal HR± 10 bpm; n = 9) were found to have experienced a lower incidence of the composite endpoint (40% versus 100%, P = 0.013) compared with those with sub-optimal HR (n = 7) with a hazard ratio of 0.10 (95% confidence interval 0.01-0.91) adjusted for actual HR at index discharge. In conclusion, HR modulation therapy using ivabradine may improve outcomes in patients with HFrEF if individualized ideal HR was achieved.

Background: Clinical outcomes of adaptive servo-ventilation (ASV) therapy have not been rigorously assessed. Optimal device settings ascertained by a pressure ramp test may increase the utility of ASV therapy. Methods and Results: Patients with congestive heart failure (CHF) who underwent ASV therapy were prospectively included in the study. Patients in the ramp test group underwent a pressure ramp test, during which the end-expiratory pressure was optimized to maximize cardiac output (assessed using the AESCLONE mini). The control group consisted of age-matched patients who received ASV therapy with a default pressure 5 cmH2O. The primary endpoint was a composite of all-cause death and heart failure recurrence, and was compared between the 2 groups. Of a total of 37 patients, 11 each were included in the ramp test and control groups. Median patient age was 73 years (interquartile range 59–75 years) and 16 were men. There were no significant differences in baseline characteristics between the 2 groups. In the ramp test group, end-expiratory pressure was optimized between 2 and 5 cmH2O in each patient. The 2-year incidence of the primary endpoint tended to be lower in the ramp test than control group (0% vs. 59%; P=0.080). Conclusions: Pressure ramp testing may be a promising strategy to optimize device pressure settings in patients with CHF undergoing ASV therapy. Larger-scale trials are needed to validate our findings.

Background: Polypharmacy in elderly patients with various comorbidities is associated with mortality and morbidity. However, the prognostic impact of polypharmacy in patients with severe aortic stenosis receiving trans-catheter aortic valve replacement remains unknown. Methods: Patients with severe aortic stenosis who received trans-catheter aortic valve replacement between 2015 and 2022 and were followed up at our institute following index discharge were included in this retrospective study. The impact of polypharmacy, which was defined as medication numbers ≥10 at index discharge, upon 2-year all-cause death was investigated. Results: A total of 345 patients (median age 85 [83, 89] years old, 99 (29%) men) were included. Median medication number was 9 (7, 10) at the index discharge and 88 (26%) were classified as receiving polypharmacy. Frailty index, including mini-mental state examination and CSHA score, were not significantly different between those with and without polypharmacy (p > 0.05 for both). Polypharmacy was associated with higher 2-year cumulative mortality with an adjusted hazard ratio of 21.4 (95% confidence interval, 6.06–74.8, p < 0.001). As a sub-analysis, the number of cardiovascular medications was not associated with 2-year mortality (hazard ratio 1.12, 95% confidence interval 0.86–1.48, p = 0.46), whereas a higher number of non-cardiovascular medications was associated with an incremental increase in 2-year mortality with a hazard ratio of 1.39 (95% confidence interval, 1.15–1.63, p < 0.001). Conclusions: In elderly patients with severe aortic stenosis, polypharmacy was associated with worse short-term survival following trans-catheter aortic valve replacement. Prognostic implication of aggressive intervention to decrease the amount of medication among those receiving TAVR requires further prospective studies.

Background: The six-minute walk test is a practical tool for assessing functional capacity in patients with a variety of etiologies including pulmonary disease and heart failure. Six-minute walk distance (6MWD) is associated with mortality and morbidity in patients with a variety of comorbidities. We aimed to assess the prognostic impact of baseline 6MWD in patients with severe aortic stenosis undergoing trans-catheter aortic valve replacement (TAVR). Methods: Patients with severe aortic stenosis who underwent a six-minute walk test after index admission and underwent TAVR between 2015 and 2022 were included in this retrospective study. Patients were followed up for two years or until November 2022 following TAVR. The impact of baseline 6MWD on the primary composite outcome, defined as all-cause death and all-cause readmission during the 2-year observation period following index discharge, was assessed. Results: A total of 299 patients (median age 86 years old, 85 men) were included. They received a 6-min walk test prior to TAVR, underwent successful TAVR procedures, and were discharged alive. The median baseline 6MWD was 204 (143, 282) meters. Shorter baseline 6MWD was associated with higher cumulative incidence of the primary outcome with an adjusted hazard ratio of 0.76 (95% confidence interval 0.58–1.01, p = 0.055) with a cutoff 6MWD of 178 m during the 2-year observation period after index discharge. Conclusions: Overall, functional capacity was impaired in the elderly patients with severe aortic stenosis prior to TAVR. Patients with severe aortic stenosis having shorter baseline 6MWD tended to have higher rates of morbidity and mortality after successful TAVR. The clinical implication of aggressive cardiac rehabilitation to improve patients’ functional capacity and 6MWD-guided optimal patient selection remain the future concerns.

Background Xanthine oxidase activity has a key role in the development of oxidative stress and progression of cardiovascular diseases. However, the change of xanthine oxidase activity following hemodialysis and its prognostic impact remain uncertain. Methods We prospectively included hemodialysis patients who did not take any anti-hyperuricemic agents and measured their xanthine oxidase activity before and after the index hemodialysis. The impact of change in xanthine oxidase activity during hemodialysis on cardiovascular death were investigated. Results A total of 46 patients (median 72 years old, 29 men) were included. During hemodialysis, a common logarithm of xanthine oxidase activity decreased significantly from 1.16 (0.94, 1.27) to 1.03 (0.80, 1.20) (p p = 0.43). Conclusions During hemodialysis, xanthine oxidase activity decreased among the overall cohort, whereas some patients experienced its increases, which might be associated with hypotension and hemoconcentration during hemodialysis. Further larger-scale studies are required to validate our findings and find clinical implication of change in xanthine oxidase activity during hemodialysis.

Background and Objectives: Small dense LDL cholesterol is a strong risk factor for atherosclerosis. However, few studies have investigated the impacts of this specific lipid profile on the incident risk of adverse cardiovascular events in patients with acute coronary syndrome. Materials and Methods: Patients with acute coronary syndrome, who underwent revascularization, were included and followed for 2 years. The levels of small dense LDL cholesterol were measured at index discharge (day 0) in the setting of newly administered therapies for secondary prevention, including aspirin and statins, during the index hospitalization. The prognostic impact of small dense LDL-cholesterol levels on the risk of a primary composite endpoint, including cardiac death, non-fatal myocardial infarction, unstable angina pectoris, stroke, and heart failure, was investigated. Results: In total, 46 patients (median 75 (59, 83) years old, 63% men) were included. Median small dense LDL cholesterol was 19.4 (13.5, 23.8) mg/dL at index discharge. All patients initiated statin treatment before the index discharge, with a median LDL-cholesterol level of 77 (64, 109) mg/dL. Small dense LDL-cholesterol level was independently associated with an incremental risk for the primary endpoint (p < 0.05 by adjusting for several potential risk factors, including LDL cholesterol) with a cutoff of 32.6 mg/dL. Conclusions: Small dense LDL-cholesterol level was a significant risk factor for cardiovascular events following presentations of acute coronary syndrome.

Background: Chest X-ray is a practical tool to semi-qualify pulmonary congestion. Remote dielectric sensing (ReDS) is a recently introduced, non-invasive, electromagnetic energy-based technology to quantify pulmonary congestion without expert technique. We compared these two modalities to clarify appropriate clinical situations for each modality. Methods: ReDS and chest X-ray measurements were prospectively performed on admission in consecutive hospitalized patients with cardiovascular diseases. In the chest X-ray, the congestive score index (CSI) was calculated blindly by two independent experts and averaged. CSIs were correlated with ReDS values. Results: A total of 458 patients (76 (69, 82) years old, 267 men, and 130 heart failure) were included. Median ReDS value was 28% (25%, 33%). There was a mild correlation between ReDS values and CSIs (r = 0.329, p < 0.001). The correlation between ReDS values and CSIs became stronger in the heart failure cohort (r = 0.538, p < 0.001). In patients with mild congestion (ReDS < 35%), ReDS values, instead of CSI, stratified the degree of congestion. In patients with severe congestion (ReDS > 35%), both modalities stratified the degree of congestion. Conclusions: Both chest X-ray and ReDS are useful for assessing severe pulmonary congestion, whereas ReDS would be preferred to chest X-ray in stratifying the severity of mild pulmonary congestion.

Background: In patients with essential hypertension, a non-dipping blood pressure pattern is a strong risk factor for cardiovascular diseases. However, background factors associating with such a blood pressure pattern remain unknown. Methods: Untreated essential hypertensive patients without chronic kidney diseases who were admitted to our outpatient clinic were included. Blood sampling and 24 h ambulatory blood pressure monitoring were mandatorily performed. Non-dipper status was defined as a maximum decrease in nocturnal systolic blood pressure within 10%. Clinical factors associating with non-dipper status were investigated. Results: A total of 154 patients (56 ± 12 years old, 86 men) were included. Among baseline characteristics, a higher serum uric acid level was independently associated with non-dipper status (odds ratio 1.03, 95% confidence interval 1.00–1.05, p < 0.05). Among those with non-dipper status, a higher high-sensitivity C-reactive protein level tended to be associated with incremental nighttime systolic blood pressure levels (p = 0.065). Conclusions: Hyperuricemia and micro-inflammation might be associated with attenuated nocturnal blood pressure dipping and incremental nighttime systolic blood pressure levels.

Background: Pulmonary congestion is quantified by a remote dielectric sensing (ReDSTM) system, while systemic congestion is estimated by calculated plasma volume. The type of clinical patient profile as defined by the ReDS system and calculated plasma volume remains uncertain. Methods: Hospitalized patients with or without heart failure were included in this prospective study. On admission, ReDS values were measured and plasma volume status (PVS) was estimated using their body weight at the same time. Cutoffs of ReDS value and PVS were defined at 34% and −2.7%, respectively. The association between the two parameters was assessed. Results: A total of 482 patients (median 76 years, 288 men) were included. The median ReDS value was 28% (25%, 32%) and median PVS was −16.4% (−26.3%, −5.9%). Of the patients, 64 had high ReDS value (and low PVS) and 80 had high PVS (and low ReDS value). The high ReDS group had a higher prevalence of clinical heart failure with a more elevated echocardiographic E/e’ ratio, whereas the high PVS group had a higher prevalence of chronic kidney disease (p < 0.05 for all). Four out of a total of six patients with high ReDS value and high PVS had both heart failure and chronic kidney disease profiles. Conclusion: The combination of ReDS value and PVS was able to clinically stratify the types of body fluid distribution and patient profiles. Utilizing these tools may assist the clinician in constructing a therapeutic strategy for the at-risk hospitalized patient.

Objective Heart rate modulation therapy using ivabradine reduces both morbidity and mortality in patients with systolic heart failure. However, the target heart rate for this patient population remains to be elucidated. Methods In this prospective observational study, we included patients with heart failure and a reduced ejection fraction who received 5.0 mg/day of ivabradine for three days. At baseline and three days later, the overlap length between E-wave and A-wave using trans-mitral Doppler echocardiography, as well as the cardiac output using AESCLONE mini, were simultaneously measured. The associations between Δ overlap length and Δ cardiac output were then investigated. Results Eight patients [77 (53, 87) years old, 2 men] were included. The heart rate decreased from 81 (69, 104) bpm down to 64 (57, 79) bpm (p=0.012). The overlap length increased in four patients and decreased in the other four patients. During the time period of ivabradine therapy, patients who had a greater decrease in overlap length had a greater increase in cardiac output (r=0.84, p=0.009). Conclusion Decreases in the overlap length between E-wave and A-wave by Doppler echocardiography were associated with an increase in the cardiac output while on ivabradine therapy. The implications of Doppler echocardiography-guided heart rate modulation therapy targeting a minimal overlap length therefore require further evaluation in larger, prospective studies.

Ivabradine, which reduces heart rate (HR) without affecting sympathetic nerve activity, improves mortality and morbidity in patients with systolic dysfunction. However, its impact on up-titrating a concomitant beta-blocker dose in such a cohort, via increasing cardiac output and blood pressure and improving tolerability to beta-blockers, remains unknown. In this single-center, prospective, randomized control trial, patients with systolic dysfunction, defined as left ventricular ejection fraction50%, sinus rhythm, heart rate75 bpm, systolic blood pressure between 90 and 110 mmHg, and New York Heart Association functional class III or IV, who are refractory to up-titration of a beta-blocker due to symptomatic hypotension, dizziness, or worsening heart failure, were assigned to the 20 ivabradine arm or the 20 conventional therapy arm and followed-up for 6 months. The primary outcome is the daily dose of beta-blocker at 6-months follow-up. The secondary outcomes are echocardiographic parameters including overlap between E-wave and A-wave in transmitral diastolic filling flow, plasma B-type natriuretic peptide level, 6-minute walk distance, and heart failure readmission rate. By conducting this study, we hope to demonstrate the clinical benefit of ivabradine therapy in up-titrating beta-blockers and improving clinical outcomes in patients with systolic dysfunction.

Background: The implications of mineralocorticoid receptor antagonists, including the newly introduced esaxerenone, on cardiac reverse remodeling in patients with heart failure with preserved ejection fraction (HFpEF) remain uncertain. Methods and Results: We included patients with HFpEF who received esaxerenone for hypertension between November 2019 and July 2021 in this retrospective study. Changes in left ventricular mass index (LVMI) were compared between the 6-month pretreatment period (without esaxerenone) and the 6-month treatment period (on esaxerenone). Thirty-three patients (median age 74 years [interquartile range {IQR} 70–81 years]; 33% male, median systolic blood pressure [SBP] 135 mmHg [IQR 123–148 mmHg]) were included in the study and completed 6-month esaxerenone therapy without any adverse events. During the pretreatment period, SBP decreased significantly (P=0.009), whereas LVMI remained unchanged (P=0.30). During the esaxerenone treatment period, both SBP and LVMI decreased significantly (P=0.003 and P=0.001, respectively). Conclusions: Esaxerenone may have beneficial effects of reverse remodeling in patients with HFpEF when used to treat hypertension. Further studies are needed to understand which patient populations may see greater benefits with esaxerenone.

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has demonstrated survival benefit and reduces heart failure hospitalization compared with enalapril in patients with heart failure and reduced ejection fraction. However, its efficacy in real-world practice in Japan remains unknown. Methods and Results: We initiated sacubitril/valsartan treatment for 37 patients (median age 68 years; median left ventricular ejection fraction 37%) between August and November 2020. Within 3 months, sacubitril/valsartan was discontinued in 3 patients due to symptomatic hypotension or worsening heart failure. Two patients were hospitalized due to worsening heart failure, with one of these patients undergoing percutaneous mitral valve repair. Three patients received scheduled non-pharmacological treatment: 1 received cardiac resynchronization therapy (CRT), 1 received CRT and underwent transcatheter aortic valve implantation, and 1 underwent left ventricular assist device implantation. Of the 30 patients who continued sacubitril/valsartan for 3–6 months without additional non-pharmacological therapy, there was a tendency for a decrease in N-terminal pro B-type natriuretic peptide concentrations (baseline vs. after 3–6 months ARNI treatment; median 733 vs. 596 pg/mL; P=0.097) and an increase in left ventricular ejection fraction (median 37% vs. 39%; P=0097). Conclusions: Sacubitril/valsartan therapy with a lower initial dose was safe and may be effective in Japanese heart failure patients in a real-world setting. Further evaluation of optimal patient selection and clinical management using sacubitril/valsartan is warranted.

Background: The prognostic impact of urinary isoxanthopterin (U-IXP), a recently proposed marker of oxidative stress, in patients with heart failure remains unknown. Methods and Results: Patients who were admitted to our institute for decompensated heart failure were prospectively included in the study; U-IXP was measured on admission. The association between the U-IXP concentration and a composite primary outcome that included cardiovascular death and heart failure readmissions following the index discharge was investigated. In all, 42 patients (median age 78 years [interquartile range {IQR} 69-85 years]; 25 males) were included in the study. The median U-IXP concentration on admission was 0.58 μmol/g creatinine (Cre; IQR 0.35-0.95 μmol/g Cre). A higher U-IXP concentration was an independent predictor of the primary outcome adjusted for clinical potential confounders and was associated with a significantly higher cumulative incidence of the primary outcome (71% vs. 16%, P=0.001) at a cut-off of 0.93 μmol/g Cre. Conclusions: U-IXP on admission was associated with cardiovascular death or heart failure readmission following the index discharge in patients with decompensated heart failure. The clinical implication of aggressive interventions to normalize U-IXP and the detailed prognostic mechanism of U-IXP in heart failure patients remain the next concerns.

In the countries like Japan where anticoagulation is not recommended in hemodialysis patients, the feasibility of percutaneous left atrial appendage closure (LAAC) in hemodialysis patients with non-valvular atrial fibrillation (NVAF) accompanying high risks of thromboembolic stroke and bleeding remains unknown. Peri-procedural and 45-day clinical outcomes following LAAC using WATCHMAN system, which were performed in our institute between Jun 2020 and April 2022 according to the Japanese Circulation Society guidelines, were retrospectively compared between those with and without hemodialysis. 118 patients (median 79 years, 81 men) consisting of 25 hemodialysis patients and 93 non-hemodialysis patients were included. CHADS score was 3 (2, 4) in the hemodialysis patients and 3 (2, 4) in the non-hemodialysis patients (p = 0.98). HAS-BREAD score was 4 (3, 5) in the hemodialysis patients and 3 (2, 3) in the non-hemodialysis patients (p

Background: pemafibrate is a newly-introduced selective peroxisome proliferator-activated receptor-α modulator, which decreases serum triglyceride levels with few drug-related adverse events and may reduce the risk of adverse cardiovascular events in carefully selected patients with hypertriglyceridemia. We aimed to understand which specific cohorts may benefit or not from pemafibrate therapy for adverse cardiovascular event risk reduction. Methods: patients with hypertriglyceridemia at baseline received pemafibrate therapy for two years or until October 2022. The factors that were associated with an increased risk of adverse cardiovascular events, defined as heart failure hospitalization, stroke, and acute coronary syndromes, were investigated. Results: a total of 121 patients (median 62 years, 88 men) remained on pemafibrate therapy for a median of 566 days without any drug-related adverse events. During a 3-month therapeutic period, triglyceride levels improved significantly from 302 (205, 581) mg/dL to 178 (117, 253) mg/dL (p < 0.001). During the overall therapeutic period, there were nine cardiovascular events. Comorbid chronic heart failure, comorbid coronary disease, and a lower pemafibrate dosing were independently associated with the primary endpoint (p < 0.05 for all). Those with multiple risk factors (N = 30) had a significantly higher cumulative incidence of the primary endpoint as compared with others (27% versus 3%, p < 0.001). Conclusion: pemafibrate significantly improves hypertriglyceridemia. A higher dose of pemafibrate should be considered to reduce the risk of adverse cardiovascular events, particularly in patients with chronic heart failure or coronary disease.

The therapeutic strategy for sustained ventricular tachycardia (VT) during left ventricular assist device usage remains unclear. We encountered a patient with durable left ventricular assist device who presented sustained VT. Electrophysiological mapping was able to be established appropriately owing to the robust mechanical hemodynamics support despite inter-device interference. The three-dimensional activation map of clinically documented VT demonstrated that the propagation exited from the right ventricular apex through the critical isthmus located at the epicardium or interventricular septum, which was successfully treated by catheter ablation at the exit site. Further experiences like ours should be accumulated to establish a therapeutic strategy.

Background: Restriction of oral potassium intake is a necessary dietary intervention for managing chronic hyperkalemia. These dietary changes may have negative impacts on nutrition status, particularly in geriatric cohorts with multiple comorbidities. Sodium zirconium cyclosilicate (SZC) is a newly introduced potassium binder intended for patients with hyperkalemia. We aimed to investigate whether the improvements in hyperkalemia with SZC therapy and the liberation of potassium intake restriction may improve nutrition status in a primarily geriatric patient cohort with chronic hyperkalemia. Methods: Patients who were maintained on SZC therapy for at least 3 months were retrospectively studied. Following the initiation of SZC and improvement in hyperkalemia, instructions on the restriction of potassium intake were loosened according to the institutional protocol. The change in nutrition status during the 3 month therapeutic period using SZC was investigated by referencing the prognostic nutritional index score (PNI), geriatric nutritional risk index score (GNRI), and controlling nutritional status (CONUT) scores. Results: A total of 24 patients (median age 78 years, 58% men, median estimated glomerular filtration rate 29.8 mL/min//1.73 m2) were included. Serum potassium level decreased significantly from 5.4 (5.1, 5.9) to 4.4 (4.2, 4.9) mEq/L without any drug-related adverse events, including hypokalemia. Nutrition-related scores, including the PNI score, the GNRI score, and the CONUT score, improved significantly following 3 months of SZC therapy (p < 0.05 for all). Psoas muscle volume and average days for one movement also improved significantly during the therapeutic period (p < 0.05 for both). Conclusions: Mid-term SZC therapy and liberation of potassium intake restriction might improve nutrition status in geriatric patients with chronic hyperkalemia.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and its prevalence increases with age. AF causes palpitations, heart failure, and cardiogenic embolism. Of them, the most critical and fatal complication is a cardio-embolic event. Oral anticoagulation plays a central role in reducing stroke risk in AF patients. Recently, when oral anticoagulation is considered in patients with non-valvular AF who are eligible for direct oral coagulations, they are preferred to vitamin K antagonist based on accumulating evidence. Although many patients can tolerate oral anticoagulation, there is a subset of patients who cannot tolerate long-term oral anticoagulation. Such a subset has a higher bleeding risk as indicated by the HAS-BLED score under oral anticoagulation. This subset of patients requires effective and safe non-pharmacological alternative therapies for stroke prevention. One of the promising non-pharmacological therapies is left atrial appendage closure. Three randomized controlled trials demonstrated non-inferiority of percutaneous left atrial appendage closure using WATCHMAN family to oral anticoagulation (Boston Scientific, Marlborough, MA, USA). WATCHMAN FLX, which was innovated following WATCHMAN 2.5, was associated with fewer safety events and a higher success rate of effective appendage closure. Nevertheless, several unsolved issues remain, including device-related thrombosis, post-treatment antithrombotic therapy, and peri-device leakage. Left atrial appendage closure for patients with non-valvular AF may be an alternative therapy to avoid cardiac embolism for high bleeding risk patients with contraindications to long-term oral anticoagulation therapy.

Objectives: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing experience, this global consensus document summarizes key management recommendations. Methods: International experts with experience in the management of patients with ongoing HVAD support were invited to summarize key aspects of patient and pump management and highlight differences in the current HeartMate 3 (Abbott Laboratories) ventricular assist device. Clinicians from high-implanting HVAD sites reviewed current literature and reported experience to generate a consensus statement. Results: Specific guidelines to assist in the management of ongoing HVAD patients are developed. Key management protocols and helpful techniques developed from experienced clinicians are combined into a short guideline document. As experience with HeartMate 3 increases, key differences in approach to management are highlighted, where appropriate. Conclusions: With decreasing worldwide experience in the ongoing management of HVAD-supported patients, this consensus guideline provides a summary of best practice techniques from international centers. Differences in HeartMate 3 management are highlighted.

Cardio-renal syndrome is a challenging clinical entity to manage, and is often associated with increased morbidity and mortality. We hypothesized that adaptive servo-ventilation (ASV), non-invasive positive pressure ventilation that ameliorates systemic/pulmonary congestion, may improve renal function in patients with symptomatic heart failure complicated by the cardio-renal syndrome. Patients with symptomatic congestive heart failure who underwent ASV therapy for over 1 month were included in this retrospective study. The trajectory of the estimated glomerular filtration ratio (eGFR) between the pre-1 month period and the post-one-month period (on ASV) were compared. A total of 81 patients (median 65 years old, 65 men) were included. eGFR decreased during the pre-1 month period from 52.7 (41.7, 64.6) down to 49.9 (37.3, 63.5) mL/minute/1.73 m2 (P < 0.001) whereas we observed an increase following one-month of ASV therapy up to 53.4 (38.6, 68.6) mL/minute/1.73 m2 (P = 0.022). A reduction in furosemide equivalent dose following the initiation of ASV therapy was independently associated with increases in eGFR with an adjusted odds ratio of 13.72 (95% confidence interval 3.40-55.3, P < 0.001). In conclusion, short-term ASV therapy was associated with the preservation of renal function, particularly when the dose of loop diuretics was concomitantly reduced.

Destination therapy (DT) is the indication to implant a left ventricular assist device (LVAD) in a patient with stage D heart failure who is not a candidate for heart transplantation. The implantable LVAD has been utilized in Japan since 2011 under the indication of bridge to transplant (BTT). After almost 10 year lag, DT has finally been approved and reimbursed in May 2021 in Japan. To initiate the DT program in Japan, revision of the LVAD indication from BTT is necessary. Also, in-depth discussion of caregiver issues as well as end-of-life care is indispensable. For that purpose, we assembled a DT committee of multidisciplinary members in August 2020, and started monthly discussions via web-based communication during the COVID-19 pandemic. This is a summary of the consensus reached after 6 months' discussion, and we have included as many relevant topics as possible. Clinical application of DT has just started, and we are willing to revise this consensus to meet the forthcoming issues raised during real-world clinical experience.

Background: Although many risk factors have been reported to be associated with poor clinical outcomes following transcatheter aortic valve replacement (TAVR), the implications of inadequate cardiac unloading following TAVR remain unknown. We investigated the prognostic impact of inadequate cardiac unloading following TAVR. Methods and Results: We retrospectively analyzed a cohort of patients with severe aortic stenosis who underwent invasive hemodynamic assessment following TAVR. The impact of inadequate cardiac unloading, defined as an elevated pulmonary capillary wedge pressure (PCWP), on the composite primary endpoint of cardiovascular mortality or heart failure readmission was investigated. Eighty-two patients (median age 86 years; 57 women) were included. Median PCWP following TAVR was 9 mmHg (interquartile range 7-13 mmHg). A higher PCWP tended to be associated with an increased risk of adverse cardiovascular events (adjusted hazard ratio 1.18; 95% confidence interval 0.99-1.41). A cut-off value of PCWP >12 mmHg, calculated by time-dependent receiver operating characteristics analysis, stratified the cumulative incidence of the primary endpoint (2-year incidence of 36% vs. 8%). Uptitration of the diuretic dose was associated with event freedom among those with PCWP >12 mmHg. Conclusions: Inadequate cardiac unloading following TAVR was associated with an increased risk of adverse clinical events. Uptitration of medical therapies to improve cardiac hemodynamics after TAVR may reduce this risk.