Transcriptomic analysis reveals differences in the regulation of amino acid metabolism in asexual and sexual planarians

Abstract Many flatworms can alternate between asexual and sexual reproduction. This is a powerful reproductive strategy enabling them to benefit from the features of the two reproductive modes, namely, rapid multiplication and genetic shuffling. The two reproductive modes are enabled by the presence of pluripotent adult stem cells (neoblasts), by generating any type of tissue in the asexual mode, and producing and maintaining germ cells in the sexual mode. In the current study, RNA sequencing (RNA-seq) was used to compare the transcriptomes of two phenotypes of the planarian Dugesia ryukyuensis: an asexual OH strain and an experimentally sexualized OH strain. Pathway enrichment analysis revealed striking differences in amino acid metabolism in the two worm types. Further, the analysis identified serotonin as a new bioactive substance that induced the planarian ovary de novo in a postembryonic manner. These findings suggest that different metabolic states and physiological conditions evoked by sex-inducing substances likely modulate stem cell behavior, depending on their different function in the asexual and sexual reproductive modes. The combination of RNA-seq and a feeding assay in D. ryukyuensis is a powerful tool for studying the alternation of reproductive modes, disentangling the relationship between gene expression and chemical signaling molecules

MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes

GLUT4 shows decreased levels in failing human adult hearts. We speculated that GLUT4 expression in cardiac muscle may be fine-tuned by microRNAs. Forced expression of miR-133 decreased GLUT4 expression and reduced insulin-mediated glucose uptake in cardiomyocytes. A computational miRNA target prediction algorithm showed that KLF15 is one of the targets of miR-133. It was confirmed that over-expression of miR-133 reduced the protein level of KLF15, which reduced the level of the downstream target GLUT4. Cardiac myocytes infected with lenti-decoy, in which the 3′UTR with tandem sequences complementary to miR-133 was linked to the luciferase reporter gene, had decreased miR-133 levels and increased levels of GLUT4. The expression levels of KLF15 and GLUT4 were decreased at the left ventricular hypertrophy and congestive heart failure stage in a rat model. The present results indicated that miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes

Prognostic Impact of Baseline Hemoglobin Levels on Long-Term Thrombotic and Bleeding Events After Percutaneous Coronary Interventions

Background: Association of baseline hemoglobin levels with long-term adverse events after percutaneous coronary interventions has not been yet thoroughly defined. We aimed to assess the clinical impact of baseline hemoglobin on long-term ischemic and bleeding risk after percutaneous coronary intervention. Methods and Results: Using the pooled individual patient-level data from the 3 percutaneous coronary intervention studies, we categorized 19 288 patients into 4 groups: high-normal hemoglobin (≥14.0 g/dL; n=7555), low-normal hemoglobin (13.0-13.9 g/dL in men and 12.0-13.9 g/dL in women; n=5303), mild anemia (11.0-12.9 g/dL in men and 11.0-11.9 g/dL in women; n=4117), and moderate/severe anemia (<11.0 g/dL; n=2313). Median follow-up duration was 3 years. Low-normal hemoglobin, mild anemia, and moderate/severe anemia correlated with significant excess risk relative to high-normal hemoglobin for GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries Trial) moderate/severe bleeding, with adjusted hazard ratios of 1.22 (95% CI, 1.04-1.44), 1.73 (95% CI, 1.47-2.04), and 2.31 (95% CI, 1.92-2.78), respectively. Moderate/severe anemia also correlated with significant excess risk relative to high-normal hemoglobin for the ischemic composite end point of myocardial infarction/ischemic stroke (adjusted hazard ratio, 1.33; 95% CI, 1.11-1.60), whereas low-normal hemoglobin and mild anemia did not. However, the excess risk of low-normal hemoglobin, mild anemia, and moderate/severe anemia relative to high-normal hemoglobin remained significant for ischemic stroke and for mortality. Conclusions: Decreasing baseline hemoglobin correlated with incrementally higher long-term risk for major bleeding, ischemic stroke, and mortality after percutaneous coronary intervention. Even within normal range, lower baseline hemoglobin level correlated with higher ischemic and bleeding risk

Impact of left ventricular ejection fraction on the effect of renin-angiotensin system blockers after an episode of acute heart failure: From the KCHF Registry

Objective: This observational study aimed to examine the prognostic association of angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin receptor blockers (ARB) in different left ventricular ejection fraction (LVEF) categories. Methods: In 3717 patients enrolled in the KCHF Registry, a multicentre registry including consecutive patients hospitalized for acute heart failure (HF), we assessed patient characteristics and association between ACE-I/ARB and clinical outcomes according to LVEF. In the three LVEF categories (reduced LVEF [HFrEF], mid-range LVEF [HFmrEF] and preserved LVEF [HFpEF]), we compared the patients with ACE-I/ARB as discharge medication and those without, and assessed their 1-year clinical outcomes. We defined the primary outcome measure as a composite of all-cause death and HF hospitalization. Results: The 1-year cumulative incidences of the primary outcome measure were 36.3% in HFrEF, 30.1% in HFmrEF and 33.8% in HFpEF (log-rank P = 0.07). The adjusted risks of the ACE-I/ARB group relative to the no ACE-I/ARB group for the primary outcome measure were significantly lower in HFrEF and HFmrEF (HR 0.66 [95%CI 0.54–0.79], P<0.001, and HR 0.61 [0.45–0.82], P = 0.001, respectively), but not in HFpEF (HR 0.95 [0.80–1.14], P = 0.61). There was a significant interaction between the LVEF category and the ACE-I/ARB use on the primary outcome measure (Pinteraction = 0.01). Conclusions: ACE-I/ARB for patients who were hospitalized for acute HF was associated with significantly lower risk for a composite of all-cause death and HF hospitalization in HFrEF and HFmrEF, but not in HFpEF. ACE-I/ARB might be a potential treatment option in HFmrEF as in HFrEF

Admission systolic blood pressure as a prognostic predictor of acute decompensated heart failure: A report from the KCHF registry

[Background] Admission systolic blood pressure has emerged as a predictor of postdischarge outcomes of patients with acute decompensated heart failure; however, its validity in varied clinical conditions of this patient subset is unclear. The aim of this study was to further explore the prognostic value of admission systolic blood pressure in patients with acute decompensated heart failure. [Methods] The Kyoto Congestive Heart Failure (KCHF) registry is a prospective, observational, multicenter cohort study enrolling consecutive patients with acute decompensated heart failure from 19 participating hospitals in Japan. Clinical characteristics at baseline and prognosis were examined by the following value range of admission systolic blood pressure: <100, 100–139, and ≥140 mmHg. The primary outcome measure was defined as all-cause death after discharge. Subgroup analyses were done for prior hospitalization for heart failure, hypertension, left ventricular ejection fraction, and medications at discharge. We excluded patients with acute coronary syndrome or insufficient data. [Results] We analyzed 3564 patients discharged alive out of 3804 patients hospitalized for acute decompensated heart failure. In the entire cohort, lower admission systolic blood pressure was associated with poor outcomes (1-year cumulative incidence of all-cause death: <100 mmHg, 26.8%; 100–139 mmHg, 20.2%; and ≥140 mmHg, 15.1%, p<0.001). The magnitude of the effect of lower admission systolic blood pressure for postdischarge all-cause death was greater in patients with prior hospitalization for heart failure, heart failure with reduced left ventricular ejection fraction, and β-blocker use at discharge than in those without. [Conclusions] Admission systolic blood pressure is useful for postdischarge risk stratification in patients with acute decompensated heart failure. Its magnitude of the effect as a prognostic predictor may differ across clinical conditions of patients

Newly Diagnosed Atrial Fibrillation in Acute Myocardial Infarction

[Background] It remains controversial whether long‐term clinical impact of newly diagnosed atrial fibrillation (AF) in the acute phase of acute myocardial infarction (AMI) is different from that of prior AF diagnosed before the onset of AMI. [Methods and Results] The current study population from the CREDO‐Kyoto AMI (Coronary Revascularization Demonstrating Outcome Study in Kyoto Acute Myocardial Infarction) Registry Wave‐2 consisted of 6228 patients with AMI who underwent percutaneous coronary intervention. The baseline characteristics and long‐term clinical outcomes were compared according to AF status (newly diagnosed AF: N=489 [7.9%], prior AF: N=589 [9.5%], and no AF: N=5150 [82.7%]). Median follow‐up duration was 5.5 years. Patients with newly diagnosed AF and prior AF had similar baseline characteristics with higher risk profile than those with no AF including older age and more comorbidities. The cumulative 5‐year incidence of all‐cause death was higher in newly diagnosed AF and prior AF than no AF (38.8%, 40.7%, and 18.7%, P<0.001). The adjusted hazard ratios (HRs) for mortality of newly diagnosed AF and prior AF relative to no AF remained significant with similar magnitude (HR, 1.31; 95% CI, 1.12–1.54; P<0.001, and HR, 1.32; 95% CI, 1.14–1.52; P<0.001, respectively). The cumulative 5‐year incidence of stroke decreased in the order of newly diagnosed AF, prior AF and no AF (15.5%, 12.9%, and 6.3%, respectively, P<0.001). The higher adjusted HRs of both newly diagnosed AF and prior AF relative to no AF were significant for stroke, with a greater risk of newly diagnosed AF than that of prior AF (HR, 2.05; 95% CI, 1.56–2.69; P<0.001, and HR, 1.33; 95% CI, 1.00–1.78; P=0.048, respectively). The higher stroke risk of newly diagnosed AF compared with prior AF was largely driven by the greater risk within 30 days. The higher adjusted HRs of newly diagnosed AF and prior AF relative to no AF were significant for heart failure hospitalization (HR, 1.73; 95% CI, 1.35–2.22; P<0.001, and HR, 2.23; 95% CI, 1.82–2.74; P<0.001, respectively) and major bleeding (HR, 1.46; 95% CI, 1.23–1.73; P<0.001, and HR, 1.36; 95% CI, 1.15–1.60; P<0.001, respectively). [Conclusions] Newly diagnosed AF in AMI had risks for mortality, heart failure hospitalization, and major bleeding higher than no AF, and comparable to prior AF. The risk of newly diagnosed AF for stroke might be higher than that of prior AF

Risk Factors and Clinical Outcomes of Nonhome Discharge in Patients With Acute Decompensated Heart Failure: An Observational Study

Background: No clinical studies have focused on the factors associated with discharge destination in patients with acute decompensated heart failure. Methods and Results: Of 4056 consecutive patients hospitalized for acute decompensated heart failure in the KCHF (Kyoto Congestive Heart Failure) registry, we analyzed 3460 patients hospitalized from their homes and discharged alive. There were 3009 and 451 patients who were discharged to home and nonhome, respectively. We investigated the factors associated with nonhome discharge and compared the outcomes between home discharge and nonhome discharge. Factors independently and positively associated with nonhome discharge were age ≥80 years (odds ratio [OR], 1.76; 95% CI, 1.28–2.42), body mass index ≤22 kg/m2 (OR, 1.49; 95% CI, 1.12–1.97), poor medication adherence (OR, 2.08; 95% CI, 1.49–2.88), worsening heart failure (OR, 2.02; 95% CI, 1.46–2.82), stroke during hospitalization (OR, 3.74; 95% CI, 1.75–8.00), functional decline (OR, 12.24; 95% CI, 8.74–17.14), and length of hospital stay >16 days (OR, 4.14; 95% CI, 3.01–5.69), while those negatively associated were diabetes mellitus (OR, 0.69; 95% CI, 0.51–0.94), cohabitants (OR, 0.62; 95% CI, 0.46–0.85), and ambulatory state before admission (OR, 0.25; 95% CI, 0.18–0.36). The cumulative 1‐year incidence of all‐cause death was significantly higher in the nonhome discharge group than in the home discharge group. The nonhome discharge group compared with the nonhome discharge group was associated with a higher adjusted risk for all‐cause death (hazard ratio, 1.66; P<0.001). Conclusions: The discharge destination of patients with acute decompensated heart failure is influenced by factors such as prehospital social background, age, body mass index, low self‐care ability, events during hospitalization (worsening heart failure, stroke, etc), functional decline, and length of hospital stay; moreover, the prognosis of nonhome discharge patients is worse than that of home discharge patients. Registration Information: clinicaltrials.gov. Identifier: NCT02334891

Left atrial reverse remodeling improves risk stratification in patients with heart failure with recovered ejection fraction

We aimed to investigate the relationship between left atrial (LA) reverse remodeling and prognosis of heart failure (HF) with recovered ejection fraction (EF) (HFrecEF). Among 1, 246 patients with acute heart failure enrolled in the prospective longitudinal follow-up study, 397 patients with HF with mildly-reduced EF and with reduced EF at discharge were analyzed. Echocardiography was performed during the index hospitalization and at the 6-month follow-up after discharge. They were divided into non-HFrecEF (n = 227) and HFrecEF (n = 170) groups. The primary outcome measure was a composite of all-cause death or hospitalization for HF. The cumulative 180-day incidence of the primary outcome measure after follow-up echocardiography was significantly lower in the HFrecEF group than in the non-HFrecEF group (8.9% versus 23.4%, log-rank P = 0.0002). LA reverse remodeling was associated with a lower cumulative 6-month incidence of the primary outcome measure in the HFrecEF group (4.7% versus 18.0%; HR: 0.27, 95%CI: 0.09-0.79, P = 0.01), but not in the non-HFrecEF group (24.4% versus 22.6%; HR: 1.13, 95%CI: 0.65-1.96, P = 0.28) with a significant LA reverse remodeling-by-HFrecEF interaction (P for interaction = 0.02). Combination of left ventricular and atrial reverse remodeling may help in improving HF risk stratification