Rapid progression of a coronary artery aneurysm caused by IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. IgG4-RD has also been reported in coronary arteries as periarteritis. IgG4-related coronary periarteritis may cause coronary artery aneurysms, and IgG4-related coronary artery aneurysms (IGCAs) are life-threatening. We describe a case of a patient with IGCA that highlights the usefulness and limitations of various IGCA evaluation modalities and provides insight into disease pathophysiology. CASE SUMMARY: A 60-year-old man with IgG4-RD diagnosed 2 years before and with IGCA at the proximal right coronary artery (RCA) on coronary angiography (CAG) 9 months prior to admission to the hospital presented with acute coronary syndrome. Emergent CAG revealed the rapid progression of IGCA at the RCA, an obstruction of the diagonal branch, and stenosis of the left anterior descending artery (LAD) and the high lateral branch (HL). The patient underwent percutaneous coronary intervention for the diagonal branch. The RCA aneurysm was resected and bypassed with a saphenous vein graft (SVG); coronary bypass grafting (left internal mammary artery to LAD and SVG to HL) was performed. Pathological findings showed inflammatory cell infiltration and disruption of the elastic plate. CONCLUSION: IGCAs require careful follow-up with computed tomography scans for early detection of aneurysmal enlargement.

Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Determinants of physical quality of life in patients with chronic thromboembolic pulmonary hypertension after treatment: Insights from invasive exercise stress test.

BACKGROUND: Impaired quality of life (QoL) is prevalent among patients with chronic thromboembolic pulmonary hypertension (CTEPH) despite improved survival due to medical advances. We clarified the physical QoL of patients with CTEPH with mildly elevated pulmonary hemodynamics and evaluated its determinants using a database of patients with CTEPH evaluated for hemodynamics during exercise. METHODS: The QoL was measured in 144 patients with CTEPH (age, 66 (58-73) years; men/women, 48/96) with mildly elevated mean pulmonary artery pressure (< 30 mmHg) at rest after treatment with balloon pulmonary angioplasty and/or pulmonary endarterectomy using the Short-Form 36 (SF-36) questionnaire. The enrolled patients were divided into two groups: physical component summary (PCS) scores in the SF-36 over 50 as PCS-good and those under 50 as PCS-poor. RESULTS: The median PCS in SF-36 score was 43.4 (IQR 32.4-49.5) points. The PCS-poor group (n = 110) was older and had lower exercise capacity and SaO2 during exercise. PCS scores were correlated with 6-minute walk distance (rs = 0.40, p < 0.001), quadriceps strength (rs = 0.34, p < 0.001), peak VO2 (rs = 0.31, p < 0.001), SaO2 at rest (rs = 0.35, p < 0.001) and peak exercise (rs = 0.33, p < 0.001), home oxygen therapy usage (rs = -0.28, p = 0.001), and pulmonary vascular resistance at peak exercise (rs = -0.26, p = 0.002). CONCLUSIONS: The impairment of physical QoL was common in patients with CTEPH with improved hemodynamics; exercise capacity, hypoxemia, and hemodynamic status during exercise were related to the physical QoL.

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer.

The clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5-year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability.

DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

Passive Smoking-Induced Mutagenesis as a Promoter of Lung Carcinogenesis.

INTRODUCTION: The International Agency for Research on Cancer has classified passive smoking (PS) or secondhand smoke exposure as a group 1 carcinogen linked to lung cancer. However, in contrast to active smoking, the mutagenic properties of PS remain unclear. METHODS: A consecutive cohort of 564 lung adenocarcinoma samples from female never-smokers, who provided detailed information about their exposure to PS during adolescence and in their thirties through a questionnaire, was prepared. Of these, all 291 cases for whom frozen tumor tissues were available were subjected to whole exome sequencing to estimate tumor mutational burden, and the top 84 cases who were exposed daily, or not, to PS during adolescence, in their thirties or in both periods, were further subjected to whole genome sequencing. RESULTS: A modest yet statistically significant increase in tumor mutational burden was observed in the group exposed to PS compared with the group not exposed to PS (median values = 1.44 versus 1.29 per megabase, respectively; p = 0.020). Instead of inducing driver oncogene mutations, PS-induced substantial subclonal mutations exhibiting APOBEC-type signatures, including SMAD4 and ADGRG6 hotspot mutations. A polymorphic APOBEC3A/3B allele-specific to the Asian population that leads to up-regulated expression of APOBEC3A accentuated the mutational load in individuals exposed daily to PS during adolescence. CONCLUSIONS: This study reveals that PS-induced mutagenesis can promote lung carcinogenesis. The APOBEC3A/3B polymorphism may serve as a biomarker for identifying passive nonsmoking individuals at high risk of developing lung cancer.

Cross-individual cancer transmission to children during the gestational and perinatal periods.

Cancer transmission may rarely occur between individuals. Besides through allogenic transplantation, cancer transmission via the hemochorial placenta, which is permissive for cell traffic, has been described in a few reports. Three etiologies of transplacental cancer transmission include (1) maternofetal transmission of maternal cancer cells, (2) transmission of gestational choriocarcinoma to the fetus, and (3) transfer of preleukemic cells from one monozygotic twin to the other. Additionally, we recently reported two pediatric cases of lung tumors in which the lung-only distribution of tumors and genomic profiling of both the child's and mother's tumor samples suggested the airway/transbronchial transmission of maternal cervical cancer cells to the child by aspiration at birth. The immune system coordinates the hemostatic balance between effector and regulatory immunity, especially during fetal development. The immunoregulatory properties are shared in both physiological pregnancy-related and pathological cancer-related conditions. Mechanistically, the survival and colonization of transmitted cancer cells within a child are likely attributed to a combination of the child's immune tolerance and the cancer's immune escape. In this review, we summarize the current understanding of gestational/perinatal cancer transmission and discuss the possible mechanism-based immunotherapy for this rare form of pediatric cancer.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Rationale and protocol of the LAQUA-HF trial: a factorial randomised controlled trial evaluating the effects of neurohormonal and diuretic agents on health-status reported outcomes in heart failure patients.

INTRODUCTION: The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects. METHODS AND ANALYSIS: In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint. ETHICS AND DISSEMINATION: The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. TRIAL REGISTRATION NUMBER: UMIN000045229.

Prevalence and clinical characteristics of diabetic cardiomyopathy in patients with acute heart failure.

BACKGROUND AND AIMS: Diabetic cardiomyopathy refers to cases of diabetes mellitus (DM) complicated by cardiac dysfunction in the absence of cardiovascular disease and hypertension. Its epidemiology remains unclear due to the high rate of coexistence between DM and hypertension. Therefore, this study aimed to examine the prevalence and clinical characteristics of diabetic cardiomyopathy among patients with acute heart failure (HF). METHODS AND RESULTS: This multicenter, retrospective study included 17,614 consecutive patients with acute HF. DM-related HF was defined as HF complicating DM without known manifestations of coronary artery disease, significant valvular heart disease, or congenital heart disease, while diabetic cardiomyopathy was defined as DM-related HF without hypertension. Univariable and multivariable logistic regression analyses were performed to identify factors associated with in-hospital mortality. Diabetic cardiomyopathy prevalence was 1.6 % in the entire cohort, 5.2 % in patients with acute HF complicating DM, and 10 % in patients with DM-related HF. Clinical characteristics, including the presence of comorbidities, laboratory data on admission, and factors associated with in-hospital mortality, significantly differed between the diabetic cardiomyopathy group and the DM-related HF with hypertension group. The in-hospital mortality rate was significantly higher in patients with diabetic cardiomyopathy than in patients with DM-related HF with hypertension (7.7 % vs. 2.8 %, respectively; P < 0.001). CONCLUSION: The prevalence of diabetic cardiomyopathy was 1.6 % in patients with acute HF, and patients with diabetic cardiomyopathy were at high risk for in-hospital mortality. The clinical characteristics of patients with diabetic cardiomyopathy were significantly different than those of patients with DM-related HF with hypertension.

Forecasting the Acute Heart Failure Admissions: Development of Deep Learning Prediction Model Incorporating the Climate Information.

BACKGROUND: Climate is known to influence the incidence of cardiovascular events. However, their prediction with traditional statistical models remains imprecise. METHODS AND RESULTS: We analyzed 27,799 acute heart failure (AHF) admissions within the Tokyo CCU Network Database from January 2014 to December 2019. High-risk AHF (HR-AHF) day was defined as a day with the upper 10th percentile of AHF admission volume. Deep neural network (DNN) and traditional regression models were developed using the admissions in 2014-2018 and tested in 2019. Explanatory variables included 17 meteorological parameters. Shapley additive explanations were used to evaluate their importance. The median number of incidences of AHF was 12 (9-16) per day in 2014-2018 and 11 (9-15) per day in 2019. The predicted AHF admissions correlated well with the observed numbers (DNN: R2 = 0.413, linear regression: R2 = 0.387). The DNN model was superior in predicting HR-AHF days compared with the logistic regression model [c-statistics: 0.888 (95% CI: 0.818-0.958) vs 0.827 (95% CI: 0.745-0.910): P = .0013]. Notably, the strongest predictive variable was the 7-day moving average of the lowest ambient temperatures. CONCLUSIONS: The DNN model had good prediction ability for incident AHF using climate information. Forecasting AHF admissions could be useful for the effective management of AHF.

Understanding Patient Perspectives Toward Shared Decision-Making in Patients With Pulmonary Hypertension.

Clinical guidelines for pulmonary hypertension (PH) recommend shared decision-making and individualized treatment. However, patient perspectives on PH treatment goals, preference toward a decision-making style of treatment, and adoption of shared decision-making remain unclear. This cross-sectional questionnaire-based study assessed the patients' preferred and actual participation role in treatment decision-making, rated on 5 scales (ranging from passive [patients leave all decisions to physicians] to active [patients make the decision after physicians show patients several options]) and evaluated the concordance between preferred and actual participation roles. The important factors underlying patients' perspectives in treatment decision-making (i.e., prognosis; symptom, financial, family, and social burdens; patient values; and physician recommendation) were evaluated. Univariate logistic regression analysis was performed to determine the patients with a positive preference toward "physician recommendation" in treatment decision-making. Among 130 patients with PH (median age: 58 years; mean pulmonary arterial pressure: 23 mm Hg; 27.7% were males), 59.2% preferred that "physicians make the decision regarding treatment after showing patients therapeutic options (i.e., intermediate between passive and active roles)." The patient-preferred and actual participation roles in decision-making had moderate agreement (Cohen's kappa = 0.46). The most important factor in treatment decisions was "symptom burden reduction" (93.8%). Although 85.0% of patients chose "physician recommendation" as an important factor, 49.6% chose "alignment with my values." The determinants of patients who chose "physician recommendation" were less severe hemodynamics and better functional capacity. In conclusion, patients with PH preferred that the "physicians make the decision after showing patients therapeutic options" and prioritized physician recommendation over their values.

Qualitative analysis of expressions used in the end-of-life discussions and their associated factors.

OBJECTIVES: Discussing end-of-life (EOL) issues with patients remains challenging for health professionals. Physicians may use various expressions, including euphemistic ones, when disclosing the prognosis to their patients to reduce their psychological impact. However, the actual expressions of EOL disclosure in clinical practice are unclear. This study aims to investigate the expressions used in EOL disclosures and explore their associated factors. METHODS: A retrospective chart review was conducted enrolling all the patients who died in a university-affiliated hospital. Expressions used in the EOL disclosure were qualitatively analyzed. The patients' participation rate and length from the discussion to death were investigated. RESULTS: EOL disclosures were observed in 341 of 358 patients. The expressions used by the physicians were categorized into 4 groups; Group 1: Clear presentation of life expectancy (n = 106; 31.1%), Group 2: Euphemistic presentation of life expectancy (n = 24; 7.0%), Group 3: Presentation of risk of sudden death (n = 147; 43.1%), Group 4: No mention on life expectancy (n = 64; 18.8%). The proportion of male patients was higher in Group 2 (79%) and lower in Group 4 (56%). Patients with cancer accounted for approximately 70% of Groups 1 and 4, but only approximately 30% of Group 3. The patient participation rate was highest in Group4 (84.4%), followed by Group 2 (50.0%). The median time from EOL disclosure to death was longer in Groups 1 and 4 (26 and 29.5 days, respectively), compared to Groups 2 and 3 (18.5 and 16 days, respectively). SIGNIFICANCE OF RESULTS: A variety of expressions are used in EOL disclosure. Patterns of communication are influenced by patients' gender and type of illness (cancer or noncancer). Euphemisms do not seem to facilitate timely disclosure of life expectancy or patient participation. For health professionals, not only devising the expressions to alleviate their patients' distress when breaking bad news but also considering the communication process and patient background are essential.

Treatment patterns and trajectories in patients after acute heart failure hospitalization.

AIMS: The trajectories of systolic function after admission for acute heart failure (HF) and their effect on clinical outcomes have not been fully elucidated. We aimed to assess changes in left ventricular ejection fraction (LVEF) between the index and 1 year after discharge and to examine their prognostic implications. METHODS AND RESULTS: We extracted data from a prospective multicentre registry of patients hospitalized for acute HF and identified 1636 patients with LVEF data at admission and 1 year after discharge. We categorized them into five groups based on LVEF changes: HF with unchanged-preserved EF [HFunc-pEF (EF ≥ 50%); N = 527, 32.2%], unchanged-mildly reduced EF [HFunc-mrEF (EF 41-49%); N = 86, 5.3%], unchanged-reduced EF [HFunc-rEF (EF ≤ 40%); N = 377, 23.0%], worsened EF (HFworEF; N = 83, 5.1%), and improved EF (HFimpEF; N = 563, 34.4%). We then evaluated the subsequent composite outcome of cardiovascular death and HF readmission. During 1 year after discharge, 53% of patients with HF with reduced EF and 67% of those with HF with mildly reduced EF (HFmrEF) transitioned to other categories, whereas 92% of those with HF with preserved EF (HFpEF) remained within the same category. Patients with HFimpEF were more likely to be younger and had relatively preserved renal function, whereas those with HFworEF were the oldest and had more comorbidities among the five groups. After multivariable adjustment, patients with HFimpEF and HFunc-pEF had a lower risk for composite outcomes when referenced to patients with HFunc-rEF [hazard ratio (95% confidence interval), P-value: 0.28 (0.16-0.49), P < 0.001, and 0.40 (0.25-0.63), P < 0.001, respectively]. Conversely, patients with HFunc-mrEF and HFworEF had a comparable risk [0.44 (0.18-1.07), P = 0.07, and 0.63 (0.29-1.39), P = 0.26, respectively]. CONCLUSIONS: A substantial number of patients with HF experienced transitions to other categories after discharge. Notably, patients with decreased EF experienced a worse prognosis, even with slight decreases (e.g. HFpEF transitioning to HFmrEF). These findings emphasize the significance of longitudinal assessments of systolic function to better manage patients following acute decompensation.

Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma.

The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints.

Initiation and Up-Titration of Guideline-Based Medications in Hospitalized Acute Heart Failure Patients　- A Report From the West Tokyo Heart Failure Registry.

BACKGROUND: Despite recommendations from clinical practice guidelines to initiate and titrate guideline-directed medical therapy (GDMT) during their hospitalization, patients with acute heart failure (AHF) are frequently undertreated. In this study we aimed to clarify GDMT implementation and titration rates, as well as the long-term outcomes, in hospitalized AHF patients.Methods and Results: Among 3,164 consecutive hospitalized AHF patients included in a Japanese multicenter registry, 1,400 (44.2%) with ejection fraction ≤40% were analyzed. We assessed GDMT dosage (ß-blockers, renin-angiotensin inhibitors, and mineralocorticoid-receptor antagonists) at admission and discharge, examined the contributing factors for up-titration, and evaluated associations between drug initiation/up-titration and 1-year post-discharge all-cause death and rehospitalization for HF via propensity score matching. The mean age of the patients was 71.5 years and 30.7% were female. Overall, 1,051 patients (75.0%) were deemed eligible for GDMT, based on their baseline vital signs, renal function, and electrolyte values. At discharge, only 180 patients (17.1%) received GDMT agents up-titrated to >50% of the maximum titrated dose. Up-titration was associated with a lower risk of 1-year clinical outcomes (adjusted hazard ratio: 0.58, 95% confidence interval: 0.35-0.96). Younger age and higher body mass index were significant predictors of drug up-titration. CONCLUSIONS: Significant evidence-practice gaps in the use and dose of GDMT remain. Considering the associated favorable outcomes, further efforts to improve its implementation seem crucial.

End-of-Life Discussions and Their Timing for Patients With Cardiovascular Diseases　- From the Perspective of Bereaved Family Members.

BACKGROUND: Enhanced discussions regarding end-of-life (EOL) are crucial to provide appropriate care for seriously ill patients. However, the current status of EOL discussions, especially their timing and influencing factors, among patients with cardiovascular diseases (CVD) remains unknown.Methods and Results: We conducted a cross-sectional questionnaire survey of bereaved family members of CVD patients who died at 10 tertiary care institutes in Japan. In all, 286 bereaved family members (38.2% male; median age 66.0 [interquartile range 58.0-73.0] years) of CVD patients were enrolled; of these, 200 (69.9%) reported that their families had had EOL discussions with physicians. The major topic discussed was resuscitation (79.0%), and 21.5% discussed the place of EOL care. Most discussions were held during hospitalization of the patient (88.2%). More than half (57.1%) the discussions were initiated less than 1 month before the patient died, and 22.6% of family members felt that this timing of EOL discussions was late. Bereaved family members' perception of late EOL discussions was associated with the family members aggressive attitude towards life-prolonging treatment, less preparedness for bereavement, and less satisfaction with EOL care. CONCLUSIONS: Approximately 70% of bereaved family members of CVD patients had EOL discussions, which were often held shortly before the patient died. Further research is required to establish an ideal approach to EOL discussions at an appropriate time, which may improve the quality of EOL care.

Temporal Trends in Heart Failure Management and Outcomes: Insights From a Japanese Multicenter Registry of Tertiary Care Centers.

Background The management of heart failure (HF) has markedly changed, due to changes in demographics and the emergence of novel pharmacotherapies. However, detailed analyses on the temporal trends in characteristics and outcomes among patients with HF are scarcely available. This study aimed to assess the temporal trends over 11 years in clinical management and outcomes in patients with HF. Methods and Results We analyzed data from a multicenter registry of hospitalized patients with acute HF, including 6877 patients registered from 2011 to 2021. Age-adjusted mortality was calculated using standardized mortality ratios. During the study period, mean age increased from 75.2 years in 2011 to 2012 to 76.4 years in 2020 to 2021 (P for trend <0.001). The proportion of HF with reduced ejection fraction (HFrEF, left ventricular ejection fraction <40%) remained constant (from 43.4% to 42.7%, P for trend=0.38). The median duration of hospital stays (from 15 to 17 days, P for trend<0.001) had increased. As for the implementation of guideline-directed medical therapy, the use of mineralocorticoid receptor antagonist at discharge increased in patients with HFrEF (from 44.3% to 60.2%, P for trend<0.001). There was also an increase in the use of sodium-glucose cotransporter-2 inhibitors following their approval for use. The age-adjusted 1-year mortality decreased in patients with HFrEF (from 18.0% to 9.3%, P for trend<0.001) but not in patients with non-HFrEF (left ventricular ejection fraction ≥40%; from 9.2% to 9.5%, P for trend=0.79). Conclusions Hospitalized patients with HF have been aging over the past decade. Their long-term outcomes after discharge have improved predominantly because of decreased mortality in patients with HFrEF.