Non-dilated left ventricular cardiomyopathy vs. dilated cardiomyopathy: clinical background and outcomes.

AIMS: Non-dilated left ventricular cardiomyopathy (NDLVC) was proposed as a new category of cardiomyopathy that included patients with non-left ventricular (LV) dilatation, LV wall motion abnormality, or LV scar. However, the clinical background and event rates of NDLVC were unclear. The aim of this study was to examine the characteristics and event rates of patients with NDLVC and reduced LV ejection fraction (NDLVC-REF) in comparison with those with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We retrospectively included 363 patients with newly diagnosed non-ischaemic cardiomyopathy and reduced LV ejection fraction (<50%) between December 2004 and January 2018. Patients who did not have LV dilatation (LV dimension index of ≦31 mm/m2 in men and ≦34 mm/m2 in women) were categorized as NDLVC-REF (n = 80, 22.2%), and the remaining patients were categorized as DCM. Cardiac events were defined as sudden cardiac death and rehospitalization for heart failure. Patients with NDLVC-REF had a higher prevalence of atrial fibrillation and a higher LV ejection fraction than those with DCM at baseline. LV ejection fraction was higher and LV end-diastolic diameter was smaller in patients with NDLVC-REF than in those with DCM at all time points after diagnosis. During the median follow-up period of 68.8 months (interquartile range: 33.0-93.7 months), 44 patients experienced cardiac events. The Kaplan-Meier curves showed no significant differences in the probability of cardiac events among NDLVC-REF and DCM patients (P = 0.349). However, patients with NDLVC-REF and LV dilatation after diagnosis (14%) had a higher risk of cardiac events than those with NDLVC-REF without LV dilatation (P = 0.049). CONCLUSIONS: There was no significant difference in the incidence of cardiac events between NDLVC-REF and DCM. Among NDLVC-REF patients, 18% of patients who showed LV dilatation after diagnosis had poor outcomes. Therefore, both NDLVC-REF and DCM patients may require equivalent attention to follow-up and regular assessment of LV function.

Characteristics and incidence of cardiac events across spectrum of age in cardiac sarcoidosis.

Background: Clinical characteristics and the risk of cardiovascular events in patients with cardiac sarcoidosis (CS) according to the age of initial diagnosis are unclear. Methods: This study is a sub-analysis of the ILLUMINATE-CS registry, which is a retrospective, multicenter registry that enrolled patients with CS between 2001 and 2017. Patients were divided into three groups according to the tertile of age at the time of initial diagnosis of CS. The study compared the clinical background at the time of CS diagnosis and the incidence rate of cardiac events across age categories. Results: A total of 511 patients were analyzed in this study. In baseline, older patients were more likely to be female. History of hypertension, heart failure admission, and atrioventricular block were more common in patients with older age. There was no significant difference in the history of ventricular arrhythmias and left ventricular ejection fraction among all age groups. During a median follow-up period of 3.2 [IQR: 1.7-4.2] years, 35 deaths, 56 heart failure hospitalization, and 98 fatal ventricular arrhythmias was observed. The incidence rate of all-cause death and heart failure hospitalization was significantly higher in patients with older age (p < 0.001), while there was no significant difference in the incidence rate of ventricular arrhythmia among age groups (p = 0.74). Conclusions: In patients with CS, the risk of all-cause death and heart failure hospitalization was higher in older patients compared with other age groups; however, the risk of ventricular arrhythmia was comparable across all age groups.

Efficacy of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Clinical Parameters in Patients with Heart Failure.

Background and Objectives: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors have been approved as an oral drug for treating anemia in chronic kidney disease (CKD). However, the clinical effect of HIF-PH inhibitors in patients with heart failure (HF) is unclear. Thus, this study investigated the effect of HIF-PH inhibitors in patients with HF and CKD. Materials and Methods: Thirteen patients with HF complicated by renal anemia who were started on vadadustat were enrolled. Clinical parameters were compared before and 1 month after vadadustat was started. Results: The mean left ventricular ejection fraction was 49.8 ± 13.9%, and the mean estimated glomerular filtration rate was 29.4 ± 10.6 mL/min/1.73 m2. The hemoglobin level was significantly increased (9.7 ± 1.3 mg/dL vs. 11.3 ± 1.3 mg/dL, p < 0.001), and the N-terminal prohormone of B-type natriuretic peptide was significantly decreased after the introduction of vadadustat [4357 (2651-15182) pg/mL vs. 2367 (1719-9347) pg/mL, p = 0.002]. Furthermore, the number of patients with New York Heart Association functional class ≥ 3 was also decreased after the introduction of vadadustat [8 (61.5%) vs. 1 (7.7%), p = 0.008]. No thromboembolic adverse events or new tumors were observed in any patient during the study period. Conclusions: The introduction of vadadustat in patients with HF complicated by renal anemia led to improvements in anemia and symptoms of HF.

Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain.

Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, including the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential for regulating neural stem cells in developing, adult and aged brains. However, the activity of these lysosomes has yet to be monitored in these brain tissues. Here, we report the development of a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results indicate that lysosomal protein degradation fluctuates in neural stem cells of the hippocampal dentate gyrus, depending on age and brain disorders. Neural stem cells increase their lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduce lysosomal activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes in the dentate gyrus. We therefore propose that three different stages of lysosomal activity exist: the state of increase during development, the stable state during adulthood and the state of reduction due to damage caused by either age or disease.

Adult-onset idiopathic peripheral pulmonary artery stenosis.

BACKGROUND: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. METHODS: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. RESULTS: 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. CONCLUSIONS: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.

Relevant adverse events and drug discontinuation of sacubitril/valsartan in a real-world Japanese cohort: REVIEW-HF registry.

BACKGROUND: The characteristics, tolerability, and outcomes in patients with heart failure (HF) who are treated with sacubitril/valsartan remain unclear in Japan. METHODS: We conducted a nationwide multicenter study to evaluate the features and outcomes of patients newly prescribed sacubitril/valsartan for the management of HF. We analyzed adverse events (AEs) related to sacubitril/valsartan at 3 months, which were defined as hypotension, worsening renal function, hyperkalemia, and angioedema. Additionally, the association between AEs and outcomes was examined. RESULTS: Among 993 patients, the mean age was 70 years and 291 (29.3 %) were female, and 22.8 % had left ventricular ejection fraction ≥50 %. Of them, 20.8 % had systolic blood pressure (sBP) <100 mmHg, and 19.5 % had estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at baseline, which were the populations excluded from the eligibility in landmark trials. AEs related to sacubitril/valsartan were observed in 22.5 % of the patients at 3 months. Overall, 22.6 % of patients discontinued sacubitril/valsartan, and hypotension was the most common event leading to drug discontinuation. After adjustment, patients who had worse HF symptoms (New York Heart Association III or IV), sBP <100 mmHg, and eGFR <30 ml/min/1.73 m2 were associated with a higher risk of AEs related to sacubitril/valsartan. Additionally, patients experiencing AEs had a higher risk of cardiovascular death or HF hospitalization than those who did not. CONCLUSION: In Japan, sacubitril/valsartan was also prescribed to patients not eligible for landmark trials, and AEs were observed at a relatively high rate from soon after treatment initiation. Physicians should closely monitor patients for these events, especially in patients anticipated to have a higher risk of AEs.

Native T1 high region and left ventricular ejection fraction recovery in patients with dilated cardiomyopathy.

Native T1 mapping is used to assess myocardial tissue characteristics without gadolinium contrast agents. The focal T1 high-intensity region can indicate myocardial alterations. This study aimed to identify the association between the native T1 mapping including the native T1 high region and left ventricular ejection fraction (LVEF) recovery in patients with dilated cardiomyopathy (DCM). Patients with newly diagnosed DCM (LVEF of < 45%) who underwent cardiac magnetic resonance imaging with native T1 mapping were included in the analysis. Native T1 high region was defined as a signal intensity of > 5 SD in the remote myocardium. Recovered EF was defined as a follow-up LVEF of ≥ 45% and an LVEF increase of ≥ 10% after 2 years from baseline. Seventy-one patients met the inclusion criteria for this study. Forty-four patients (61.9%) achieved recovered EF. Logistic regression analysis showed that the native T1 value (OR: 0.98; 95% CI: 0.96-0.99; P = 0.014) and the native T1 high region (OR: 0.17; 95% CI: 0.05-0.55; P = 0.002), but not late gadolinium enhancement, were independent predictors of recovered EF. Compared with native T1 value alone, combined native T1 high region and native T1 value improved the area under the curve from 0.703 to 0.788 for predicting recovered EF. Myocardial damage, which was quantified using native T1 mapping and the native T1 high region were independently associated with recovered EF in patients with newly diagnosed DCM.

The efficacy and safety of sacubitril/valsartan in heart failure with reduced ejection fraction patients with hypotension.

Despite previous studies showing that patients with low systolic blood pressure (sBP) in heart failure with reduced ejection fraction (HFrEF) has a poor prognosis, it has few treatment options. This study aimed to investigate the efficacy and safety of sacubitril/valsartan (S/V) in HFrEF patients with hypotension. We included 43 consecutive HFrEF patients with sBP < 100 mmHg despite guideline-directed medical therapy for at least 3 months and who received S/V between September 2020 and July 2021. Patients admitted for acute heart failure were excluded and 29 patients were evaluated for safety endpoints. Furthermore, patients who performed non-pharmacological therapy or died within 1 month were excluded, finally, 25 patients were evaluated for efficacy endpoints. The mean initial S/V dose was 53.0 ± 20.5 mg/day and the mean dosage was increased to 84.0 ± 34.5 mg/day in 1 month. Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values significantly decreased from 2200 [interquartile range (IQR): 1462-3666] pg/ml to 1409 (IQR: 964-2451) pg/ml. (p < 0.0001). No significant change in sBP occurred (pre-sBP: 93.2 ± 4.9 mmHg, post-sBP: 93.4 ± 9.6 mmHg, p = 0.91), and no patients discontinued the S/V due to symptomatic hypotension in 1 month after S/V initiation. S/V can be safely introduced in HFrEF patients with hypotension to reduce serum NT-proBNP values. Thus, S/V may be useful for the treatment of HFrEF patients with hypotension.

Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial　- Protocol for a Multicenter Randomized Controlled Trial.

Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear. Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2 from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated. Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.

CCPG1 recognizes endoplasmic reticulum luminal proteins for selective ER-phagy.

The endoplasmic reticulum (ER) is a major cell compartment where protein synthesis, folding, and posttranslational modifications occur with assistance from a wide variety of chaperones and enzymes. Quality control systems selectively eliminate abnormal proteins that accumulate inside the ER due to cellular stresses. ER-phagy, that is, selective autophagy of the ER, is a mechanism that maintains or reestablishes cellular and ER-specific homeostasis through removal of abnormal proteins. However, how ER luminal proteins are recognized by the ER-phagy machinery remains unclear. Here, we applied the aggregation-prone protein, six-repeated islet amyloid polypeptide (6xIAPP), as a model ER-phagy substrate and found that cell cycle progression 1 (CCPG1), which is an ER-phagy receptor, efficiently mediates its degradation via ER-phagy. We also identified prolyl 3-hydroxylase family member 4 (P3H4) as an endogenous cargo of CCPG1-dependent ER-phagy. The ER luminal region of CCPG1 contains several highly conserved regions that we refer to as cargo-interacting regions (CIRs); these interact directly with specific luminal cargos for ER-phagy. Notably, 6xIAPP and P3H4 interact directly with different CIRs. These findings indicate that CCPG1 is a bispecific ER-phagy receptor for ER luminal proteins and the autophagosomal membrane that contributes to the efficient removal of aberrant ER-resident proteins through ER-phagy.

Neuroendocrine hormone status and diuretic response to atrial natriuretic peptide in patients with acute heart failure.

AIMS: Given the various effects of sacubitril/valsartan in heart failure, a deeper understanding of atrial natriuretic peptide (ANP) actions is warranted. Natriuresis is a fundamental action of ANP in acute heart failure (AHF), whereas the diuretic effect of ANP is different in each patient according to the diversity of renal response to ANP, which is affected by baseline plasma ANP status and deficiency of circulating ANP. Meanwhile, associations between other neuroendocrine hormones and the diuretic response to ANP are unclear. This study investigated the impact of pivotal neuroendocrine hormones on the diuretic effects of exogenous ANP, carperitide. METHODS AND RESULTS: Plasma ANP, renin, aldosterone, and vasopressin levels and the diuretic effect of 0.0125 µg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 75 patients with AHF. Lower ANP levels were significantly associated with a greater diuretic response to exogenous ANP (r = -0.35, P = 0.002). Additionally, higher vasopressin levels were significantly related to the poor diuretic effects of exogenous ANP (r = -0.54, P < 0.001). Plasma ANP and vasopressin concentrations were not significantly correlated (r = 0.19, P = 0.10). Baseline systolic blood pressure, renal function, and prior use of loop diuretics did not predict the diuretic response to exogenous ANP, whereas vasopressin levels independently predicted a diuretic response to exogenous ANP (P < 0.001), as well as lower plasma ANP levels (P = 0.027). CONCLUSIONS: Vasopressin status was significantly associated with the diuretic response to exogenous ANP in AHF, independent of plasma ANP status. The results may provide a better understanding of the actions of sacubitril/valsartan.

Inhaled nitric oxide for ECPELLA management in fulminant myocarditis complicated with severe right ventricular dysfunction: A case report.

Combination therapy with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and Impella (ECPELLA) has been known to be a favorable strategy of mechanical circulation support for patients with fatal cardiogenic shock. However, the practical strategy for weaning ECPELLA in patients with right ventricular (RV) dysfunction remains unclear. We describe a case of a 63-year-old male with fulminant myocarditis presenting with cardiogenic shock who required ECPELLA to improve hemodynamics. Because of persistent severe RV dysfunction despite the introduction of intravenous dobutamine and milrinone, VA-ECMO could not be weaned. Inhaled nitric oxide (iNO) was introduced at 20 ppm to reduce RV afterload, resulting in increased cardiac output (from 1.6 to 5.5 L/min) and ameliorated RV performance (the pulmonary artery pulsatility index was from 0.47 to 1.11). Subsequently, VA-ECMO could be weaned. iNO, a selective pulmonary vasodilator, reduces pulmonary vascular resistance, resulting in reduced RV afterload. This is the first case of iNO usage for the management of cardiogenic shock supported by ECPELLA. iNO could be a favorable strategy in ECPELLA patients with refractory RV dysfunction for weaning VA-ECMO through bridging to recovery. Learning objective: The practical strategy for weaning venoarterial extracorporeal membrane oxygenation and Impella (ECPELLA) in patients with concomitant right ventricular dysfunction remains unclear. Inhaled nitric oxygen is a novel weaning strategy for patients with biventricular dysfunction supported by ECPELLA. If the response of inhaled nitric oxygen was insufficient under ECPELLA support, implantable ventricular assist devices or transplantation should be considered.

A retrospective investigation to establish new screening approach for the detection of patients at high risk of Fabry disease in male left ventricular hypertrophy patients.

BACKGROUND: The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability. METHODS: We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD. RESULTS: There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval < 40 msec, SV1 + RV5 > 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF < 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD. CONCLUSIONS: In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram.

Variation in heart rate range by 24-h Holter monitoring predicts heart failure in patients with atrial fibrillation.

AIMS: The analysis of heart rate (HR) changes, such as the HR variability or HR turbulence, has been reported as a marker of cardiovascular events during sinus rhythm; however, those relationships during atrial fibrillation (AF) remain controversial, and those parameters are not commonly used in AF patients. We sought to investigate the relationship between a simple index focused on the HR and heart failure (HF) events in patients with permanent AF. METHODS AND RESULTS: We enrolled 198 patients with permanent AF and evaluated the HR range, defined as the maximum HR minus the minimum HR on 24-h Holter electrocardiogram recordings. The patients were divided into two groups, i.e., the larger (n = 101) and smaller (n = 97) HR range (HRR) groups, determined by the median value. The HF events were defined as hospitalizations for HF or urgent hospital visits due to exacerbations of one's HF status. The observation period of this study was set at 5 years from registration. The median age was 73 (68-77) years, and 29% were female. The median HRR was 84 (63-118) beats per minutes (bpm). During the observational period of 1825 days (median), HF events occurred in 37 (0.047 per patient-year) patients. In a log-rank test, the larger HRR group had more frequent HF events than the smaller HRR group (P = 0.0078). In the adjusted Cox proportional hazards model using the significantly different factors from the univariate analysis (Model 1) and factors and medications associated with HF (Model 2), the larger HRR group had a higher prevalence of HF events than the smaller HRR group for both models [Model 1, adjusted hazard ratio = 3.21, 95% confidence interval (CI) 1.593-6.708, P = 0.0009; Model 2, adjusted hazard ratio = 3.12, 95% CI 1.522-6.685, P = 0.002]. When analysed using the time-dependent Cox proportional hazards model, the HRR was associated with HF with a statistically significant difference in both the univariate and multivariate analyses [hazard ratio = 1.01, 95% CI 1.006-1.020, P = 0.0002; Model 1, adjusted hazard ratio = 1.02, 95% CI 1.011-1.027, P < 0.0001; Model 2, adjusted hazard ratio = 1.01, 95% CI 1.008-1.021, P = 0.0003). There was no significant difference in the chronotropic medications between the two groups. CONCLUSIONS: In patients with permanent AF, a larger HRR was associated with HF events.

Hemodynamic assessment and risk classification for successful weaning of Impella in patients with cardiogenic shock.

BACKGROUND: Clinical predictors for successful weaning of patients from Impella heart pump have not been clarified. We aimed to elucidate the relationship between pulmonary artery catheter (PAC) parameters at the time of Impella weaning and subsequent outcomes. METHODS: We enrolled consecutive patients who had received Impella for cardiogenic shock. PAC data were collected immediately before Impella weaning. Patients were classified as non-survivors if they died or required any mechanical circulatory support reintroduction within 30 days of weaning. RESULTS: Of 81 patients enrolled, 61 underwent Impella weaning. Of these, 16 were non-survivors. Predictive indicators of non-survival were high pulmonary artery wedge pressure (PAWP; hazard ratio [HR] per 5 mm Hg 1.97, 95% CI 1.35-2.80; p < 0.001), high mean pulmonary artery pressure (MPAP; HR per 5 mm Hg 1.90, 1.38-2.58; p < 0.001), and low cardiac power output (CPO; HR per 0.1 Watts 0.71, 0.52-0.92; p = 0.006). Cutoff values of PAWP 20 mm Hg, MPAP 22 mm Hg, and CPO 0.59 Watts showed strong associations with 30-day non-survival risk (low risk 8% in patients with low PAWP and high CPO or 4% in patients with low MPAP and high CPO; high risk 100% in patients with high PAWP and low CPO or 82% in patients with high MPAP and low CPO). CONCLUSIONS: PAWP or MPAP higher than the cutoff with CPO below the cutoff at Impella weaning were associated with worse outcomes. We proposed a risk classification model for successful Impella weaning using PAC.

Re-worsening left ventricular ejection fraction after response to cardiac resynchronization therapy.

BACKGROUND: Although cardiac resynchronization therapy (CRT) provided functional and clinical improvement in patients with heart failure (HF) and electrical intraventricular conduction disturbances, some patients had re-worsening left ventricular (LV) function after a favorable CRT response. We analyzed the clinical variables and cardiac outcomes associated with this re-worsening LV function after CRT. METHODS: In this study, 71 patients with CRT response who received CRT between 2006 and 2017 were included. CRT response was defined as a "≥ 10% improvement in LV ejection fraction (LVEF) on follow-up." Patients were classified into two groups: (i) persistent: (n = 48, 68%), defined as those with a CRT response and (ii) re-worsening: (n = 23, 32%), consisting of those who fell out of the definition of a CRT response after an initial CRT response. RESULTS: Half of the patients in the re-worsening group failed to maintain a CRT response from two years upwards. A longer duration from HF diagnosis to CRT implantation, nonspecific intraventricular conduction delay (NIVCD) on electrocardiogram at CRT implantation, and a lower increased LVEF at initial CRT response were independent predictors for the re-worsening group. Patients in the re-worsening group had a higher incidence rate for HF hospitalization and cardiac deaths, compared with those in the persistent group. CONCLUSION: One-third of CRT responders experienced re-worsening LVEF, which was associated with poor outcomes. CRT responders with NIVCD, longer HF duration, and a lower increased LVEF at initial CRT response should be monitored with caution.

HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis.

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans in vivo. While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria. In complementary overexpression and gene deletion experiments HIVEP1 was shown to inhibit NF-ĸB activity and induction of NF-ĸB responsive genes. RNA sequencing demonstrated profound transcriptomic changes in HIVEP1 deficient monocytic cells and transcription factor binding site analysis showed enrichment for κB site regions. HIVEP1 bound to the promoter regions of NF-ĸB responsive genes. Inhibition of cytokine production by HIVEP1 was confirmed in LPS-stimulated murine Hivep1-/- macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen Streptococcus pneumoniae. These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists in vitro and in vivo.

Concomitant use of tea catechins affects absorption and serum triglyceride-lowering effects of monoglucosyl hesperidin.

The present study investigated whether combined ingestion of green tea catechins (GTC) and monoglucosyl hesperidin (GHES) influences the pharmacokinetic parameters of polyphenols and serum triglycerides (TG). We conducted 2 randomized, controlled trials. Study 1: 8 healthy male subjects participated in a crossover study in which they ingested a test beverage containing GHES (0, 84, 168, or 336 mg GHES) with GTC, or 336 mg GHES without GTC. After ingestion, the pharmacokinetic changes in plasma hesperetin (HEP) and catechins were measured. Study 2: 36 healthy male and female subjects (mean age, 53 ± 2 years; mean BMI, 25.2 ± 0.5 kg m-2) were recruited for a double-blind, placebo-controlled study in which they ingested a test beverage containing 165 mg GHES with 387 mg GTC or a placebo beverage daily for 4 weeks. Fasting serum TG and other lipids and glucose metabolites were analyzed. Study 1 showed that the pharmacokinetics of HEP did not differ significantly between the 336 mg GHES without GTC treatment and the 168 mg GHES with GTC treatment. Study 2 showed that continuous ingestion of 165 mg GHES and 387 mg GTC for 4 weeks significantly decreased fasting serum TG levels compared with baseline values (change in TG, -30 ± 13 mg dl-1, P = 0.040) in the intention-to-treat analysis. In conclusion, our findings suggest that GTC affects the oral bioavailability of GHES, and combined ingestion of low doses of GHES with GTC effectively improves fasting TG levels.

Labeling and measuring stressed mitochondria using a PINK1-based ratiometric fluorescent sensor.

Mitochondria are essential organelles that carry out a number of pivotal metabolic processes and maintain cellular homeostasis. Mitochondrial dysfunction caused by various stresses is associated with many diseases such as type 2 diabetes, obesity, cancer, heart failure, neurodegenerative disorders, and aging. Therefore, it is important to understand the stimuli that induce mitochondrial stress. However, broad analysis of mitochondrial stress has not been carried out to date. Here, we present a set of fluorescent tools, called mito-Pain (mitochondrial PINK1 accumulation index), which enable the labeling of stressed mitochondria. Mito-Pain uses PTEN-induced putative kinase 1 (PINK1) stabilization on mitochondria and quantifies mitochondrial stress levels by comparison with PINK1-GFP, which is stabilized under mitochondrial stress, and RFP-Omp25, which is constitutively localized on mitochondria. To identify compounds that induce mitochondrial stress, we screened a library of 3374 compounds using mito-Pain and identified 57 compounds as mitochondrial stress inducers. Furthermore, we classified each compound into several categories based on mitochondrial response: depolarization, mitochondrial morphology, or Parkin recruitment. Parkin recruitment to mitochondria was often associated with mitochondrial depolarization and aggregation, suggesting that Parkin is recruited to heavily damaged mitochondria. In addition, many of the compounds led to various mitochondrial morphological changes, including fragmentation, aggregation, elongation, and swelling, with or without Parkin recruitment or mitochondrial depolarization. We also found that several compounds induced an ectopic response of Parkin, leading to the formation of cytosolic puncta dependent on PINK1. Thus, mito-Pain enables the detection of stressed mitochondria under a wide variety of conditions and provides insights into mitochondrial quality control systems.

Clinical valuables related to resolution of complete or advanced atrioventricular block after steroid therapy in patients with cardiac sarcoidosis.

BACKGROUND: Prediction of atrioventricular block (AVB) resolution after steroid therapy in patients with cardiac sarcoidosis (CS) is difficult. METHODS: We identified 24 patients with CS and complete or advanced AVB receiving steroid therapy. AVB resolution was assessed by reviewing surface electrocardiogram and the percentage of ventricular pacing required on subsequent device interrogation reports. RESULTS: AVB resolution was noted in eight (33%) patients 1 year after receiving steroid therapy. Univariate Cox regression analysis demonstrated that left ventricular ejection fraction (LVEF) (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.01-1.14, P = .016), interval from recognized AVB to start of steroid therapy (HR 0.98, 95% CI 0.95-0.99, P < .001), and lysozyme (HR 1.51, 95% CI 1.12-2.19, P = .013) were significantly associated with resolution of AVB. Combination of area under the curve (AUC) of each variable that was significantly related to resolution of AVB (AUC, 0.969; 95% CI 0.921-1.000, P < .001) was tended to be higher compared with each variable alone. CONCLUSIONS: A shorter interval from recognition of AVB to start of steroid therapy, higher LVEF, and higher lysozyme levels were significantly associated with resolution of AVB after steroid therapy in patients with CS. The combination of each variable could be able to distinguish patients with resolution of AVB from those without.