Open-Label, Single-Center, Single-Arm Study Evaluating the Efficacy and Safety of Elobixibat for Chronic Constipation in Patients With Heart Failure.

Background: Neither the efficacy nor safety of elobixibat has been investigated in the treatment of chronic constipation in patients with heart failure (HF). Methods and Results: In this prospective, single-center, single-arm study elobixibat (10 mg/day) was administered for 12 weeks to 18 HF patients with chronic constipation defined according to the Rome IV criteria. Spontaneous bowel movement (SBM), stool consistency as measured by the Bristol Stool Form Scale, and degree of straining during defecation were recorded. In addition, biomarkers, blood pressure (BP) measured by ambulatory monitoring, and adverse events were assessed. Although there was no significant difference, the frequency of SBM increased by 2.0/week from baseline to Week 12. Both the degree of straining during defecation and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased at Week 12 (straining, -0.79 [95% confidence interval (CI), -1.40 to -0.17]; LDL-C, -10.4 mg/dL [95% CI, -17.9 to -2.9]). Although not significant, the difference in BP before and after defecation tended to decrease from baseline by approximately 10 mmHg at Week 12. Serious adverse events were not observed. Conclusions: Elobixibat reduced the degree of straining during defecation, and improved the lipid profile in HF patients with chronic constipation.

A new staging system using right atrial strain in patients with immunoglobulin light-chain cardiac amyloidosis.

AIMS: There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with immunoglobulin light-chain (AL) cardiac amyloidosis. METHODS AND RESULTS: Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from 2007 to 2022, 72 patients with sufficient two-dimensional speckle tracking imaging data without chemotherapy before the diagnosis were retrospectively analysed. During a median follow-up of 403 days, 31 deaths occurred. Age and the rate of male sex were not significantly different between the all-cause death group and the survival group (age, 70.4 ± 8.8 years vs. 67.0 ± 10.0 years, P = 0.14, male sex, 65% vs. 66%, P = 0.91). The estimated glomerular filtration rate (eGFR) was significantly lower, and B-type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs-cTnT) were significantly higher, in the all-cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m2 vs. 59.4 ± 24.4 mL/min/1.73 m2 , P < 0.05, BNP, 725 [360-1312] pg/mL vs. 123 [81-310] pg/mL, P < 0.01, hs-cTnT, 0.12 [0.07-0.18] ng/mL vs. 0.05 [0.03-0.08] ng/mL, P < 0.01). Left ventricular (LV) global longitudinal strain (GLS) (LV-GLS), left atrial strain during the reservoir phase (LASr), right ventricular GLS (RV-GLS), and RASr were significantly lower in the all-cause death group versus the survival group (LV-GLS, 8.5 ± 4.3% vs. 11.8 ± 3.8%, P < 0.01, LASr, 8.8 ± 7.1% vs. 14.3 ± 8.1%, P < 0.01, RV-GLS, 11.6 ± 5.1% vs. 16.4 ± 3.9%, P < 0.01, RASr, 10.2 ± 7.3% vs. 20.7 ± 9.5%, P < 0.01). RASr was significantly associated with all-cause death after adjusting for RV-GLS, LV-GLS and LASr (hazard ratio [HR]: 0.91, 95% confidence interval [95% CI]: 0.83-0.99, P < 0.05). RASr and log-transformed BNP were significantly associated with all-cause death after adjusting for log-transformed troponin T and eGFR (RASr, HR: 0.93, 95% CI: 0.87-1.00, P < 0.05; log-transformed BNP, HR: 2.10, 95% CI: 1.17-3.79, P < 0.05). The optimal cut-off values were RASr: 16.4% (sensitivity: 66%, specificity: 84%, area under curve [AUC]: 0.81) and BNP: 311.2 pg/mL (sensitivity: 83%, specificity: 78%, AUC: 0.82) to predict all-cause mortality using ROC analysis. Kaplan-Meier analysis revealed that patients with low RASr (<16.4%) or high BNP (>311.2 pg/mL) had a significantly high probability of all-cause death (both, P < 0.01). We devised a new staging score by adding 1 point if RASr decreased or BNP levels increased more than each cut-off value. The HR for all-cause death using score 0 as a reference was 5.95 (95% CI: 1.19-29.79; P < 0.05) for score 1 and 23.29 (95% CI: 5.37-100.98; P < 0.01) for score 2. CONCLUSIONS: The new staging system using RASr and BNP predicted prognosis in patients with AL cardiac amyloidosis.

Impaired Cholesterol Efflux Capacity rather than Low HDL-C Reflects Oxidative Stress under Acute Myocardial Infarction.

AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.

MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response.

Hematopoietic stem cell (HSC) divisional fate and function are determined by cellular metabolism, yet the contribution of specific cellular organelles and metabolic pathways to blood maintenance and stress-induced responses in the bone marrow remains poorly understood. The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 (encoded by the Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and to promote cell survival. Here, we investigated the functional involvement of MITOL in HSC maintenance by generating MX1-cre inducible Mitol knockout mice. MITOL deletion in the bone marrow resulted in HSC exhaustion and impairment of bone marrow reconstitution capability in vivo. Interestingly, MITOL loss did not induce major mitochondrial dysfunction in hematopoietic stem and progenitor cells. In contrast, MITOL deletion induced prolonged ER stress in HSCs, which triggered cellular apoptosis regulated by IRE1α. In line, dampening of ER stress signaling by IRE1α inihibitor KIRA6 partially rescued apoptosis of long-term-reconstituting HSC. In summary, our observations indicate that MITOL is a principal regulator of hematopoietic homeostasis and protects blood stem cells from cell death through its function in ER stress signaling.

Metabolic regulation in erythroid differentiation by systemic ketogenesis in fasted mice.

Erythroid terminal differentiation and maturation depend on an enormous energy supply. During periods of fasting, ketone bodies from the liver are transported into circulation and utilized as crucial fuel for peripheral tissues. However, the effects of fasting or ketogenesis on erythroid behavior remain unknown. Here, we generated a mouse model with insufficient ketogenesis by conditionally knocking out the gene encoding the hepatocyte-specific ketogenic enzyme hydroxymethylglutary-CoA synthase 2 (Hmgcs2 KO). Intriguingly, erythroid maturation was enhanced with boosted fatty acid synthesis in the bone marrow of a hepatic Hmgcs2 KO mouse under fasting conditions, suggesting that systemic ketogenesis has a profound effect on erythropoiesis. Moreover, we observed significantly activated fatty acid synthesis and mevalonate pathways along with reduced histone acetylation in immature erythrocytes under a less systemic ketogenesis condition. Our findings revealed a new insight into erythroid differentiation, in which metabolic homeostasis and histone acetylation mediated by ketone bodies are essential factors in adaptation toward nutrient deprivation and stressed erythropoiesis.

Exosomal miR206 Secreted From Growing Muscle Promotes Angiogenic Response in Endothelial Cells.

BACKGROUND: Resistance exercise is beneficial in patients with lower extremity arterial disease. Muscle-derived exosomes contain many types of signaling molecules, including microRNAs (miRNAs). Here, we tested the hypothesis that exosomal miRNAs secreted by growing muscles promote an angiogenic response in endothelial cells (ECs).Methods and Results: Skeletal muscle-specific conditional Akt1 transgenic (Akt1-TG) mice, in which skeletal muscle growth can be induced were used as a model of resistance training. Remarkable skeletal muscle growth was observed in mice 2 weeks after gene activation. The protein amount in exosomes secreted by growing muscles did not differ between Akt1-TG and control mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway frequency analysis of 4,665 target genes, identified using an miRNA array miRNAs, revealed a significant increase in Akt and its downstream signaling pathway genes. Among the upregulated miRNAs, miR1, miR133, and miR206 were significantly upregulated in the serum of Akt1-TG mice. miR206 was also increased in insulin-like growth factor (IGF)-1-stimulated hypertrophied myotubes. Exogenous supplementation of exosomal miR206 to human umbilical vein ECs promoted angiogenesis, as assessed using the spheroid assay, and increased the expression of angiogenesis-related transcripts. CONCLUSIONS: Exosomal miR206 is upregulated in the blood of Akt1-TG mice and in IGF-stimulated cultured myotubes. Exogenous supplementation of miR206 promoted an angiogenic response in ECs. Our data suggest that miR206 secreted from growing muscles acts on ECs and promotes angiogenesis.

Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells.

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid-mediated apoptosis. The release of this metabolic adaptation by FDA-approved anti-inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.

Prognostic impact of diabetes mellitus on in-hospital mortality in patients with acute myocardial infarction complicating renal dysfunction according to age and sex.

BACKGROUND: Patients with acute myocardial infarction (AMI) complicating renal dysfunction (RD) are recognized as being at high risk. Although diabetes mellitus (DM) is a major cause of RD, the prognostic impact of coexisting DM on mortality in patients with AMI complicating RD is ill-defined. This study compared the prognostic impact of coexisting DM in patients with AMI complicating RD according to both age and sex. METHODS: A multicenter retrospective study was conducted on 2988 consecutive patients with AMI complicating RD (estimated glomerular filtration rate <60 mL/min per 1.73 m2). Multivariable Cox regression analysis was performed to investigate the effects of DM on in-hospital mortality. RESULTS: Statistically significant interactions between age and DM and between sex and DM for in-hospital mortality were revealed in the entire cohort. Coexisting DM was identified as an independent risk factor for in-hospital mortality (hazard ratio [HR], 2.543) in young (aged <65 years), but not old (aged ≥65 years), patients. DM was identified as an independent risk factor (HR, 1.469) in male, but not female, patients. Kaplan-Meier survival curves showed that DM correlated with significantly low survival rates in patients that were young or male as compared to those who were old or female. CONCLUSIONS: There were significant differences in the prognostic impact of DM on in-hospital mortality between young and old as well as male and female patients with AMI complicating RD. These results have implications for future research and the management of patients with DM, RD, and AMI comorbidities.

Prognostic Significance of Soluble PD-L1 on Cardiovascular Outcomes in Patients with Coronary Artery Disease.

AIMS: Programmed cell death-1 (PD-1) and its ligand (PD-L1) regulate T cells, leading to immunotolerance. We previously demonstrated that patients with coronary artery disease (CAD) had increased circulating levels of soluble PD-L1 (sPD-L1). However, the prognostic significance of sPD-L1 on cardiovascular outcomes is unknown. In the present study, we evaluated the association between sPD-L1 and cardiovascular events in patients with CAD. METHODS: We prospectively measured sPD-L1 in patients with CAD admitted to Kumamoto University Hospital between December 2017 and January 2020 and observed their cardiovascular event rate. The primary outcome was a composite of death from non-cardiovascular causes, death from cardiovascular causes, non-fatal myocardial infarction, unstable angina pectoris, revascularization, hospitalization for heart failure, and ischemic stroke. RESULTS: Finally, 627 patients were enrolled, and 35 patients were lost to follow-up. The median follow-up duration was 522 days. In total, 124 events were recorded. The Kaplan-Meier curve showed that the event rate was higher in the higher sPD-L1 group (median ≥ 136 pg/dL) than in the lower sPD-L1 group (25.0% vs. 16.9%; p=0.028, log-rank test). Univariate Cox proportional hazards analysis showed that high-sensitivity C-reactive protein, an estimated glomerular filtration rate of ＜60 mL/min/1.73m 2, B-type natriuretic peptide, left ventricular ejection fraction, and sPD-L1 were significantly associated with cardiovascular events. Multivariable Cox proportional hazards analysis of factors that were significant in univariate analysis identified that sPD-L1 was significantly and independently associated with cardiovascular events (hazard ratio: 1.364, 95% confidence interval: 1.018-1.828, p=0.038). CONCLUSIONS: Higher sPD-L1 levels were significantly associated with future cardiovascular events in patients with CAD.

The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.

Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.

Coronary artery established through amniote evolution.

Coronary arteries are a critical part of the vascular system and provide nourishment to the heart. In humans, even minor defects in coronary arteries can be lethal, emphasizing their importance for survival. However, some teleosts survive without coronary arteries, suggesting that there may have been some evolutionary changes in the morphology and function of coronary arteries in the tetrapod lineage. Here, we propose that the true ventricular coronary arteries were newly established during amniote evolution through remodeling of the ancestral coronary vasculature. In mouse (Mus musculus) and Japanese quail (Coturnix japonica) embryos, the coronary arteries unique to amniotes are established by the reconstitution of transient vascular plexuses: aortic subepicardial vessels (ASVs) in the outflow tract and the primitive coronary plexus on the ventricle. In contrast, amphibians (Hyla japonica, Lithobates catesbeianus, Xenopus laevis, and Cynops pyrrhogaster) retain the ASV-like vasculature as truncal coronary arteries throughout their lives and have no primitive coronary plexus. The anatomy and development of zebrafish (Danio rerio) and chondrichthyans suggest that their hypobranchial arteries are ASV-like structures serving as the root of the coronary vasculature throughout their lives. Thus, the ventricular coronary artery of adult amniotes is a novel structure that has acquired a new remodeling process, while the ASVs, which occur transiently during embryonic development, are remnants of the ancestral coronary vessels. This evolutionary change may be related to the modification of branchial arteries, indicating considerable morphological changes underlying the physiological transition during amniote evolution.

Coronary arteries are tasked with supplying the heart with oxygenated blood and nutrients. Any blockage or developmental problem in these blood vessels can have severe and sometimes lethal consequences. Due to their importance for health, researchers have extensively studied how coronary arteries form in humans and mice; a more limited range of studies have also looked at their equivalent in zebrafish. However, little is known about these structures develop in animals such as birds, amphibians, or other groups of fish. This makes it difficult to retrace the evolutionary processes that have given rise to the coronary arteries we are familiar with in mammals. To address this knowledge gap, Mizukami et al. set out to compare blood vessel development around the heart of mammals, birds, amphibians, and fish. To do this, they performed detailed anatomical studies of blood vessel structure at different stages of development in mice as well as quail, frogs and newts, zebrafish and sharks. In both mice and quail, small arterial subepicardial vessels (or ASVs) emerged early in development around the heart; these subsequently reorganised and remodelled themselves to give rise to the 'true' coronary arteries characteristic of the mature heart. Frogs and newts also developed similar ASV-like structures; however, unlike their mammalian and bird equivalents, these vessels did not reorganise, instead being retained into adulthood. In fish, blood vessel development resembled that of amphibians, suggesting that the coronary artery-like structures seen in some fish are an 'ancestral' form of ASVs, rather than the equivalent of the mature coronary arteries in mammals and birds. This work sheds light on the evolutionary processes shaping essential structures in the heart. In the future, Mizukami et al. hope that this knowledge will help develop a greater range of experimental animal models for studying heart disease and potential treatments.

Usefulness of automatic assessment for longitudinal strain to diagnose wild-type transthyretin amyloid cardiomyopathy.

Background: Left ventricular (LV) apical sparing by transthoracic echocardiography (TTE) has not been widely accepted to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM), because it is time consuming and requires a level of expertise. We hypothesized that automatic assessment may be the solution for these problems. Methods-and-Results: We enrolled 63 patients aged ≥70 years who underwent 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy on suspicion of ATTR-CM and performed TTE by EPIQ7G, and had enough information for two-dimensional speckle tracking echocardiography at Kumamoto University Hospital from January 2016 to December 2019. LV apical sparing was described as a high relative apical longitudinal strain (LS) index (RapLSI). Measurement of LS was repeated using the same apical images with three different measurement packages as follows: (1) full-automatic assessment, (2) semi-automatic assessment, and (3) manual assessment. The calculation time for full-automatic assessment (14.7 ± 1.4 sec/patient) and semi-automatic assessment (66.7 ± 14.4 sec/patient) were significantly shorter than that for manual assessment (171.2 ± 59.7 sec/patient) (p < 0.01 for both). Receiver operating characteristic curve analysis showed that the area under curve of the RapLSI evaluated by full-automatic assessment for predicting ATTR-CM was 0.70 (best cut-off point; 1.14 [sensitivity 63%, specificity 81%]), by semi-automatic assessment was 0.85 (best cut-off point; 1.00 [sensitivity, 66%; specificity, 100%]) and by manual assessment was 0.83 (best cut-off point; 0.97 [sensitivity, 72%; specificity, 97%]). Conclusion: There was no significant difference between the diagnostic accuracy of RapLSI estimated by semi-automatic assessment and that estimated by manual assessment. Semi-automatically assessed RapLSI is useful to diagnose ATTR-CM in terms of rapidity and diagnostic accuracy.

Genomic approaches to identify and investigate genes associated with atrial fibrillation and heart failure susceptibility.

Atrial fibrillation (AF) and heart failure (HF) contribute to about 45% of all cardiovascular disease (CVD) deaths in the USA and around the globe. Due to the complex nature, progression, inherent genetic makeup, and heterogeneity of CVDs, personalized treatments are believed to be critical. To improve the deciphering of CVD mechanisms, we need to deeply investigate well-known and identify novel genes that are responsible for CVD development. With the advancements in sequencing technologies, genomic data have been generated at an unprecedented pace to foster translational research. Correct application of bioinformatics using genomic data holds the potential to reveal the genetic underpinnings of various health conditions. It can help in the identification of causal variants for AF, HF, and other CVDs by moving beyond the one-gene one-disease model through the integration of common and rare variant association, the expressed genome, and characterization of comorbidities and phenotypic traits derived from the clinical information. In this study, we examined and discussed variable genomic approaches investigating genes associated with AF, HF, and other CVDs. We collected, reviewed, and compared high-quality scientific literature published between 2009 and 2022 and accessible through PubMed/NCBI. While selecting relevant literature, we mainly focused on identifying genomic approaches involving the integration of genomic data; analysis of common and rare genetic variants; metadata and phenotypic details; and multi-ethnic studies including individuals from ethnic minorities, and European, Asian, and American ancestries. We found 190 genes associated with AF and 26 genes linked to HF. Seven genes had implications in both AF and HF, which are SYNPO2L, TTN, MTSS1, SCN5A, PITX2, KLHL3, and AGAP5. We listed our conclusion, which include detailed information about genes and SNPs associated with AF and HF.

HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion.

Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminishes the development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism. SIGNIFICANCE: An antisense gene encoded in HTLV-1, HBZ, reprograms lactate metabolism and epigenetic modification by inducing TAp73 in virus-positive leukemic cells. A positive correlation between TAp73 and its target genes is also observed in many other cancer cells, suggesting that this is a common mechanism for cellular oncogenesis. This article is featured in Selected Articles from This Issue, p. 337.

Prognostic value of right ventricular global longitudinal strain in patients with immunoglobulin light-chain cardiac amyloidosis.

Aims: Left ventricular (LV) global longitudinal strain (GLS) (LV-GLS) is a strong and independent predictor of outcomes in patients with immunoglobulin light-chain (AL) cardiac amyloidosis. This study was performed to investigate whether right ventricular (RV) GLS (RV-GLS) provides prognostic information in patients with AL amyloidosis. Methods and results: Among 74 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from December 2005 to December 2022, 65 patients who had enough information for two-dimensional speckle tracking imaging and did not receive chemotherapy before the diagnosis of cardiac amyloidosis were retrospectively analysed. During a median follow-up of 359 days, 29 deaths occurred. In two-dimensional echocardiographic findings, LV-GLS, left atrium reservoir strain (LASr), and RV-GLS were significantly lower in the all-cause death group than in the survival group (LV-GLS: 8.9 ± 4.2 vs. 11.7 ± 3.9, P < 0.01; LASr: 9.06 ± 7.28 vs. 14.09 ± 8.32, P < 0.05; RV-GLS: 12.0 ± 5.1 vs. 16.8 ± 4.0, P < 0.01). Multivariable Cox proportional hazard analysis showed RV-GLS was significantly and independently associated with all-cause death in patients with AL cardiac amyloidosis (hazard ratio 0.85; 95% confidence interval, 0.77-0.94; P < 0.01). Receiver operating characteristic analysis showed that the area under the curve of RV-GLS for all-cause death was 0.774 and that the best cut-off value of RV-GLS was 14.5% (sensitivity, 75%; specificity, 72%). In the Kaplan-Meier analysis, patients with AL cardiac amyloidosis who had low RV-GLS (<14.5%) had a significantly higher probability of all-cause death (P < 0.01). Conclusion: RV-GLS has prognostic value in patients with AL cardiac amyloidosis and provides greater prognostic power than LV-GLS and LASr.

Clinical, electrocardiographic, and echocardiographic parameters associated with the development of pacing and implantable cardioverter-defibrillator indication in patients with transthyretin amyloid cardiomyopathy.

AIMS: This study aimed to identify factors for attention leading to future pacing device implantation (PDI) and reveal the necessity of prophylactic PDI or implantable cardioverter-defibrillator (ICD) implantation in transthyretin amyloid cardiomyopathy (ATTR-CM) patients. METHODS AND RESULTS: This retrospective single-center observational study included consecutive 114 wild-type ATTR-CM (ATTRwt-CM) and 50 hereditary ATTR-CM (ATTRv-CM) patients, neither implanted with a pacing device nor fulfilling indications for PDI at diagnosis. As a study outcome, patient backgrounds were compared with and without future PDI, and the incidence of PDI in each conduction disturbance was examined. Furthermore, appropriate ICD therapies were investigated in all 19 patients with ICD implantation. PR-interval ≥220 msec, interventricular septum (IVS) thickness ≥16.9 mm, and bifascicular block were significantly associated with future PDI in ATTRwt-CM patients, and brain natriuretic peptide ≥35.7 pg/mL, IVS thickness ≥11.3 mm, and bifascicular block in ATTRv-CM patients. The incidence of subsequent PDI in patients with bifascicular block at diagnosis was significantly higher than that of normal atrioventricular (AV) conduction in both ATTRwt-CM [hazard ratio (HR): 13.70, P = 0.019] and ATTRv-CM (HR: 12.94, P = 0.002), whereas that of patients with first-degree AV block was neither (ATTRwt-CM: HR: 2.14, P = 0.511, ATTRv-CM: HR: 1.57, P = 0.701). Regarding ICD, only 2 of 16 ATTRwt-CM and 1 of 3 ATTRv-CM patients received appropriate anti-tachycardia pacing or shock therapy, under the number of intervals to detect for ventricular tachycardia of 16-32. CONCLUSIONS: According to our retrospective single-center observational study, prophylactic PDI did not require first-degree AV block in both ATTRwt-CM and ATTRv-CM patients, and prophylactic ICD implantation was also controversial in both ATTR-CM. Larger prospective, multi-center studies are necessary to confirm these results.

Japanese high bleeding risk criteria status predicts low thrombogenicity and bleeding events in patients undergoing percutaneous coronary intervention.

Although the Japanese high bleeding risk criteria (J-HBR) were established to predict bleeding risk in patients undergoing percutaneous coronary intervention (PCI), the thrombogenicity in the J-HBR status remains unknown. Here, we examined the relationships among J-HBR status, thrombogenicity and bleeding events. This study was a retrospective analysis of 300 consecutive patients who underwent PCI. Blood samples obtained on the day of PCI were used in the total thrombus-formation analysis system (T-TAS) to investigate the thrombus-formation area under the curve (AUC; PL18-AUC10 for platelet chip; AR10-AUC30 for atheroma chip). The J-HBR score was calculated by adding 1 point for any major criterion and 0.5 point for any minor criterion. We assigned patients to three groups based on J-HBR status: a J-HBR-negative group (n = 80), a low score J-HBR-positive group (positive/low, n = 109), and a high score J-HBR-positive group (positive/high, n = 111). The primary end point was the 1-year incidence of bleeding events defined by the Bleeding Academic Research Consortium types 2, 3, or 5. Both PL18-AUC10 and AR10-AUC30 levels were lower in the J-HBR-positive/high group than the negative group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the J-HBR-positive/high group compared with the negative group. In addition, both T-TAS levels in J-HBR positivity were lower in those with bleeding events than in those without bleeding events. In multivariate Cox regression analyses, the J-HBR-positive/high status was significantly associated with 1-year bleeding events. In conclusion, the J-HBR-positive/high status could reflect low thrombogenicity as measured by T-TAS and high bleeding risk in patients undergoing PCI.

Differential effects of overweight/obesity depending on the severity of heart failure complicating acute myocardial infarction in Japan.

BACKGROUND: The existence of a paradoxical association between overweight/obesity and survival benefits, the so-called obesity paradox, in heart failure (HF) as well as coronary artery disease (CAD) remains contentious. Previously, we reported that a past history of CAD negated the obesity paradox in the general population with acute HF. Herein, we further focused on HF complicating acute myocardial infarction (AMI) and compared the prognostic effects of overweight/obesity with respect to the severity of HF. METHODS: We conducted a multicenter retrospective study of 7265 consecutive patients with AMI. The severity of HF was categorized according to the Killip classification. Overweight/obesity was defined as a body mass index (BMI) of ≥25 kg/m2. The interaction between overweight/obesity and the Killip classification for in-hospital mortality was tested in the entire cohort. Multivariable logistic regression analyses were performed to examine the effects of overweight/obesity on in-hospital mortality. RESULTS: Across the entire study cohort, 1931 patients had HF. Overweight/obesity had a significant association with reductions in in-hospital mortality in patients with mild HF (Killip class II; odds ratio [OR], 0.284; P = 0.019). Conversely, overweight/obesity was a significant risk factor for in-hospital mortality in patients with severe HF (Killip class IV; OR, 2.152; P = 0.001). The effects of overweight/obesity on in-hospital mortality in patients with moderate HF (Killip class III) were intermediate between those with mild HF and severe HF. CONCLUSION: Opposing effects of overweight/obesity on in-hospital mortality in patients with mild HF versus severe HF were demonstrated, suggesting a balance between beneficial and deleterious effects of overweight/obesity may be inclined toward the latter with the severity of HF complicating AMI.

Effect of the ALDH2 Variant on the Prevalence of Atrial Fibrillation in Habitual Drinkers.

Background: Alcohol-a risk factor for atrial fibrillation (AF)-is metabolized by aldehyde dehydrogenase 2 (ALDH2). Dysfunctional alleles of ALDH2 (ALDH2-deficient variants) are prevalent among East Asians. Objectives: Because the prevalence of AF is estimated to be high in ALDH2-deficient variant carriers, we investigated the correlation between AF and ALDH2-deficient variant carriers, including the association with habitual alcohol consumption. Methods: A total of 656 consecutive patients were included in this investigation. ALDH2 genotypes were divided into ALDH2 homozygous wild-type (∗1/∗1), ALDH2 heterozygous-deficient allele (∗1/∗2), and ALDH2 homozygous-deficient allele (∗2/∗2). Multivariate analyses were applied to determine the correlation between ALDH2 genotype and AF. Results: ALDH2∗1/∗2 and ALDH2∗2/∗2 carriers who were ALDH2-deficient variant carriers comprised 199 (30.3%) and 27 (4.1%) patients, respectively. Among these patients, the proportions of habitual alcohol consumption were 26.1% and 0%, respectively. Multivariate analysis revealed that ALDH2∗1/∗2 itself was not a risk factor for AF (odds ratio [OR]: 1.28; P = 0.21). However, habitual alcohol consumption in ALDH2∗1/∗2 carriers was an independent risk factor of AF (OR: 4.13; P = 0.001). Contrary to expectations, ALDH2∗2/∗2 itself had a lower incidence of AF among other risk factors (OR: 0.37; P = 0.03). Conclusions: Although the ALDH2∗1/∗2 itself was not associated with AF, ALDH2∗1/∗2 carriers with habitual alcohol consumption could experience AF because of slow alcohol metabolism. In contrast, ALDH2∗2/∗2 itself had a lower incidence of AF. This might be related to the absence to habitual alcohol consumption in ALDH2∗2/∗2 carriers because of the negligible activity of ALDH2. Thus, abstaining from alcohol consumption might prevent the development of AF in patients who are ALDH2∗1/∗2 carriers.

Time-dependent change of relative apical longitudinal strain index in patients with wild-type transthyretin amyloid cardiomyopathy.

Aim: This study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Methods and results: 165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52 %) had LV apical sparing (relative apical longitudinal strain index (RapLSI) > 1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95 % confidence interval (CI), 1.01-1.41; p < 0.05); E/e' ratio (OR, 1.06; 95 % CI, 1.00-1.11; p < 0.05); and heart-to-contralateral ratio by 99mTc-labeled pyrophosphate scintigraphy (OR, 3.40; 95 % CI, 1.07-10.83; p < 0.05).Next, we compared RapLSI at the time of diagnosis with that during the follow-up period (396 days (346-458) after diagnosis) in 92 patients. RapLSI increased significantly during the follow-up period compared with RapLSI at diagnosis in the non-LV apical sparing group (0.89 ± 0.32 vs 0.74 ± 0.18, p < 0.01) but not in the LV apical sparing group (1.33 ± 0.53 vs 1.39 ± 0.45, p = 0.46). A total of 12 patients (29 %) in the non-LV apical sparing group developed LV apical sparing and 11 patients (22 %) in LV apical sparing group diminished LV apical sparing during the follow-up period. Conclusion: Approximately half of ATTRwt-CM patients did not have LV apical sparing at diagnosis. Because RapLSI in ATTRwt-CM significantly changed over time, repeated two-dimensional speckle tracking analysis is important for suspected ATTR-CM patients.