Introduction: Adenine has been demonstrated to be involved in the development of diabetic kidney disease. We postulate that adenine may play a similar role in the progression of cardiovascular disease. The underlying metabolic changes in ischemic cardiomyopathy (ICM) progression are not fully understood and may present novel targets to mitigate ischemic heart injury. This study aims to identify common metabolic targets based on adenine metabolism in both coronary artery calcification and ICM. Methods: Coronary arteries from human donor hearts with and without calcification were analyzed by mass spectrometry imaging (MSI) and serial section von Kossa’s staining for image co-registration with identified metabolites. Bulk tissue LC-MS of the same artery samples were measured for adenine pathway metabolites. Another cohort of human heart tissues from healthy donors and those with a history of ICM were analyzed for bulk left ventricle tissue LC-MS measurement of adenine pathway metabolites. Further, to evaluate a mechanistic role for adenine in the development of ICM, a rat model of MI was studied with and without pharmacologic inhibition of MTAP, the enzyme responsible for adenine production. Infarct size was used as the readout of heart injury. Results: An untargeted analysis by MSI reveals an increase in adenine highly localized to arterial calcification as well as other metabolites such as glycolytic intermediates and C16 ceramide-derived lipids. Bulk tissue LC-MS showed calcified arteries have an overall increase in adenine, 5’-methylthioadenosine (MTA), S- adenosylmethionine (SAM). Left ventricle tissue from human donors with a history of ICM showed a significant increase in adenine by bulk LC-MS compared to controls (t-Test, **p<0.01). There was a negative correlation of heart adenine with LVEF (Pearson R = -0.6807, **p<0.01). In a rat model of MI, inhibition of MTAP resulted in significantly reduced infarct size (from 50% to 10%, t-Test, *p<0.05). Conclusion: Spatial metabolomics revealed increased adenine, several glycolytic intermediates, and C16 ceramide-derived lipids as highly co-localized to arterial calcification. Further, adenine was found to be increased in LV tissues with ICM and was negatively correlated with LVEF. Inhibition of adenine production reduced infarct size in a rat model of MI by >80%. Taken together, multimodal metabolomics reveals adenine to be mechanistically involved in cardiovascular disease and presents as a novel therapeutic target.

Percutaneous ventricular assist devices (pVADs) incorporated with admittance electrodes have been validated in animal studies for accurate instantaneous volumetric measurements. Since miniaturization of the pVAD profile is a priority to reduce vascular complications in patients, our study aimed to validate admittance measurements using three electrodes instead of the standard four. Complex admittance was measured between an electrode pair and a pVAD metallic blood-intake tip, both with finite element analysis and on the benchtop. The catheter and electrode arrays were first simulated inside prolate ellipsoid models of the left ventricle (LV) demonstrating current flow throughout all parts of the LV as well as minimal influence of off-center catheter placement in the recorded signal. Admittance measurements were validated in 3D-printed models of healthy and dilated hearts (100–400 mL end-diastolic volumes). Minimal interference between a pVAD motor and the current signal of our admittance system was demonstrated. A modified Wei’s equation focused on three electrodes was developed to be compatible with reduced profile pVADs occurring clinically, incorporated with admittance electrodes and wires. The modified equation was compared against Wei’s original equation showing improved accuracy of calculated volumes. Reducing electrode footprint can simplify the incorporation of Admittance technology on any pVAD, allowing for instantaneous recognition of native heart recovery and assistance with pVAD weaning.

Objective The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder.Design Multicentre, randomised feasibility trial, with embedded qualitative study.Setting Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services.Participants Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder.Interventions Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2–3 weeks later.Primary feasibility objectives (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months.Results Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%.Conclusion This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment.Trial registration number ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

Key points Agents which dissolve hydroxyapatite may synergize with intravascular lithotripsy (IVL) to treat calcium plates more extensively, facilitating greater penetration of drug‐coated balloons delivered agents and maintain gain in lumen area without stenting. Dissolving hydroxyapatite could potentially allow more frequent use of high‐pressure balloons without IVL or atherectomy to fracture calcium plates, offering a lower cost approach. Other mechanisms such as debonding between calcium plate and fibrous tissue junctions may also be enhanced with IVL and calcium‐modifying agents to improve calcified vessel compliance.

There is growing interest in non-psychoactive phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), and cannabichromene, as potential leads for novel therapeutic agents. In this study, we report on the development of new derivatives in which we methylated either position 4 of olivetol or the phenolic positions of olivetol, or both. We introduce a refinement on previously reported chemical procedures for phytocannabinoid derivatization as well as the biological evaluation of all derivatives in anti-inflammatory in vivo models. Compounds such as the CBD derivative, 2 and the CBG derivative, 11, significantly reduced cytokine levels when compared to their parent compounds. Moreover, both of these derivatives proved to be as potent as dexamethasone for the inhibition of IL-1β. We believe that these new derivatives, as described herein, can be further developed as novel drug candidates for inflammatory conditions.

Leadless pacemakers are an emerging implantable medical device technology that improves patient outcomes through miniaturization; however, these devices still need to be replaced due to battery depletion, creating additional risk due to surgery. With energy harvesting, the lifetime of a battery may be extended. Latest research has investigated the use of harvesting devices that replace the bulk of the pacemaker's inner electronics and battery. Integrating the energy harvesting element with the current leadless pacemaker becomes more challenging due to this factor. Positioning the energy harvesting element on the outer shell of the leadless pacemaker would mitigate interference with the inner electronics and potentially enable a more seamless integration of the device. We hypothesize that a piezoelectric outer layer on an implanted leadless pacemaker can harvest energy from the heart's motion due to heart tissue contracting around the device during systole. We fabricated an all-electron energy harvesting device with piezoelectric and conductive nanofibers as a coating for a leadless pacemaker. A drop treatment step is investigated for improving material properties and its effect on the energy harvesting output. The final device was characterized in vitro with a custom-built simulated heart contraction test and in vivo with animal studies. This resulted in a highly scalable method to fabricate an energy harvesting device on a leadless pacemaker, as well as a system for evaluating energy harvesting performance from simulated squeezing of heart tissue. We observed a voltage output of up to 60 mVpp (peak-to-peak) in a swine's heart, and device performance was shown experimentally to be mainly affected by relative motion, such as an increased heart rate and movement within the ventricle. The strategy demonstrated the seamless coupling of a leadless pacemaker with a scalable piezoelectric energy harvesting device and presented a potential solution for powering various implantable medical devices.

Management of intracoronary calcium (ICC) continues to be a challenge for interventional cardiologists. There have been significant advances in calcium treatment devices. However, there still exists a knowledge gap regarding which devices to choose for the treatment of ICC. The purpose of this manuscript is to review the principles of intravascular lithotripsy (IVL) and clinical data. The technique of IVL will then be compared to alternative calcium treatment devices. Clinical data will be reviewed concerning the treatment of coronary, peripheral artery and valvular calcifications. Controversies to be discussed include how to incorporate IVL into your practice, what is the best approach for treating calcium subtypes, how to approach under-expanded stents, what is the ideal technique for performing IVL, how safe is IVL, whether imaging adds value when performing IVL, and how IVL fits into a treatment program for peripheral arteries and calcified valves.

Radial artery occlusion (RAO) has been the most common postprocedural complication of transradial artery access. The optimal method of prevention of RAO is still lacking. In our study, we aimed to evaluate the effect of patent hemostasis on early (24 hours) and late (2 weeks) RAO prevention. The Open Radial Artery Study was a single-arm, prospective, and multicenter study. The primary end points were early and late RAO at the vascular access site after transradial coronary procedures. Secondary end points were access site hematoma, pseudoaneurysm formation, arteriovenous fistula, and nerve injury. A total of 2,181 patients were analyzed (67% male, mean age 68 years). The mean interventional duration and hemostatic times were 75.6 ± 55.6 and 60 ± 5.6 minutes, respectively. Radial artery spasm occurred in 10% of patients (n = 218). Catheter kinking, radial artery rupture, or dissection were not observed during the procedure. RAO, hematoma, pseudoaneurysm, arteriovenous fistula, or nerve damage was not observed in any of the patients in the early or late period. In patients who undergo coronary diagnostic or interventional procedures through transradial artery access, the patent hemostasis method seems a critical step in the prevention of early and late RAO.

Coronary atherosclerosis is a leading cause of death as a result of coronary thrombosis and acute myocardial infarction. Drug-eluting stents (DES) have dramatically improved the treatment of coronary artery stenosis. However, stent thrombosis (ST) and in-stent-restenosis (ISR) have remained a vexing limitation of the DES. After DES implantation, despite taking dual antiplatelet (DAPT) therapy, very late ST results in myocardial infarction and death. This occurs regardless of the type of polymer or antiproliferative agent used in the contemporary DES. Such adverse events occur at a rate of approximately 2% to 3% per year after the first year, which have been attributed to strut fractures, loss of vessel compliance, and neoatherosclerosis. Bioresorbable scaffolds (BRS) have been introduced to overcome the above shortfalls and to a “leave nothing behind” approach. While BRS are novel and interesting, the initial experience with BRS was hampered by the increased rate of thrombosis compared with DES. Accordingly, in this review, we summarized underlying mechanisms leading to BRS failure and provided insights into optimizing BRS deployment with intravascular imaging. In addition, we outlined the perspectives of new generations of BRS with thinner struts and new designs as well as alternative materials to improve outcomes.

JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.

BACKGROUND:Previous studies have compared Impella use to intra-aortic balloon pump (IABP) use in patients with acute myocardial infarction and cardiogenic shock (AMI-CS) undergoing percutaneous coronary intervention (PCI). Our objective was to compare clinical outcomes in patients with AMI-CS undergoing PCI who received Impella (percutaneous left ventricular assist device) without vasopressors, IABP without vasopressors, and vasopressors without mechanical circulatory support (MCS).METHODS:We queried the National Inpatient Sample (NIS) using ICD-10 codes (2015-2018) to identify patients with AMI-CS undergoing PCI. We created three propensity-matched cohorts to examine clinical outcomes in patients receiving Impella versus IABP, Impella versus vasopressors without MCS, and IABP versus vasopressors without MCS.RESULTS:Among 17,762 patients, Impella use was associated with significantly higher in-hospital major bleeding (31.4% vs. 13.6%; p < 0.001) and hospital charges (p < 0.001) compared to IABP use, with no benefit in mortality (34.1% vs. 26.9%; p = 0.06). Impella use was associated with significantly higher mortality (42.3% vs. 35.7%; p = 0.02), major bleeding (33.9% vs. 22.7%; p = 0.001), and hospital charges (p < 0.001), when compared to the use of vasopressors without MCS. There were no significant differences in clinical outcomes between IABP use and the use of vasopressor without MCS.CONCLUSIONS:In this analysis of retrospective data of patients with AMI-CS undergoing PCI, Impella use was associated with higher mortality, major bleeding, and in-hospital charges when compared to vasopressor therapy without MCS. When compared to IABP use, Impella was associated with no mortality benefit, along with higher major bleeding events and in-hospital charges. A vasopressor-only strategy suggested no difference in clinical outcomes when compared to IABP. This study uses the NIS for the first time to highlight outcomes in AMI-CS patients undergoing PCI when treated with vasopressor support without MCS, compared to Impella and IABP use.

Objective Proteomic profiling can identify useful biomarkers. Monozygotic(MZ) twins, discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well characterised cohorts. Research Design and Methods A broad, multiplex analysis of 4068 proteins in sera from MZ twins concordant (n=43) and discordant for type 1 diabetes (n=27) identified major differences which were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n=39) and discordant (n=42) for type 1 diabetes, individuals at-risk (n=195) and with type 1 diabetes (n=990), as well as with non-insulin requiring adult-onset diabetes diagnosed as either autoimmune (n=96) or type 2 (n=291). Results Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite strong correlation between twins, whether concordant or discordant for type 1 diabetes (p<0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes compared with non-diabetic co-twins (p<0.0001) and healthy controls (p<0.0001). In recently-diagnosed cases, trypsin(ogen) levels were lower than in controls across a broad age range. In at-risk relatives, levels <15 ng/ml were associated with increased risk of progression (uncorr. p=0.009). Multiple linear regression in recently-diagnosed cases showed that trypsin(ogen) levels were associated with insulin dose and diabetic ketoacidosis while age and BMI were confounders. Conclusions Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and non-genetically determined factors. Exocrine/endocrine interactions are important under-investigated factors in type 1 diabetes.

Background: Electrical intravascular lithotripsy (E-IVL) uses shock waves to fracture calcified plaque. Aims: We aimed to demonstrate the ability of laser IVL (L-IVL) to fracture calcified plaques in ex vivo human coronary arteries and to identify and evaluate the mechanisms for increased vessel compliance. Methods: Shock waves were generated by a Ho:YAG (Holmium: yttrium-aluminium-garnet) laser (2 J, 5 Hz) and recorded by a high-speed camera and pressure sensor. Tests were conducted on phantoms and 19 fresh human coronary arteries. Before and after L-IVL, arterial compliance and optical coherence tomography (OCT) pullbacks were recorded, followed by histology. Additionally, microcomputed tomography (micro-CT) and scanning electron microscopy (SEM) were performed. Finite element models (FEM) were utilised to examine the mechanism of L-IVL. Results: Phantom cracks were obtained using 230 mu m and 400 mu m fibres with shock-wave pressures of 84 +/- 5.0 atm and 62 +/- 0.4 atm, respectively. Post-lithotripsy, calcium plaque modifications, including fractures and debonding, were identified by OCT in 78% of the ex vivo calcified arteries (n=19). Histological analysis revealed calcium microfractures (38.7 +/- 10.4 mu m width) in 57% of the arteries which were not visible by OCT. Calcium microfractures were verified by micro-CT and SEM. The lumen area increased from 2.9 +/- 0.4 to 4.3 +/- 0.8 mm(2) (p<0.01). Arterial compliance increased by 2.3 +/- 0.6 atm/ml (p<0.05). FEM simulations suggest that debonding and intimal tears are additional mechanisms for increased arterial compliance. Conclusions: L-IVL has the capability to increase calcified coronary artery compliance by multiple mechanisms.

BACKGROUND:The current Impella cardiopulmonary (CP) pump, used for mechanical circulatory support in patients with cardiogenic shock (CS), cannot assess native cardiac output (CO) and left ventricular (LV) volumes. These data are valuable in facilitating device management and weaning. Admittance technology allows for accurate assessment of cardiac chamber volumes. OBJECTIVES:This study tested the ability to engineer admittance electrodes onto an existing Impella CP pump to assess total and native CO as well as LV chamber volumes in an instantaneous manner. METHODS:Impella CP pumps were fitted with 4 admittance electrodes and were placed in the LVs of adult swine (n = 9) that were subjected to 3 different hemodynamic conditions, including Impella CP speed adjustments, administration of escalating doses of dobutamine and microsphere injections into the left main artery to result in cardiac injury. CO, according to admittance electrodes, was calculated from LV volumes and heart rate. In addition, CO was calculated in each instance via thermodilution, continuous CO measurement, the Fick principle, and aortic velocity-time integral by means of echocardiography. RESULTS:Modified Impella CP pumps were placed in swine LVs successfully. CO, as determined by admittance electrodes, was similar by trend to other methods of CO assessment. It was corrected for pump speed to calculate native CO, and calculated LV chamber volumes trended as expected in each experimental protocol. CONCLUSIONS:We report, for the first time, that an Impella CP pump can be fitted with admittance electrodes and used to determine total and native CO in various hemodynamic situations. CONDENSED ABSTRACT:Transvalvular mechanical circulatory support devices such as the Impella CP do not have the ability to provide real-time information on native cardiac output (CO) and left ventricular (LV) volumes. This information is critical in device management and in weaning in patients with cardiogenic shock. We demonstrate, for the first time, that Impella CP pumps coupled with admittance electrodes are able to determine native CO and LV chamber volumes in multiple hemodynamic situations such as Impella pump speed adjustments, escalating dobutamine administration and cardiac injury from microsphere injection.

Introduction: These is significant research into the development of new medications and devices to treat chronic total occlusions (CTO). However, there is a lack of large animal models which reproduce the anatomy of clinical CTOs. Aim: Create an experimental model that mimics the anatomic features of human CTOs. Methods: CTOs were created in coronary arteries of live Yorkshire pigs (weight 80-120 lbs). The bioactive dental plug material (OsteoGen® Plug, Impladent Ltd) was implanted into the middle segment of one of coronary arteries (LAD, LCX or RCA). Angiography (C- Arm, Siemens) was performed before, immediately after plug implantation and before autopsy to confirm the presence of a CTO lesion. Animals were sacrificed at 9 hours to 3 months (n=12) and all coronary arteries underwent histopathological examination. Results: Histopathologic assessment confirmed that the bioactive plug composed of calcium apatite crystals and bovine collagen matrix mimics the pathological appearances of human CTOs. Serial histological sections showed complete resorption of the collagen matrix with replacement by fibrotic tissue 2 months after plug implantation, while the calcium content remains in the CTO. Conclusions: We have developed a reproducible model of calcified CTOs in pigs. Our model can provide a platform for evaluation of new drugs and devices for the treatment of calcified CTOs as well as to serve as a live model for training interventional cardiologists learning to cross CTOs.

Screening for carcinoid heart disease is an important, yet frequently neglected aspect of the management of patients with neuroendocrine tumours (NETs). Screening is advocated in international guidelines, although recommendations on the modality and frequency are poorly defined. We mapped current practice for the screening and management of carcinoid heart disease in specialist NET centres throughout the UK and Republic of Ireland.Thirty-five NET centres were invited to complete an online questionnaire outlining the size of NET service, patient selection criteria for carcinoid heart disease screening and the modality and frequency of screening.Twenty-eight centres responded (80%), representing over 5500 patients. Eleven per cent of centres screen all patients with any NET, 14% screen only patients with midgut NETs, 32% screen all patients with liver metastases and/or carcinoid syndrome and 43% screen all patients with evidence of syndrome or raised urinary/serum/plasma 5-hydroxyindoleacetic acid (5HIAA). The mode of screening included clinical examination, echocardiography and biomarker measurement: 89% of centres carry out echocardiography, ranging from at initial presentation only (24%), periodically without clearly defined intervals (28%), annually (36%) or less than annually (12%); three centres use a scoring system to report their echocardiograms. Fifty per cent of centres utilise biomarkers for screening (chromogranins, plasma/urinary 5HIAA or most commonly N-terminal pro-brain natriuretic peptide) at varying time intervals.There is considerable heterogeneity across the UK and Ireland in multiple aspects of screening and management of carcinoid heart disease.

An efficient O3-monodesilylation method has been developed for the derivatization of per-3-O-silylated cyclodextrin (CD) derivatives. Using hydrochloric acid as a reagent, the O3-monodesilylation was found to be regioselective, mild, practical and general as it can be applied to all α-, β- and γ-CDs. The advantage of the methodology is that the acid-catalyzed O3-desilylation can be carried out in a stepwise manner so that different types of functional groups can be introduced to a CD molecule at different stage of the O3-desilylations. This makes the current methodology flexible and versatile. This current methodology constitutes one of the few methodologies available for the regioselective modification of CDs at the secondary face.