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Background: The ACURATE neo2 is a contemporary transcatheter aortic valve implantation (TAVI) system approved for the treatment of severe aortic stenosis in Europe. The ACURATE neo2 has not been evaluated in bicuspid aortic valve (BAV) stenosis., Aims: We sought to evaluate the safety and efficacy of ACURATE neo2 in patients with BAV stenosis., Methods: We retrospectively analysed consecutive severe BAV stenosis patients undergoing TAVI with ACURATE neo2 at 10 European centres. Imaging data from preprocedural multislice computed tomography, pre- and postprocedural echocardiography, and procedural cinefluoroscopy were evaluated by a core laboratory. Valve Academic Research Consortium 3 (VARC-3)-defined 30-day procedure safety and efficacy were the primary endpoints. Adverse events were site-reported according to VARC-3 criteria., Results: Among 181 patients with BAV stenosis treated with the ACURATE neo2, the mean age was 77.5±7.2 years, 58.0% were female, and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 2.3% (1.6-3.7%). Most procedures were transfemoral, and predilatation was performed in all cases. A second valve was required in 4 cases (2.2%). VARC-3-defined technical success was 95.6%. The primary endpoints of device success and early safety occurred in 90.6% and 82.3%, respectively. At 30 days, cardiovascular death occurred in 2.2% (N=4) and stroke in 1.6% (N=3). Core laboratory-adjudicated echocardiography reported an effective orifice area of 2.0 (1.7-2.5) cm 2 and a mean transvalvular gradient of 6.5 (4.6-9.0) mmHg. Half of all cases (51.2%) had no paravalvular leak, while moderate leak occurred in 4.3%. A new permanent pacemaker was required in 11 patients (6.5%)., Conclusions: The ACURATE neo2 demonstrated favourable clinical outcomes and bioprosthetic valve performance at 30 days in selected patients with severe BAV stenosis.

Background: There are different definitions of periprocedural myocardial infarction (PPMI) both in terms of thresholds for cardiac biomarkers and the ancillary criteria for myocardial ischemia. Cardiac Troponin I (cTnI) and cardiac Troponin T (cTnT) are used interchangeably to diagnose PPMI., Objectives: This study evaluated the frequency of periprocedural myocardial injury and infarction as defined by the Society of Cardiovascular Angiography & Interventions (SCAI), the Academic Research Consortium-2 (ARC-2), and the 4th Universal definition of MI (4UDMI) stratified using cTnT versus cTnI, among patients with chronic coronary syndrome (CCS) and unstable angina., Results: Among 830 patients, PPMI rates according to the SCAI, ARC2 and 4UDMI criteria were 4.34 %, 2.05 %, and 4.94 % respectively, with higher rates seen for all definitions when using cTnI versus cTnT (SCAI: 9.84 % vs. 1.91 %, p < 0.001; ARC 2: 3.15 % vs. 1.56 %, p = 0.136; and 4UDMI 5.91 % vs. 4.51 %, p = 0.391). Minor and major periprocedural myocardial injury was respectively observed in 58.31 % and 27.10 % of patients, with rates of both significantly higher when using cTnI versus cTnT (Minor: 69.29 % vs. 53.47 %, p < 0.001, Major: 49.21 % vs. 17.36 %, p < 0.001)., Conclusions: Among patients with CCS and unstable angina, PPMIs defined by SCAI occurred more frequently when using cTnI as opposed to cTnT, whereas the type of troponin had no impact on the incidence of PPMIs according to the ARC-2 and 4UDMI., Competing Interests: Declaration of competing interest Dr. Ninomiya reports a grant from Abbott Medical Japan outside the submitted work. Dr. Kotoku has received a grant for studying overseas from Fukuda Foundation for Medical Technology. Dr. Serruys reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Onuma reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Sabate is a consultant for Abbott vascular and iVascular outside the submitted work. Dr. Mollmann is a consultant for Abbott vascular, Boston Scientific, Medtronic and SMT outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

A total of 1001 subjects (82.0 years, 62.5% female, 63.7% NYHA III/IV at baseline) with severe aortic stenosis at high surgical risk were enrolled in the prospective CONFIDENCE registry and treated with a Portico™ transcatheter heart valve (THV) using either a first-generation delivery system (DS) or the FlexNav™ DS. The objective of this registry is to characterize the procedural safety and device performance of the Portico™ THV at 30 days. The study collected 'standard-of-care' clinical and device performance data, with adverse events adjudicated by an independent clinical event committee according to the Valve Academic Research Consortium-2 criteria. The implantation of a single Portico™ THV was successful in 97.5% of subjects. The 30-day all-cause mortality, cardiovascular mortality, and disabling stroke rates were 2.6%, 2.1%, and 1.8%, respectively. A new pacemaker was implanted in 19.0% of subjects at 30 days. At 30 days, the effective orifice area and mean gradient values were 1.82 cm 2 and 7.1 mmHg, respectively. The 30-day rate of moderate paravalvular leak (PVL) was 2.1%, with no occurrence of severe PVL. The Portico™ THV demonstrated improved hemodynamic performance and low rates of safety events at 30 days in a large cohort of subjects implanted with the Portico™ THV with either the first-generation DS or FlexNav™ DS.

The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336 mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800 mg, the distribution volume (V d ) averaged 1.17 L/kg, and the model predicted elimination half-life (t 1/2 ) was 2.6 h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t 1/2 of 1.7 min, and followed by MPL phosphate (MPPS) 3.8 min, MPL hemisuccinate (MPHS) 16 min, and MPL suleptanate (MPSP) 2.9 h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (k a ) of 1.5 h -1 for MPSS and 96 h -1 for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and k a of 2.1 h -1 , while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans., Competing Interests: Declarations. Conflict of Interest: The authors declare that there are no conflicts of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Prolonged periods of extreme heat or drought in the first year after fire affect the resilience and diversity of fire-dependent ecosystems by inhibiting seed germination or increasing mortality of seedlings and resprouting individuals. This interaction between weather and fire is of growing concern as climate changes, particularly in systems subject to stand-replacing crown fires, such as most Mediterranean-type ecosystems. We examined the longest running set of permanent vegetation plots in the Fynbos of South Africa (44 y), finding a significant decline in the diversity of plots driven by increasingly severe postfire summer weather events (number of consecutive days with high temperatures and no rain) and legacy effects of historical woody alien plant densities 30 y after clearing. Species that resprout after fire and/or have graminoid or herb growth forms were particularly affected by postfire weather, whereas all species were sensitive to invasive plants. Observed differences in the response of functional types to extreme postfire weather could drive major shifts in ecosystem structure and function such as altered fire behavior, hydrology, and carbon storage. An estimated 0.5 °C increase in maximum temperature tolerance of the species sets unique to each survey further suggests selection for species adapted to hotter conditions. Taken together, our results show climate change impacts on biodiversity in the hyperdiverse Cape Floristic Region and demonstrate an important interaction between extreme weather and disturbance by fire that may make flammable ecosystems particularly sensitive to climate change., Competing Interests: The authors declare no conflict of interest.

Objectives: The aim of this study was to evaluate the initial and short-term results of a new apical access and closure device to facilitate and standardize the transapical (TA) approach to transcatheter aortic valve implantation (TAVI)., Methods: The apical access, stabilization and closure (ASC™) device consists of three components: an introducer system, a left ventricular low-profile titanium coil and a closure cap. The ASC™ introducer system is anchored and rotated into the myocardium almost like a corkscrew, using the titanium coil. Following the TA-AVI procedure, the closure cap is introduced and delivered through the system into the titanium coil for final sealing., Results: A total of 11 high-risk elderly patients (EuroSCORE I: 27.8 ± 16.7; EuroSCORE II: 6.6 ± 5.0 and The Society of Thoracic Surgeons (STS) score: 5.9 ± 2.7%) were evaluated for TA-AVI by our interdisciplinary Heart Team and subsequently included in the trial after informed consent was obtained. One patient was excluded due to the presence of deep epicardial fat tissue. In all other cases, the titanium coil provided sufficient sealing throughout the procedure without the presence of perisheath bleeding. After delivery of the closure cap, no relevant bleeding was observed in any patient. Pericardial drainages were removed early in all patients. One patient suffered from non-device-related pericardial effusion requiring surgical decompression on postoperative day 6. Two patients suffered from delayed minor strokes, most likely due to arrhythmia. All patients received aspirin, clopidogrel and low molecular heparin after the procedure. Discharge echocardiography revealed no changes in left ventricular function when compared with baseline and no new onset wall motion abnormalities. All 10 patients were alive at 30 days., Conclusions: TA access and closure are both feasible and safe using the APICA ASC™ device. The system facilitates and standardizes TA access and closure by providing a sufficient and secure sealing during and after the TA-AVI procedure.

Aims: We aimed to evaluate the incremental value of high-sensitive troponin T (hsTnT) for risk prediction prior to non-cardiac surgery in comparison with the established revised cardiac index., Methods and Results: In this prospective, international multicentre observational study, 979 patients prior to non-cardiac surgery were enrolled. The endpoints were in-hospital mortality, the combination of death, acute myocardial infarction, cardiac arrest, cardio-pulmonary resuscitation, and acute decompensated heart failure. Twenty-five patients (2.6%) deceased and 36 (3.7%) of the patients experienced the combined endpoint. Cardiac markers were elevated in those patients who died when compared with survivors (hsTnT: 21 ng/L vs. 7 ng/L; P < 0.001; NT-proBNP: 576 pg/mL vs. 166 pg/mL; P < 0.001). Applying a cut-off for hsTnT of 14 ng/L and for NT-proBNP of 300 pg/mL, those patients with elevated hsTnT had a mortality of 6.9 vs. 1.2% (P < 0.001) and with elevated NT-proBNP 4.8 vs. 1.4% (P = 0.002). The highest AUC of the ROC curve was found for hsTnT as a predictor for mortality of 0.809. In a multivariate Cox regression analyses, hsTnT was the strongest independent predictor for the combined endpoint [HR 2.6 (95% CI: 1.3-5.3); P = 0.01]., Conclusion: High-sensitive troponin T provides strong prognostic information in patients undergoing non-cardiac surgery incremental to the widely accepted revised cardiac index.

Chronic arterial occlusion leads to growth of collaterals - a process termed arteriogenesis, in which macrophages play a prominent role in remodelling and growth. However, a detailed analysis which of distinct macrophage subpopulations involved in arteriogenesis has never been performed. In the present study the temporal and spatial distribution of macrophage subtypes during arteriogenesis in a rat model with chronically elevated fluid shear stress (FSS) is investigated. Local macrophage subpopulations were histologically immuno-phenotyped using CD68 (a ubiquitous macrophage marker) and CD163, a specific M2 macrophage marker. Without occlusion few M2-macrophages reside in the perivascular space. Early after occlusion (12h) the number of M2 macrophages increases strongly and M1 macrophages begin emerging into the collateral. After 3 days they appear in the perivascular space. Both macrophage subtypes increase until 28d after treatment, whereas M2 macrophages dominate at the site of collateral growth. The local distribution of the subpopulations changes during the arteriogenic process. Whereas M1 macrophages are detected directly adjacent to the media, M2 macrophages are present in the most outer perivascular region of the growing collateral vessel. Systemic alterations of blood leucocytes in mice after femoral artery ligature (FAL) were investigated by FACS analysis of serial blood samples. During collateral remodelling histological changes were not reflected in circulating monocytes in the peripheral blood. The activation state of macrophages in mice with FAL was modulated by injections of either dexamethasone or the interleukins IL10 or IL3/IL14. The arteriogenic response was assessed by hind limb perfusion with laser Doppler measurements after 3, 7 and 14d. Suppressing inflammatory monocyte subtypes (M1) with dexamethasone led to impaired perfusion recovery after FAL in mice, whereas IL10 or IL4/IL13 application significantly increased perfusion recovery. This investigation demonstrates that a forced shift towards M2 macrophages improves the arteriogenic response. The distinct early increase and spatial distribution of M2 macrophages support the idea that this subtype plays a predominant role during collateral remodelling.

A new cardiac syndrome with transient left ventricular dysfunction has been recently reported and is referred to as Tako-Tsubo cardiomyopathy, which is characterized by a transient akinesia of the apex and compensatory basal hyperkinesis. Today, the etiology remains unknown. We report for the first time of a patient with multiple episodes of a transient global left ventricular dysfunction which is reminiscent to apical ballooning. These episodes were always preceded by severe emotional stress proposing a potential common pathomechanism., (Copyright 2007 S. Karger AG, Basel.)

Triamcinolone acetonide (TCA) is a corticosteroid that is frequently used in the treatment of asthma. After inhalation, TCA can become systemically available when the inhaled formulation is swallowed, causing undesirable systemic effects. A clinical study was conducted to determine the systemic side effects of TCA after intravenous (2 mg as phosphate ester), oral (5 mg), and inhaled (2 mg) administration. Blood samples were collected at appropriate times over 24 hours, and TCA concentrations in plasma were measured by high-performance liquid chromatography and radioimmunoassay. Free drug concentrations were determined by ultrafiltration for correlating pharmacokinetics and pharmacodynamics. The free fraction of TCA (+/- standard deviation) was 29.0 +/- 1.3% and was independent of the investigated concentration range up to 1,000 ng/mL. Pharmacodynamic parameters were determined by monitoring lymphocytes, granulocytes, and cortisol. Pharmacokinetic/pharmacodynamic modeling was performed using a modified Emax model for lymphocytes and granulocytes. A novel linear release rate model was used to characterize the cortisol data. The E50 values determined from all three pharmacodynamic endpoints were not significantly different for the three treatments, indicating that these effects can be explained based on systemic steroid concentrations.

Background: Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling., Methods: Surgical bilateral SCGx was performed in 9-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery., Results: The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery., Conclusions: Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β 2 -adrenergic receptor (β 2 -AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome., Objectives: The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy., Methods: Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours., Results: The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β 2 -AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels., Conclusion: Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β 2 -AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Coronary chronic total occlusions (CTO) are common in patients undergoing coronary angiography, yet the optimal management strategy remains uncertain, with conflicting results from randomized trials. Appropriate patient selection and careful periprocedural planning are imperative for successful patient management. We review the role of adjunctive imaging modalities including myocardial perfusion imaging (MPI), cardiac magnetic resonance imaging (CMR), echocardiography and computed tomography coronary angiography (CTCA) in myocardial ischemic quantification, myocardial viability assessment, as well as procedural planning for CTO revascularization. An appreciation of the value, indications and limitations of these modalities prior to planned intervention are essential for optimal management., (© 2020. American Society of Nuclear Cardiology.)

Background: Little is known about the impact of the ID on outcomes and device success using balloon-expandable devices. This study sought to analyze the impact of implantation depth (ID) on procedural outcomes., Methods: In consecutive patients (n = 969) undergoing transfemoral TAVR with new-generation balloon-expandable prostheses, the mean ID (ID Mean ) was determined by aortography and categorized into low, correct, and high device position. Outcomes of interest were device success (VARC-2), paravalvular regurgitation (PVR) ≥ moderate, severe prosthesis-patient mismatch (PPM), permanent pacemaker implantation (PPI), and the composite of the three latter outcome measures (COMP PPP )., Results: ID Mean was greater among patients with PPI (median 4.0 [interquartile range 2.0; 4.0] vs. 3.5 [1.5; 5.5] mm; p = 0.002), severe PPM (3.5 [1.5; 5.0] vs. 4.0 [2.0; 6.0] mm; p = 0.028), and COMP PPP (4.0 [2.0; 6.0] vs. 3.0 [1.5; 5.5] mm; p < 0.001) when compared with the respective groups without these complications. There was no significant association between ID Mean and device success or PVR ≥ moderate. Categorization into low (7.3%), correct (90.7%), and high (2.0%) device position showed significant discrimination with an increase of severe PPM, PPI, and COMP PPP with lower position, whereas device success was not significantly affected by position. Only PVR ≥ moderate showed an asymmetric distribution with highest rates in the high and low position group, which was non-significant. However, among patients without correct position the rate of device success was 45.6%., Conclusions: A higher device position was associated with improved outcomes. Malpositioning without functional impairment should not be classified as device failure. The odds ratio of ID Mean was calculated by univariate logistic regression for each outcome variable, showing that with higher values of ID Mean (i.e., low implantation depth), the risk of severe PPM, PPI, and COMP PPP increases. The bar charts under the heading "Position category" denote the frequency of each outcome measure across patients with high, correct, and low device position. The p values are derived from chi-squared test., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Transcatheter aortic valve replacement (TAVR) has become the dominant procedural modality for aortic valve replacement in the United States. The reported rates of neurological complications in patients undergoing TAVR have changed over time and are dependent on diagnostic definitions and modalities. Most strokes after TAVR are likely embolic in origin, and the incidence of stroke has decreased over time. Studies have yielded conflicting results when comparing stroke rates between TAVR and surgical aortic valve replacement (SAVR), especially due to differences in diagnostic criteria and neurocognitive testing. In this narrative review, we summarize the available data on the incidence of stroke, delirium, and cognitive decline after TAVR and highlight potential areas in need of future research. We also discuss silent cerebral ischemic lesions (SCILs) and their association with a decline in postoperative neurocognitive status after TAVR. Finally, we describe that the risk of delirium and postoperative decline is increased when nonfemoral access routes are used, and we highlight the need for standardized imaging and valid, repeatable methodologies to assess cognitive changes after TAVR., Competing Interests: Conflicts of Interest, Funding: See DISCLOSURES at the the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

We herein describe the first example of ligand-controlled, copper-catalyzed regiodivergent asymmetric difunctionalization of terminal alkynes through a cascade hydroboration and hydroallylation process. The catalytic system, consisting of (R)-DTBM-Segphos and CuBr, could efficiently achieve asymmetric 1,1-difunctionalization of aryl terminal alkynes, while ligand switching to (S,S)-Ph-BPE could result in asymmetric 1,2-difunctionalization exclusively. In addition, alkyl substituted terminal alkynes, especially industrially relevant acetylene and propyne, were also valid feedstocks for asymmetric 1,1-difunctionalization. This protocol is characterized by good functional group tolerance, a broad scope of substrates (>150 examples), and mild reaction conditions. We also showcase the value of this method in the late-stage functionalization of complicated bioactive molecules and simplifying the synthetic routes toward the key intermediacy of natural product (bruguierol A). Mechanistic studies combined with DFT calculations provide insight into the mechanism and origins of this ligand-controlled regio- and stereoselectivity., (© 2024 Wiley-VCH GmbH.)

Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood-brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC 50 /SC 50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC 50 ), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Objectives: The aim of this study was to compare outcomes of transcatheter and surgical aortic valve implantation in chronic dialysis patients with aortic valve stenosis (AS)., Background: Chronic dialysis patients undergoing heart valve surgery are at higher risk for morbidity and mortality. Whether interventional techniques can reduce this risk is unclear because dialysis patients have thus far been excluded from randomized trials., Methods: Chronic dialysis patients with AS enrolled in the German Aortic Valve Registry (GARY) between 2012 and 2015 were analyzed to compare transcatheter aortic valve implantation (TAVI n = 661) with surgical aortic valve replacement (SAVR n = 457). Propensity scores for inverse probability of treatment weighting (IPTW) were used to adjust the comparison of the two treatment groups for potential confounders., Results: TAVI patients were older (78 ± 7.3 vs. 69 ± 10.2 years, p < 0.01, unadjusted) and had more comorbidities. Mortality at 1 year was the same (TAVI: 33.4% vs. SAVR 35.0%, p = 0.72, IPTW-adjusted) while it was lower with TAVI at 30 days (8.6% vs. 15.0%, p = 0.02, IPTW-adjusted). TAVI patients required more pacemaker implantation and showed more aortic regurgitation. SAVR patients required more blood transfusions and had longer hospital stay. Diabetes mellitus, atrial fibrillation, previous PCI, urgent procedure and EuroSCORE were associated with elevated 30-day mortality. Atrial fibrillation and older age were independent risk factor of 1-year mortality in both groups., Conclusions: Chronic dialysis patients with AS undergoing TAVI or SAVR had the same 1-year mortality, although survival at 30 days was better with TAVI. These results suggest that TAVI may improve peri-procedural outcomes.

Background: Currently, patient selection in TAVI is based upon a multidisciplinary heart team assessment of patient comorbidities and surgical risk stratification. In an era of increasing need for precision medicine and quickly expanding TAVI indications, machine learning has shown promise in making accurate predictions of clinical outcomes. This study aims to predict different intrahospital clinical outcomes in patients undergoing TAVI using a machine learning-based approach. The main clinical outcomes include all-cause mortality, stroke, major vascular complications, paravalvular leakage, and new pacemaker implantations., Methods and Results: The dataset consists of 451 consecutive patients undergoing elective TAVI between February 2014 and June 2016. The applied machine learning methods were neural networks, support vector machines, and random forests. Their performance was evaluated using five-fold nested cross-validation. Considering all 83 features, the performance of all machine learning models in predicting all-cause intrahospital mortality (AUC 0.94-0.97) was significantly higher than both the STS risk score (AUC 0.64), the STS/ACC TAVR score (AUC 0.65), and all machine learning models using baseline characteristics only (AUC 0.72-0.82). Using an extreme boosting gradient, baseline troponin T was found to be the most important feature among all input variables. Overall, after feature selection, there was a slightly inferior performance. Stroke, major vascular complications, paravalvular leakage, and new pacemaker implantations could not be accurately predicted., Conclusions: Machine learning has the potential to improve patient selection and risk management of interventional cardiovascular procedures, as it is capable of making superior predictions compared to current logistic risk scores.

Background: Rates of permanent pacemaker implantation (PPI) have been low using the self-expanding ACURATE neo device, but data regarding risk factors of PPI for this specific device are scarce., Methods: The study cohort consisted of patients (n = 1000) with severe aortic stenosis undergoing transfemoral transcatheter aortic valve implantation (TAVI) using the ACURATE neo prosthesis in our center between May 2012 and December 2019. For the present analysis, we excluded patients with previous permanent pacemaker (n = 110), high-grade AV block prior to TAVI (n = 3), and patients requiring conversion to surgical valve replacement (n = 4) or the implantation of a second prosthesis as valve-in-valve (n = 15). Preexisting conduction abnormalities were determined, and the implantation depth of the prosthesis was measured on final angiography. Differences across quartiles based on the original consecutive cohort were analyzed with respect to implantation depth and PPI rate. Predictors of PPI were identified using logistic regression., Results: The PPI rate was 10%. Preexisting AV block I°, right bundle branch block (RBBB), and the implantation depth were independent predictors of PPI. Across quartiles, the implantation depth differed significantly with lowest values in the last quartile, whereas differences of PPI rates across quartiles were not statistically significant, but showed a notable decrease in the last quartile., Conclusion: Preexisting RBBB, AV block I°, and low implantation depth were independent predictors of PPI following TAVI using the ACURATE neo device. Instead of deliberately aiming at a high position, avoidance of a low implantation depth may represent a reasonable compromise to reduce the rate of PPI without increasing the risk of malpositioning., (© 2020 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Takotsubo syndrome (TTS) is an acute and mostly reversible cardiomyopathy that mimics an acute coronary syndrome with left ventricular (LV) systolic dysfunction without relevant obstructive coronary artery disease. Its prevalence is probably underestimated and reaches 1.2-2% in patients with acute coronary syndrome undergoing coronary catheterization. Although supraphysiological epinephrine levels have been associated with TTS, the detailed pathophysiology is incompletely understood. Chest pain is the most common clinical presentation; however, cardiac decompensation, cardiogenic shock, and sudden cardiac death due to ventricular fibrillation may also be the first clinical manifestations. Patients are mostly postmenopausal women, in whom the condition is commonly associated with emotional triggers; however, men have a higher prevalence of TTS being associated with physical triggers, which has a worse prognosis compared with TTS associated with emotional triggers. As a diagnosis of exclusion, TTS has no single definitive diagnostic test. According to the distribution of LV wall motion abnormalities, various morphological subtypes have been identified. The final diagnosis depends on cardiac imaging with left ventricular angiography during acute heart catheterization, as well as on echocardiography and cardiac magnetic resonance. Most patients recover completely, albeit several factors have been associated with worse prognosis. Management is based on observational data, while randomized multicenter studies are still lacking. This review provides a general overview of TTS and focuses on the hypothesized pathophysiology, and especially on current practices in diagnosis, prognosis, and treatment.

Background and Purpose: Excessive fibrogenesis is associated with adverse cardiac remodelling and heart failure. The myofibroblast, primarily derived from resident fibroblast, is the effector cell type in cardiac fibrosis. Megakaryocytic leukaemia 1 (MKL1) is considered the master regulator of fibroblast-myofibroblast transition (FMyT). The underlying transcriptional mechanism is not completely understood. Our goal was to identify novel transcriptional targets of MKL1 that might regulate FMyT and contribute to cardiac fibrosis., Experimental Approach: RNA sequencing (RNA-seq) performed in primary cardiac fibroblasts identified insulin-like growth factor binding protein 5 (IGFBP5) as one of the genes most significantly up-regulated by constitutively active (CA) MKL1 over-expression. IGFBP5 expression was detected in heart failure tissues using RT-qPCR and western blots., Key Results: Once activated, IGFBP5 translocated to the nucleus to elicit a pro-FMyT transcriptional programme. Consistently, IGFBP5 knockdown blocked FMyT in vitro and dampened cardiac fibrosis in mice. Of interest, IGFBP5 interacted with nuclear factor of activated T-cell 4 (NFAT4) to stimulate the transcription of microfibril-associated protein 5 (MFAP5). MFAP5 contributed to FMyT and cardiac fibrosis by enabling sterol response element binding protein 2 (SREBP2)-dependent cholesterol synthesis., Conclusions and Implications: Our data unveil a previously unrecognized transcriptional cascade, initiated by IGFBP5, that promotes FMyT and cardiac fibrosis. Screening for small-molecule compounds that target this axis could yield potential therapeutics against adverse cardiac remodelling., (© 2024 British Pharmacological Society.)

William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator. Although beta-blockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic co-transmitter neuropeptide-Y (NPY) as being released during AMI, leading to larger infarcts and life-threatening arrhythmia in both animal models and patients. Here, we discuss recently published data demonstrating that peripheral venous NPY levels are associated with heart failure hospitalisation and mortality after AMI, and all cause cardiovascular mortality in CHF, even when adjusting for known risk factors (including brain natriuretic peptide). We have investigated the mechanistic basis for these observations in human and rat stellate ganglia and cardiac tissue, manipulating NPY neurochemistry at the same time as using state-of-the-art imaging techniques, to establish the receptor pathways responsible for NPY signalling. We propose NPY as a new mechanistic biomarker in AMI and CHF patients and aim to determine whether specific NPY receptor blockers can prevent arrhythmia and attenuate the development of heart failure., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular disease including stroke, heart failure, and ischemic heart disease (IHD). To prevent the occurrence and progression of CVD, a reliable prognostic cardiac biomarker is essential. We investigated the prognostic value of NT-proBNP for each incident type of CVD., Methods: Male patients from the Ibaraki Dialysis Initiation Cohort (iDIC) study with preserved serum samples from dialysis initiation day (n = 212) were analyzed. Patients were classified into four groups according to quartiles of baseline NT-pro BNP levels. The relationship between NT-proBNP levels at the initiation of dialysis and the subsequent incidence of hospitalization events due to IHD, heart failure, and stroke was analyzed., Results: The incidence rate for hospitalization due to IHD was significantly higher in the highest NT-proBNP category (Log rank p = 0.008); those of stroke and heart failure showed no significant differences among quartiles. Cox proportional hazards regression analysis revealed that serum NT-proBNT was the only prognostic factor for hospitalization for IHD after adjustment by major known IHD risk factors. (HR, 1.008; 95% confidence interval, 1.002-1.014; p = 0.01) The ROC curve analysis for the incidence of hospitalization due to IHD showed that NT-proBNP had an area under the curve (AUC) of 0.759 (95% CI 0.622-0.897; p = 0.004) at a cut-off value of 956.6 pg/mL., Conclusion: NT-proBNP measurement at the initiation of dialysis therapy is useful to predict later hospitalization for IHD., Trial Registration: UMIN000010806., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Low-dose prasugrel demonstrated a similar effectiveness profile to clopidogrel in East Asian ACS patients, but its comparison with another new-generation potent P2Y 12 inhibitor, ticagrelor, remains unclear. To compare the effectiveness and safety of low-dose prasugrel against those of standard-dose ticagrelor in East Asian patients with ACS. This retrospective cohort study used Taiwan's National Health and Welfare Database. This study included ACS patients who underwent percutaneous coronary intervention and, at discharge between January 1, 2018 and December 31, 2020, were prescribed with low-dose prasugrel plus aspirin or standard-dose ticagrelor plus aspirin. Stabilized inverse probability of treatment weighting was used to balance the covariates across these two groups. The primary effectiveness outcome was a composite of acute myocardial infarction, ischemic stroke, and cardiovascular death; the secondary effectiveness outcome was each of the individual components of the primary outcome, transient ischemic attack, and repeat revascularization. The primary safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding, and the two secondary safety outcomes were intracranial hemorrhage and gastrointestinal bleeding. A total of 24,807 patients were included in this study. Among them, 1,493 were low-dose prasugrel users and 23,314 were standard-dose ticagrelor users. No significant differences were found in primary effectiveness [HR: 0.97 (0.74-1.28)] or primary safety outcomes [HR: 1.22 (0.73-2.01)] between the two study groups. For East Asian patients with ACS, low-dose prasugrel provides comparable effectiveness without increasing bleeding risk compared to standard-dose ticagrelor. Low-dose prasugrel may be an appropriate alternative for East Asian populations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hydrocortisone (HC) is the optimal drug for adolescents diagnosed with congenital adrenal hyperplasia (CAH). Because traditional dosage regimens HC are inconvenient, our study used fused deposition modeling (FDM) three-dimensional (3D) printing technology to solve the problems caused by traditional preparations. First, we designed a core-shell structure tablet with an inner instant release component and an outer delayed release shell. The instant release component was Kollicoat IR: glycerol (GLY): HC = 76.5:13.5:10. Then, we used Affinisol® HPMC 15LV to realize delayed release. Furthermore, we investigated the relationship between the thickness of the delayed release shell and the delayed release time, and an equation was derived through binomial regression analysis. Based on that equation, a novel triple pulsatile tablet with an innovative structure was devised. The tablet was divided into three components, and the drug was released multiple times at different times. The dose and release rate of the tablets can be adjusted by modifying the infill rate of the printing model. The results indicated that the triple pulsatile tablet exhibited desirable release behavior in vitro. Moreover, the physicochemical properties of the drug, excipients, filaments, and tablets were characterized. All these results indicate that the FDM 3D printing method is a convenient technique for producing preparations with intricate structures., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Anxiety and limited patient comprehension may pose significant barriers when informing elderly patients about complex procedures such as transcatheter aortic valve implantation (TAVI)., Objectives: We aimed to evaluate the utility of medical graphics to improve the patient informed consent (IC) before TAVI., Methods: In this prospective, randomized dual center study, 301 patients were assigned to a patient brochure containing medical graphics (Comic group, n = 153) or sham information (Control group, n = 148) on top of usual IC. Primary outcomes were patient understanding of central IC-related aspects and periprocedural anxiety assessed by the validated Spielberger State Trait Anxiety Inventory (STAI), both analyzed by cognitive status according to the Montreal Cognitive Assessment (MoCA)., Results: Patient understanding was significantly higher in the Comic group [mean number of correct answers 12.8 (SD 1.2) vs. 11.3 (1.8); mean difference 1.5 (95% CI 1.2-1.8); p < 0.001]. This effect was more pronounced in the presence of cognitive dysfunction (MoCA < 26) [12.6 (1.2) in the Comic vs. 10.9 (1.6) in the Control group; mean difference 1.8 (1.4-2.2), p < 0.001]. Mean STAI score declined by 5.7 (95% CI 5.1-6.3; p < 0.001) in the Comic and 0.8 points (0.2-1.4; p = 0.015) in the Control group. Finally, mean STAI score decreased in the Comic group by 4.7 (3.8-5.6) in cognitively impaired patients and by 6.6 (95% CI 5.8 to 7.5) in patients with normal cognitive function (p < 0.001 each)., Conclusions: Our results prove beneficial effects for using medical graphics to inform elderly patients about TAVI by improving patient understanding and reducing periprocedural anxiety (DRKS00021661; 23/Oct/2020). Medical graphics entailed significant beneficial effects on the primary endpoints, patient understanding and periprocedural anxiety, compared to the usual patient informed consent (IC) procedure. Patient understanding of IC-related aspects was significantly higher in the Comic group, with a more pronounced benefit in patients with cognitive impairment (p for IC method and cognitive status < 0.001, respectively; p for IC method x MoCA category interaction = 0.017). There further was a significant decline of periprocedural anxiety in patients with and without cognitive impairment (p for IC method x measuring time point < 0.001; p for IC method x MoCA category x measuring time point interaction = 0.018)., (© 2023. The Author(s).)

Background: Valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) is a viable alternative to redo surgery in selected patients with bioprosthetic valve dysfunction. Most ViV-TAVI procedures have been performed in stented bioprosthetic valves (ST); stentless bioprostheses (SL) lack fluoroscopic markers and could be more challenging for ViV-TAVI. Data on more recent patients applying Valve Academic Research Consortium (VARC)-3 defined outcomes are scarce. We compared patient characteristics, procedural outcomes, and 5-year mortality of patients with SL versus ST aortic bioprosthetic valve failure undergoing ViV-TAVI., Methods: Patients undergoing ViV-TAVI between 2007 and 2022 (52.5% of cases after 2015) at 3 German centers were included in this analysis. The co-primary outcome measures were technical success, device success, and early safety defined by VARC-3. Mortality was assessed up to 5 years., Results: Overall, 43 (11.8%) SL and 313 (88.2%) ST ViV-TAVI were included. Patients were comparable with regard to age, sex, clinically relevant baseline comorbidities, and surgical risk. Technical success (SL: 83.7% versus ST: 79.9%, p = 0.552), device success (SL: 67.4% versus ST: 54.3%, p = 0.105), and early safety (SL: 74.4% versus ST: 66.5%, p = 0.296) were comparable between groups. The 30-day mortality (SL: 7.0% versus ST: 2.6%, p = 0.136) and 5-year mortality rates (SL: 23.3% versus ST: 24.6%, p = 0.874) were not significantly different between groups., Conclusion: SL and ST ViV-TAVI led to comparable short-term outcomes according to VARC-3- defined endpoints and similar mortality rates up to 5 years of follow-up. VARC-3 defined technical success, device success, and early safety as well as 5-year all-cause mortality in patients undergoing valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) into stentless (SL) compared with stented (ST) failed aortic bioprostheses., (© 2023. The Author(s).)

Background: The Portico transcatheter aortic heart valve is a self-expandable, fully resheathable bioprosthetic valve with a nitinol frame and porcine pericardial sealing cuff. It has been used among symptomatic severe aortic stenosis (AS) who are at high or extreme surgical risk. However, till date very few studies has been reported with inconclusive evidence for its postprocedure safety outcomes., Objective: The authors aim to evaluate the safety of the Portico transcatheter aortic valve replacement system among patients with AS., Methodology: The authors conducted a systematic literature search on PubMed, Embase, and Scopus from inception till 10th April 2023 by using predefined MESH terms using 'AND' and 'OR'. The following search terms were used: 'Aortic Stenosis' AND 'Transcatheter aortic valve replacement' OR 'Portico valve'. Finally, descriptive statistics were used to summarize the data in this paper. The mean and SD were adopted to describe continuous variables, whereas frequencies and percentages were used for dichotomous data., Results: A total of 7 studies with 2782 patients were included in the analysis. The mean age of patients was 82.3 years, and 54.63% were female. The most common comorbidity was hypertension (65.21%) and diabetes mellitus (26.45%). Among patients of AS with Portico valve implants, postprocedural outcomes including 30-day mortality (2.32%), cardiovascular mortality (2.37%), stroke (2.23%), myocardial infarction (0.94%), major bleeding (3.97%), major vascular complications (4.91%), acute kidney injury (1.37%), and permanent pacemaker implantations in 15.73% patients were reported. Overall, device success was observed in 95.82% of patients., Conclusion: Transcatheter aortic valve replacement with the repositionable Portico valve, a new bioprosthesis, appears to have a low postprocedural mortality rate and other clinical outcomes in high-risk patients with severe AS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cardiac fibroblasts (CFs) and cardiomyocytes are the major cell populations in the heart. CFs not only support cardiomyocytes by producing extracellular matrix (ECM) but also assimilate myocardial nutrient metabolism. Recent studies suggest that the classical intercellular lactate shuttle may function in the heart, with lactate transported from CFs to cardiomyocytes. However, the underlying mechanisms regarding the generation and delivery of lactate from CFs to cardiomyocytes have yet to be explored., Results: In this study, we found that angiotensin II (Ang II) induced CFs differentiation into myofibroblasts that, driven by cell metabolism, then underwent a shift from oxidative phosphorylation to aerobic glycolysis. During this metabolic conversion, the expression of amino acid synthesis 5-like 1 (GCN5L1) was upregulated and bound to and acetylated mitochondrial pyruvate carrier 2 (MPC2) at lysine residue 19. Hyperacetylation of MPC2 k19 disrupted mitochondrial pyruvate uptake and mitochondrial respiration. GCN5L1 ablation downregulated MPC2 K19 acetylation, stimulated mitochondrial pyruvate metabolism, and inhibited glycolysis and lactate accumulation. In addition, myofibroblast-specific GCN5L1-knockout mice (GCN5L1 fl/fl : Periostin-Cre) showed reduced myocardial hypertrophy and collagen content in the myocardium. Moreover, cardiomyocyte-specific monocarboxylate transporter 1 (MCT1)-knockout mice (MCT1 fl/fl : Myh6-Cre) exhibited blocked shuttling of lactate from CFs to cardiomyocytes and attenuated Ang II-induced cardiac hypertrophy., Conclusions: Our findings suggest that GCN5L1-MPC2 signalling pathway alters metabolic patterns, and blocking MCT1 interrupts the fibroblast-to-cardiomyocyte lactate shuttle, which may attenuate cardiac remodelling in hypertension., (© 2023. Society of Chinese Bioscientists in America (SCBA).)

Timely formation of collagen-rich-scar is of importance to prevent ventricular rupture after myocardial infarction (MI). Chil1 (Chitinase 3-like 1) is a secreted protein associated with tissue remodeling response. However, its function in MI progression remains elusive. Chil1 was downregulated in the injured area overall post-MI. Overexpression of Chil1 markedly reduced cardiac rupture, increased wall thickness, and improved cardiac function post-MI due to collagen-rich-scar formation and extracellular matrix remodeling. In vitro, Chil1 induced the transformation of fibroblasts to myofibroblasts. Mechanistically, a phosphoproteomics study revealed that Chil1 binded to the EGFR enhancing RAF/MEK1/ERK signaling pathway to exert cardiac protection function. The effects of Chil1 on fibroblasts transformation and cardiac protections after MI were partially abolished by co-treated with RAF inhibitor. Together, our findings identify Chil1 as a protection factor in MI progression through binding to EGFR which further activates RAF/MEK1/ERK signaling pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The COVID-19 pandemic caused massive disruption in usual care delivery patterns in hospitals across the USA, and highlighted long-standing inequities in health care delivery and outcomes. Its effect on hospital operations, and whether the magnitude of the effect differed for hospitals serving historically marginalized populations, is unknown., Objective: To investigate the perspectives of hospital leaders on the effects of COVID-19 on their facilities' operations and patient outcomes., Methods: A survey was administered via print and electronic means to hospital leaders at 588 randomly sampled acute-care hospitals participating in Medicare's Inpatient Prospective Payment System, fielded from November 2020 to June 2021. Summary statistics were tabulated, and responses were adjusted for sampling strategy and non-response., Results: There were 203 responses to the survey (41.6%), with 20.7% of respondents representing safety-net hospitals and 19.7% representing high-minority hospitals. Over three-quarters of hospitals reported COVID testing shortages, about two-thirds reported staffing shortages, and 78.8% repurposed hospital spaces to intensive care units, with a slightly higher proportion of high-minority hospitals reporting these effects. About half of respondents felt that non-COVID inpatients received worsened quality or outcomes during peak COVID surges, and almost two-thirds reported worsened quality or outcomes for outpatient non-COVID patients as well, with few differences by hospital safety-net or minority status. Over 80% of hospitals participated in alternative payment models prior to COVID, and a third of these reported decreasing these efforts due to the pandemic, with no differences between safety-net and high-minority hospitals., Conclusions: COVID-19 significantly disrupted the operations of hospitals across the USA, with hospitals serving patients in poverty and racial and ethnic minorities reporting relatively similar care disruption as non-safety-net and lower-minority hospitals., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

The ACURATE neo transcatheter aortic valve is a self-expanding device. Several studies have investigated safety and efficacy, but meta-analysis and pooled data are lacking. We aimed to provide a comprehensive systematic review and meta-analysis on the clinical outcomes of transcatheter aortic valve implantation with the ACURATE neo valve. A systematic literature search for eligible records was conducted. The primary endpoint was device success as designated by Valve Academic Research Consortium-2 criteria. The secondary endpoints (time frame: 30 days) were all-cause mortality, stroke, myocardial infarction, need for new permanent pacemaker, major vascular complications, major bleeding, acute kidney injury stage II or III, and paravalvular regurgitation grade moderate or severe (II or III). Our search yielded a total of 355 records, 20 of those (n = 5858 ACURATE neo receivers) were included in our meta-analysis. Device success was achieved in 94.5% (95% confidence interval [CI], 91.4-96.5%) of the patients. The 30-day all-cause mortality incidence proportion was 1.8% (95% CI, 1.3-2.4%). New pacemaker implantation was required in 7.7% (95% CI, 6.4-9.2%) of the patients, stroke occurred in 1.9% (95% CI, 1.6-2.3%), myocardial infarction in 0.5% (95% CI, 0.3-0.7%), major bleeding in 5.0% (95% CI, 3.9-6.5%), major vascular complication in 5.6% (95% CI, 4.0-7.8%), acute kidney injury stage ≥2 in 2.5% (95% CI, 1.8-3.4%), and paravalvular leak grade ≥moderate was observed in 4.3% (95% CI, 3.0-6.2%). Balloon predilatation and postdilatation incidence was 93.9% (95% CI, 87.0-97.3%) and 43.2% (95% CI, 37.9-48.6%), respectively. ACURATE neo appears to be safe and effective in our analysis with high device success incidence, low mortality, and low new pacemaker implantations., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Renal sympathetic denervation (RDN) reduces blood pressure (BP). However, one out of three patients does not exhibit a significant BP response to the therapy. This study investigates the association between noninvasive vascular stiffness indices and RDN-mediated BP reduction., Methods: In this prospective, single-arm pilot study, patients with systolic office BP at least 140 mmHg, mean 24-h systolic ambulatory blood pressure (ABP) at least 130 mmHg and at least three prescribed antihypertensive drugs underwent radiofrequency RDN. The primary efficacy endpoint was temporal evolution of mean 24-h systolic ABP throughout 1-year post RDN (measured at baseline and 3-6-12 months). Effect modification was studied for baseline ultrasound carotid-femoral and magnetic resonance (MR) pulse wave velocity (PWV), MR aortic distensibility, cardiac MR left ventricular parameters and clinical variables. Statistical analyses were performed using linear mixed-effects models, and effect modification was assessed using interaction terms., Results: Thirty patients (mean age 62.5 ± 10.7 years, 50% women) with mean 24-h ABP 146.7/80.8 ± 13.7/12.0 mmHg were enrolled. Following RDN, mean 24-h systolic ABP changed with -8.4 (95% CI: -14.5 to -2.3) mmHg/year ( P  = 0.007). Independent effect modifiers were CF-PWV [+2.7 (0.3 to 5.1) mmHg/year change in outcome for every m/s increase in CF-PWV; P  = 0.03], daytime diastolic ABP [-0.4 (-0.8 to 0.0) mmHg/year per mmHg; P  = 0.03], age [+0.6 (0.2 to 1.0) mmHg/year per year of age; P  = 0.006], female sex [-14.0 (-23.1 to -5.0) mmHg/year as compared with men; P  = 0.003] and BMI [+1.2 (0.1 to 2.2) mmHg/year per kg/m 2 ; P  = 0.04]., Conclusion: Higher CF-PWV at baseline was associated with a smaller reduction in systolic ABP following RDN. These findings could contribute to improve identification of RDN responders., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Primary percutaneous coronary intervention with implantation of a metallic drug-eluting stent (DES) is the standard treatment for patients presenting with ST-elevation myocardial infarction (STEMI). Implantation of a bioresorbable scaffold (BRS) during STEMI represents a novel strategy without intravascular metal., Objective: The aim of the study was to investigate 12-month healing response in an STEMI population after implantation of either the Absorb BRS or Xience DES (Abbott Vascular, USA)., Methods: The present trial was a prospective, randomized, controlled, nonblinded, noninferiority study with planned inclusion of 120 patients with STEMI. Patients were randomly assigned 1:1 to treatment with Absorb BRS or Xience DES. Implantation result and healing response were evaluated by angiography and optical coherence tomography (OCT) at baseline and 12-month follow-up. The primary endpoint was minimum flow area (MFA) assessed at 12 months. Coronary stent healing index (CSHI) was calculated from OCT images., Results: Out of 66 included patients, 58 had follow-up OCT after 12 months, and 49 entered matched analysis. One death occurred in each group; none were stent-related. MFA was 5.13 ± 1.70 mm2 (95% CI, 4.44-5.82) in the BRS group compared with 6.30 ± 2.49 mm2 (95% CI, 5.22-7.37) (P = 0.06) in the DES group. Noninferiority could not be evaluated. CSHI for both groups had a median score of 3., Conclusion: The DES group performed numerically better in primary and secondary endpoints, but the CSHI showed good stent healing in both groups., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Takotsubo syndrome (TS), also known as apical ballooning syndrome, is a transient stress-related cardiomyopathy characterised by acute but reversible left ventricular dysfunction. The condition tends to occur in postmenopausal women after a stressful event. At presentation, TS typically mimics acute myocardial infarction (MI) and the incidence of TS has been increasing worldwide. This is likely a consequence of an improved awareness of the existence of this syndrome and easier access to early echocardiography and coronary angiography. However, its aetiology remains poorly understood and it is probably still underdiagnosed. Similar to other countries, TS is being increasingly recognised in New Zealand. In this review, we discuss the demographics, clinical features and outcomes of patients with TS in New Zealand. Doing so informs us not only of the pattern of disease in New Zealand but it also provides insights into the condition itself., (© 2022 Royal Australasian College of Physicians.)

Objectives: To evaluate feasibility and diagnostic performance of coronary CT angiography (CCTA)-derived fractional flow reserve (CT-FFR) for detection of significant coronary artery disease (CAD) and decision-making in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) to potentially avoid additional pre-TAVR invasive coronary angiography (ICA)., Methods: Consecutive patients with severe AS (n = 95, 78.6 ± 8.8 years, 53% female) undergoing pre-procedural TAVR-CT followed by ICA with quantitative coronary angiography were retrospectively analyzed. CCTA datasets were evaluated using CAD Reporting and Data System (CAD-RADS) classification. CT-FFR measurements were computed using an on-site machine-learning algorithm. A combined algorithm was developed for decision-making to determine if ICA is needed based on pre-TAVR CCTA: [1] all patients with CAD-RADS ≥ 4 are referred for ICA; [2] patients with CAD-RADS 2 and 3 are evaluated utilizing CT-FFR and sent to ICA if CT-FFR ≤ 0.80; [3] patients with CAD-RADS < 2 or CAD-RADS 2-3 and normal CT-FFR are not referred for ICA., Results: Twelve patients (13%) had significant CAD (≥ 70% stenosis) on ICA and were treated with PCI. Twenty-eight patients (30%) showed CT-FFR ≤ 0.80 and 24 (86%) of those were reported to have a maximum stenosis ≥ 50% during ICA. Using the proposed algorithm, significant CAD could be identified with a sensitivity, specificity, and positive and negative predictive value of 100%, 78%, 40%, and 100%, respectively, potentially decreasing the number of necessary ICAs by 65 (68%)., Conclusion: Combination of CT-FFR and CAD-RADS is able to identify significant CAD pre-TAVR and bears potential to significantly reduce the number of needed ICAs., Key Points: • Coronary CT angiography-derived fractional flow reserve (CT-FFR) using machine learning together with the CAD Reporting and Data System (CAD-RADS) classification safely identifies significant coronary artery disease based on quantitative coronary angiography in patients prior to transcatheter aortic valve replacement. • The combination of CT-FFR and CAD-RADS enables decision-making and bears the potential to significantly reduce the number of needed invasive coronary angiographies., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Pulmonary artery acceleration time (PAT) and PAT: ejection time (PATET) ratio are echocardiographic measurements of pulmonary arterial hypertension (PAH). These noninvasive quantitative measurements are ideal to follow longitudinally through the clinical course of PAH, especially as it relates to the need for and/or response to treatment. This review article focuses on the current literature of PATET measurement for infants and children as it relates to the shortening of the PATET ratio in PAH. At the same time, further development of PATET as an outcome measure for PAH in preclinical models, particularly mice, such that the field can move forward to human clinical studies that are both safe and effective. Here, we present what is known about PATET in infants and children and discuss what is known in preclinical models with particular emphasis on neonatal mouse models. In both animal models and human disease, PATET allows for longitudinal measurements in the same individual, leading to more precise determinations of disease/model progression and/or response to therapy. IMPACT: PATET ratio is a quantitative measurement by a noninvasive technique, Doppler echocardiography, providing clinicians a more precise/accurate, safe, and longitudinal assessment of pediatric PAH. We present a brief history/state of the art of PATET ratio to predict PAH in adults, children, infants, and fetuses, as well as in small animal models of PAH. In a preliminary study, PATET shortened by 18% during acute hypoxic exposure compared to pre-hypoxia. Studies are needed to establish PATET, especially in mouse models of disease, such as bronchopulmonary, as a routine measure of PAH., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Severe aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries. Heart failure (HF) is a frequent comorbidity of this condition and represents a diagnostic and therapeutic challenge. The spectrum of both conditions has become progressively wider in the last decade; HF has been divided in three groups according to left ventricular ejection fraction (LVEF) and severe AS has been reclassified into four groups according to aortic valve (AV) gradient, AV flow measured by LV stroke index, and LVEF. Although all four AS types may be found in patients with signs and symptoms of HF, low-flow AS with low or normal gradient is the most common type in these patients. Several studies have documented that patients with low-flow severe AS have a higher mortality risk than patients with normal-flow and high-gradient AS not only during the natural progression of the disease, but also after either interventional or surgical AV replacement. Existing data support transcatheter AV replacement (TAVR) in patients with severe AS, irrespective of AV gradient, AV flow, and LVEF. Controversial issues, however, are still present on this topic, which has not been adequately addressed by large studies and trials. This clinical review summarizes the epidemiology of the different HF types in patients with severe AS, as well as the impact of HF and LVEF on clinical outcomes of AS patients either untreated or after AV replacement. In particular, we addressed the influence of AV gradient and AV flow on all-cause and cardiovascular mortality in AS patients after TAVR., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Newer generation bioresorbable scaffolds (BRSs) with thinner struts and improved deliverability are expected to enhance safety and efficacy profiles. Bioheart (Bio-Heart, Shanghai, China) BRS is constructed from a PLLA (poly-l-lactic acid) backbone coated with a PDLLA (poly D-l-lactic acid) layer eluting sirolimus. We report 2-year serial intracoronary imaging findings., Methods: In this first-in-human study, 46 patients with single de novo lesions in native coronary vessels (vessel size 3.0-3.75 mm, lesion length ≤ 25 mm) were enrolled at a single institution. Baseline intravascular ultrasound (IVUS) and post-implantation IVUS and optical coherence tomography (OCT) examinations were mandatory. After successful implantations of BRS, the 46 patients were randomized to two different follow-up cohorts in a 2:1 ratio. Thirty patients in cohort 1 had to undergo angiography, IVUS, and OCT follow-ups at 6 and 24 months, respectively. The 16 patients in cohort 2 underwent the same types of imaging follow-ups at 12 and 36 months, respectively. Clinical follow-ups were scheduled uniformly in both cohorts at 1, 6, and 12 months and annually up to 5 years for all patients., Results: Between August and November 2016, a total of 54 patients were assessed. However, 8 patients could not meet all the inclusion criteria; thus, the remaining 46 patients (age 57.5 ± 8.7 years, 34.8% female, 50.0% with unstable angina, 26.1% diabetics) with 46 target lesions were enrolled in this study. All patients in both cohorts were required to complete clinical follow-up uniformly and regularly. In cohort 1, one patient had definite scaffold thrombosis within 6 months of follow-up; thus, after 6 months, cohort 1 had 96.7% patients . Imaging follow-up was available in 24 patients, and in-scaffold late loss was 0.44 ± 0.47 mm; intracoronary imaging confirmed the late loss was mainly due to to neointimal hyperplasia, but not scaffold recoil., Conclusions: Serial 2-year clinical and imaging follow-up results confirmed the preliminary safety and efficacy of Bioheart BRS for treatment of simple coronary lesions., (© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and lead candidates. The "phosphate" is one of the key counterions/promoiety used in the salt formation and prodrug synthesis. Salification with phosphoric acid enhances the aqueous solubility and thereby facilitates the administration of a drug by the parenteral route. Phosphate moiety in prodrug synthesis mainly improves permeability by lipophilic substitution. Histamine phosphate is the first phosphate salt, and hydrocortisone phosphate was the first prodrug approved by FDA in 1939 and 1952, respectively. The orange book enlists 12 phosphate salts and 17 phosphate prodrugs. Phosphate prodrugs, namely combretastatin A-4 diphosphate, combretastatin A-4 phosphate, lufotrelvir, TP-1287, pyridoxal phosphate, riboflavin phosphate, and psilocybin are clinical candidates. This review focuses on the FDA-approved phosphate salts and prodrugs from 1939 to 2021. The biopharmaceutical advantage of phosphate salts and prodrugs over the parent molecule is also deliberated., (© 2022 Wiley Periodicals LLC.)

The coronavirus disease 2019 (COVID-19) resulted in a marked decrease in the number of patient visits for acute myocardial infarction and delayed patient response and intervention in several countries. This study evaluated the effect of the COVID-19 pandemic on the number of patients, patient response time (pain-to-door), and intervention time (door-to-balloon) for patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). Patients with STEMI or NSTEMI visiting a hospital in South Korea who underwent primary coronary intervention during the COVID-19 pandemic (January 29, 2020, to December 31, 2020) were compared with those in the equivalent period from 2018 to 2019. Patient response and intervention times were compared for the COVID-19 pandemic window (2020) and the equivalent period from 2018 to 2019. We observed no decrease in the number of patients with STEMI (P = .88) and NSTEMI (P = 1.00) during the COVID-19 pandemic compared to that in the previous years. Patient response times (STEMI: P = .39; NSTEMI: P = .59) during the overall COVID-19 pandemic period did not differ significantly. However, we identified a significant decrease in door-to-balloon time among patients with STEMI (14%; P < .01) during the early COVID-19 pandemic. We found that the number of patients with STEMI and NSTEMI was consistent during the COVID-19 pandemic and that no time delays in patient response and intervention occurred. However, the door-to-balloon time among patients with STEMI significantly reduced during the early COVID-19 pandemic, which could be attributed to decreased emergency care utilization during the early pandemic., Competing Interests: The authors have no conflicts of interest to disclose. The authors have no financial conflicts of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Accurate reconstruction of transcatheter aortic valve (TAV) geometries and other stented cardiac devices from computed tomography (CT) images is challenging, mainly associated with blooming artifacts caused by the metallic stents. In addition, bioprosthetic leaflets of TAVs are difficult to segment due to the low signal strengths of the tissues. This paper describes a method that exploits the known device geometry and uses an image registration-based reconstruction method to accurately recover the in vivo stent and leaflet geometries from patient-specific CT images. Error analyses have shown that the geometric error of the stent reconstruction is around 0.1mm, lower than 1/3 of the stent width or most of the CT scan resolutions. Moreover, the method only requires a few human inputs and is robust to input biases. The geometry and the residual stress of the leaflets can be subsequently computed using finite element analysis (FEA) with displacement boundary conditions derived from the registration. Finally, the stress distribution in self-expandable stents can be reasonably estimated by an FEA-based simulation. This method can be used in pre-surgical planning for TAV-in-TAV procedures or for in vivo assessment of surgical outcomes from post-procedural CT scans. It can also be used to reconstruct other medical devices such as coronary stents., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Despite advances in transcatheter aortic valve replacement (TAVR) technology, periprocedural stroke remains a complication of TAVR procedures. The TriGUARD 3 device is designed to be positioned in the aortic arch to deflect debris away from the brachiocephalic, left common carotid, and left subclavian arteries during TAVR. The United States Food and Drug Administration (FDA) assembled the Circulatory System Devices Panel to review safety and effectiveness data for the TriGUARD 3 device. Because of the coronavirus disease 2019 pandemic, this meeting was held virtually. In this manuscript, we summarize the data presented by both the sponsor and FDA, as well as the panel discussion., (© 2022 Wiley Periodicals LLC.)