Different Coactivator Recruitment to Human PPARα/δ/γ Ligand-Binding Domains by Eight PPAR Agonists to Treat Nonalcoholic Fatty Liver Disease.

Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they recruit multiprotein coactivator complexes to specific genomic regulatory loci to cooperatively activate gene transcription. Several coactivators are expressed in a single cell; however, a ligand-bound PPAR can be associated with only one coactivator through a consensus LXXLL motif. Therefore, altered gene transcription induced by PPAR subtypes/agonists may be attributed to the recruitment of various coactivator species. Using a time-resolved fluorescence resonance energy transfer assay, we analyzed the recruitment of four coactivator peptides (PGC1α, CBP, SRC1, and TRAP220) to human PPARα/δ/γ-ligand-binding domains (LBDs) using eight PPAR dual/pan agonists (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, lanifibranor, saroglitazar, and seladelpar) that are/were anticipated to treat nonalcoholic fatty liver disease. These agonists all recruited four coactivators to PPARα/γ-LBD with varying potencies and efficacy. Only five agonists (bezafibrate, pemafibrate, elafibranor, lanifibranor, and seladelpar) recruited all four coactivators to PPARδ-LBD, and their concentration-dependent responses differed from those of PPARα/γ-LBD. These results indicate that altered gene expression through consensus PPREs by different PPAR subtypes/agonists may be caused, in part, by different coactivators, which may be responsible for the unique pharmacological properties of these PPAR agonists.

Cusp overlap technique decreases paravalvular leakage in self-expandable transcatheter aortic valve replacement.

The cusp overlap technique allows greater visual separation between the basal annular plane and the conduction system and decreases the permanent pacemaker implantation rate. We assessed the impact of the cusp overlap technique on conduction disturbance and paravalvular leakage after transcatheter aortic valve replacement. A total of 97 patients underwent transfemoral transcatheter aortic valve replacement with self-expandable valves at our institution from November 2018 to January 2023. The mean age of the patients was 85 years, and 23% were male. The patients were divided into two groups: the cusp overlap technique group and the non-cusp overlap technique group. We compared the clinical results between the two groups. The 30-day permanent pacemaker implantation rate was similar between the two groups (cusp overlap technique: 6.3% vs. non-cusp overlap technique: 10.2%, p = 0.48). The rate of new-onset conduction disturbance was slightly lower in the cusp overlap than non-cusp overlap technique group (18.8% vs. 34.7%, respectively; p = 0.08). The implanted valve function was similar between the two groups, but the rate of trivial or less paravalvular leakage (PVL) was significantly higher in the cusp overlap technique group on echocardiography (69% vs. 45%, p = 0.02). On multidetector computed tomography, the implantation depth at the membranous septum was significantly shorter in the cusp overlap technique group (2.0 ± 2.3 vs. 2.9 ± 1.5 mm, p = 0.02). The degree of canting was slightly smaller in the cusp overlap technique group (1.0 ± 2.2 vs. 1.7 ± 1.9 mm, p = 0.07). The relative risk of PVL equal to or greater than mild was 1.76 times higher for valve implantation without the cusp overlap technique (adjusted odds ratio, 3.74; 95% confidence interval, 1.45-9.69; p < 0.01). Transcatheter aortic valve replacement using the cusp overlap technique is associated with an optimized implantation depth, leading to fewer conduction disturbances. Optimal deployment may also maximize the radial force of self-expanding valves to reduce paravalvular leakage.

Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease.

The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and hepatocellular carcinoma requires liver transplantation to avoid death. Therefore, therapeutic intervention is required in the NASH stage, although no therapeutic drugs are currently available for this. Several anti-NASH candidate drugs have been developed that enable treatment via the modulation of distinct signaling cascades and include a series of drugs targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) that are considered to be attractive because they can regulate both systemic lipid metabolism and inflammation. Multiple PPAR dual/pan agonists have been developed but only a few of them have been evaluated in clinical trials for NAFLD/NASH. Herein, we review the current clinical trial status and future prospects of PPAR-targeted drugs for treating NAFLD/NASH. In addition, we summarize our recent findings on the binding modes and the potencies/efficacies of several candidate PPAR dual/pan agonists to estimate their therapeutic potentials against NASH. Considering that the development of numerous PPAR dual/pan agonists has been abandoned because of their serious side effects, we also propose a repositioning of the already approved, safety-proven PPAR-targeted drugs against NAFLD/NASH.

Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, and PPARα-LBD-elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD-elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions.

Transcatheter aortic valve implantation for aortic valve stenosis 17 years after aortic root remodeling via the Yacoub method.

Yacoub operation, aimed at valve-sparing aortic root replacement, is performed to treat aortic root aneurysm with aortic regurgitation. Here we first report a successful transcatheter aortic valve implantation with a balloon-expandable prosthetic valve in an elderly patient having severe aortic valve stenosis and a small sinus of Valsalva 17 years after the Yacoub operation. Learning objectives: In transcatheter aortic valve implantation (TAVI) for aortic valve stenosis with a small sinus of Valsalva post-Yacoub operation, the use of a balloon-expandable prosthetic valve may be desirable for the TAVI; a detailed analysis of the anatomy of the valve-sparing aortic root with computed tomography is essential for the valve selection.

Compression Stockings Improve Lower Legs Symptom in Patients with Pulmonary Artery Hypertension Treated by Pulmonary Vasodilators-A Pilot Study.

Pulmonary vasodilators have improved pulmonary arterial hypertension (PAH) symptoms and prognosis; however, the drugs cause some side effects, including lower legs pain, which impair quality of life (QOL). The present study examined if compression stockings improved lower extremity symptoms and QOL caused by pulmonary vasodilators in PAH patients. We retrospectively enrolled consecutively ten patients with PAH treated by pulmonary vasodilators, who were regularly followed in Kurume University Hospital from January 2022 to June 2022. Oral questionnaire surveys, the Numeric Rating Scale for Pain (NRS) and the Pain Disability Assessment Scale (PDAS), were conducted regarding lower extremity symptoms before wearing elastic stockings and one month later, to evaluate how the lower extremity symptoms affected daily life. All ten patients were female, with a mean age of 50.2 ± 11.5 years, out of whom intravenous prostacyclin analogue (PGI2) was administered in five patients. In no intravenous PGI2 group, NRS score was significantly improved from 4.6 ± 2.3 to 2.8 ± 1.2 (p = 0.037), while from 9.4 ± 1.2 to 5.4 ± 1.6 (p = 0.002) in intravenous PGI2 group. PDAS score was also significantly improved [no intravenous PGI2 group; 18.0 (15.0-24.0) to 15.0 (10.0-19.0), intravenous PGI2 group; 25.0 (17.0-37.0) to 17.0 (5.0-27.0)]. Lower extremity symptoms in patients using pulmonary vasodilators were improved by wearing compression stockings.

Rapidly Moving Vanishing Tumor of the Lung After Open-heart Surgery.

Vanishing tumor of the lung, also known as phantom tumor, is uncommonly observed in congestive heart failure. We report a case of a vanishing tumor that rapidly disappeared and reappeared in just a few minutes due to repositioning in a patient after open-heart surgery.

Predictive factors and clinical impact of ICU-acquired weakness on functional disability in mechanically ventilated patients with COVID-19.

BACKGROUND: Patients with critical COVID-19 often require invasive mechanical ventilation (IMV) and admission to the intensive care unit (ICU), resulting in a higher incidence of ICU-acquired weakness (ICU-AW) and functional decline. OBJECTIVE: This study aimed to examine the causes of ICU-AW and functional outcomes in critically ill patients with COVID-19 who required IMV. METHODS: This prospective, single-center, observational study included COVID-19 patients who required IMV for ≥48 h in the ICU between July 2020 and July 2021. ICU-AW was defined as a Medical Research Council sum score <48 points. The primary outcome was functional independence during hospitalization, defined as an ICU mobility score ≥9 points. RESULTS: A total of 157 patients (age: 68 [59-73] years, men: 72.6%) were divided into two groups (ICU-AW group; n = 80 versus non-ICU-AW; n = 77). Older age (adjusted odds ratio [95% confidence interval]: 1.05 [1.01-1.11], p = 0.036), administration of neuromuscular blocking agents (7.79 [2.87-23.3], p < 0.001), pulse steroid therapy (3.78 [1.49-10.1], p = 0.006), and sepsis (7.79 [2.87-24.0], p < 0.001) were significantly associated with ICU-AW development. In addition, patients with ICU-AW had significantly longer time to functional independence than those without ICU-AW (41 [30-54] vs 19 [17-23] days, p < 0.001). The development of ICU-AW was associated with delayed time to functional independence (adjusted hazard ratio: 6.08; 95% CI: 3.05-12.1; p < 0.001). CONCLUSIONS: Approximately half of the patients with COVID-19 requiring IMV developed ICU-AW, which was associated with delayed functional independence during hospitalization.

Discontinuation of Intravenous Catecholamine by Oral Ivabradine in a Patient with Decompensated Heart Failure with Low Cardiac Output Syndrome.

Ivabradine has been shown to improve heart failure with sinus tachycardia by reducing the heart rate without affecting left ventricular systolic function or blood pressure. Here we report a case of a catecholaminedependent patient, New York Heart Association (NYHA) class IV, LVEF of 18%, and low cardiac output, who was able to discontinue intravenous catecholamine by oral administration of ivabradine.

Effects of olmesartan and amlodipine on blood pressure, endothelial function, and vascular inflammation.

BACKGROUND: Anti-hypertensive drugs can improve vascular endothelial function. However, the mechanism remains to be elucidated. OBJECTIVES: This study sought to investigate mechanisms of anti-hypertensive drugs on improvement of vascular endothelial function in patients with essential hypertension. METHODS: Forty-five patients (mean age 58.5 ± 11.2 years) with uncontrolled essential hypertension were randomly assigned to receive olmesartan, an angiotensin II type 1 receptor blocker (ARB) (N = 23), or amlodipine, a calcium channel blocker (CCB) (N = 22), for 6 months. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR) within the carotid arteries using 18F-fluorodeoxyglucose-positron emission tomography combined with computed tomography. RESULTS: There were no significant differences of baseline clinical data between the ARB and CCB groups. Both anti-hypertensive drugs comparably lowered blood pressure and increased %FMD. TBR values were reduced by olmesartan (P < .001), while blood pressure variability was decreased by amlodipine (P = .004). Changes in %FMD from baseline (Δ%FMD) were inversely associated with ΔTBR in the olmesartan group (r = - .606, P = .003) and with Δsystolic blood pressure variability in the amlodipine group (r = - .434, P = .039). CONCLUSION: Our study indicated that olmesartan and amlodipine could improve endothelial function in patients with essential hypertension in different manners, suppression of vascular inflammation, and decrease in blood pressure variability, respectively.

Ongoing vascular inflammation evaluated by 18F-fluorodeoxyglucose positron emission tomography in patients long after Kawasaki disease.

BACKGROUND: This study aimed to determine whether ongoing vascular inflammation presents in patients who had coronary artery aneurysms (CAAs) caused by Kawasaki disease (KD). METHODS: Subjects were 26 patients with a history of KD; 15 had giant CAA (gCAA) ≥ 8.0 mm and 11 had smaller CAA (smCAA) < 8 mm in the acute phase. They underwent X-ray computed tomography and 18F-fluorodeoxyglucose positron emission tomography. We determined the maximum coronary target-to-background ratio (CaTBR) and the mean thoracic aorta TBR (TaTBR) in each patient. They were compared between groups, and their correlation with various variables was determined. RESULTS: CaTBR and TaTBR were significantly higher in gCAA than in smCAA (P < .005 for both values) and were significantly higher even in patients without any metabolic risk factor (P < .05 for both values). The CAA size in acute phase significantly positively correlated with CaTBR (R2 = 0.32) as well as TaTBR (R2 = 0.28). Also, TaTBR significantly positively correlated with CaTBR (R2 = 0.32) as well as cumulative number of metabolic risk factors (trend, P = .03). CONCLUSIONS: Ongoing vascular inflammation may present long after KD, especially in patients with severe inflammation expressed as gCAA in the acute phase.

[The Perspective of PPAR Dual/Pan Agonists as Therapeutic Drugs against NAFLD].

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and a more advanced condition with inflammation/fibrosis, nonalcoholic steatohepatitis (NASH), is emerging as one of the most prevalent chronic diseases associated with the worldwide expansion of the obese population; however, there are currently only symptomatic therapy but no cure. Among multiple candidate drugs that have been developed and tried in clinical trials against NAFLD/NASH, peroxisome proliferator-activated receptor (PPAR) dual/pan agonists continue to be the most expected ones. This review summarizes the current condition of several PPAR agonists that were and are in clinical trials against NAFLD/NASH. In addition, we recently expanded structural information about PPARα/δ/γ-ligand interactions by X-ray crystallography and executed comparative functional analyses of PPARα/δ/γ activation by those ligands; based on those knowledge, we propose the reevaluation or repositioning of currently approved PPAR agonists, saroglitazar, bezafibrate, and pemafibrate, for the treatment of NAFLD/NASH.

Analysis of the relationship between the amplitude of aortic wall motion and heart function.

PURPOSE: Because the posterior wall of the aorta and left atrium are interlocked, the amplitude of motion of the aortic wall (AMAW) may reflect cardiac and vessel functions. This study examined the relationship between cardiac and vessel functions and AMAW. METHODS: Patients with cardiovascular diseases or patients undergoing health examinations who visited a participating hospital and underwent echocardiography and brachial-ankle pulse-wave velocity (baPWV) examinations were registered. The correlations between echocardiographic indices, ankle-brachial index, and baPWV and AMAW on M-mode echocardiography were analyzed. RESULTS: Overall, 184 patients were enrolled. Heart rate (r = - 0.1587), ejection fraction (EF; r = 0.3240), wall thickness (r = - 0.1598), peak early diastolic mitral annular velocity (E) to peak early diastolic mitral annular velocity ratio (e'; r = - 0.2463), and baPWV (r = - 0.1928) significantly correlated with AMAW. In the stratified multiple regression analysis, E/e' (standardized partial regression coefficients = - 0.1863) and mean baPWV (standardized partial regression coefficients = - 0.1917) in patients with an EF of ≥ 60% (n = 114) significantly correlated with AMAW. In patients with an EF of < 60% (n = 70), E/e' (standardized partial regression coefficients = - 0.2443) significantly correlated with AMAW. CONCLUSION: Because E/e' correlated with AMAW in patients with an EF of < 60% or ≥ 60%, AMAW might be an indicator of left atrial pressure elevation. Moreover, because AMAW correlated with baPWV in patients with an EF of ≥ 60%, changes in the restricted left atrial volume might influence diastolic dysfunction. AMAW may be related to cardiac and vessel functions.