Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial.

BACKGROUND AND AIMS: The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. This study addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) without attaining thresholds of LVEF. METHODS: Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (age 59±13 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS and 3D echocardiography were tracked over 12 months. A total of 105 patients (age 59±13 years, 75% women, 69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) between cardioprotection with neurohormonal antagonists versus usual care were randomized. The primary endpoint was 12-month change in MRI-LVEF; the secondary endpoint was MRI LVEF-defined CTRCD. RESULTS: During follow-up, 2 patients died and 2 developed heart failure. Most patients were randomized at 3 months (62%). Median doses of angiotensin inhibition/blockade and beta-blockade were 75% and 50% of respective targets; 21 (43%) had side-effects attributed to cardioprotection. Due to a smaller LVEF change from baseline with cardioprotection than usual care (-2.5±5.4% vs -5.6±5.9%, p=0.009), follow-up LVEF was higher after cardioprotection (59±5% vs 55±6%, p<0.0001). After adjustment for baseline LVEF, the mean (95% confidence interval) difference in the change in LVEF between the two groups was -3.6% (-1.8% to -5.5%, p<0.001). After cardioprotection, 1/49 patients developed 12-month LVEF-CTRCD, compared to 6/56 in usual care (p=0.075). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. CONCLUSIONS: In patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care.

Use of artificial intelligence-guided echocardiography to detect cardiac dysfunction and heart valve disease in rural and remote areas: Rationale and design of the AGILE-echo trial.

BACKGROUND: Transthoracic echocardiography (TTE) is essential in the diagnosis of cardiovascular diseases (CVD), including but not limited to heart failure (HF) and heart valve disease (HVD). However, its dependence on expert acquisition means that its accessibility in rural areas may be limited, leading to delayed management decisions and potential missed diagnoses. Artificial intelligence-guided (AI)-TTE offers a solution by permitting non-expert image acquisition. The impact of AI-TTE on the timing of diagnosis and early initiation of cardioprotection is undefined. METHODS: AGILE-Echo (use of Artificial intelligence-Guided echocardiography to assIst cardiovascuLar patient managEment) is a randomized-controlled trial conducted in 5 rural and remote areas around Australia. Adults with CV risk factors and exercise intolerance, or concerns regarding HVD are randomized into AI-TTE or usual care (UC). AI-TTE participants may have a cardiovascular problem excluded, identified (leading to AI-guided interventions) or unresolved (leading to conventional TTE). UC participants undergo usual management, including referral for standard TTE. The primary endpoint is a composite of HVD or HF diagnosis at 12-months. Subgroup analysis, stratified based on age range and sex, will be conducted. All statistical analyses will be conducted using R. RESULTS: Of the first 157 participants, 78 have been randomized into AI-TTE (median age 68 [IQR 17]) and 79 to UC (median age 65 [IQR 17], P = .034). HVD was the primary concern in 37 participants (23.6%) while 84.7% (n = 133) experienced exercise intolerance. The overall 10-year HF incidence risk was 13.4% and 20.0% (P = .089) for UC and AI-TTE arm respectively. Atrial remodeling, left ventricular remodeling and valvular regurgitation were the most common findings. Thirty-three patients (42.3%) showed no abnormalities. CONCLUSIONS: This randomized-controlled trial of AI-TTE will provide proof-of-concept for the role of AI-TTE in identifying pre-symptomatic HF or HVD when access to TTE is limited. Additionally, this could promote the usage of AI-TTE in rural or remote areas, ultimately improving health and quality of life of community dwelling adults with risks, signs or symptoms of cardiac dysfunction.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Comparison of Echocardiography and Multi-Planar Gated Acquisition Scans for Predicting Cancer-Treatment-Related Cardiovascular Dysfunction.

BACKGROUND: Current guidelines recommend using sequential cardiac imaging to monitor for cancer treatment-related cardiac dysfunction (CTRCD) in patients undergoing potentially cardiotoxic chemotherapy. Multiple different imaging cardiac modalities are available and there are few prospective head-to-head comparative studies to help guide treatment. OBJECTIVES: To perform an exploratory prospective cohort study of "real-world" CTRCD comparing multigated acquisition nuclear ventriculography (MUGA) at the referring cancer specialist's discretion with a novel echocardiographic strategy at an Australian tertiary hospital. METHOD: Patients were recruited from haematology and oncology outpatient clinics if they were scheduled for treatment with anthracyclines and/or trastuzumab. Patients underwent simultaneous MUGA-based cardiac imaging (conventional strategy) at a frequency according to evidenced-based guidelines in addition to researcher-conducted echocardiographic imaging. The echocardiographic imaging was performed in all patients at time points recommended by international society guidelines. Outcomes included adherence to guideline recommendations, concordance between MUGA and echocardiographic left ventricular ejection fraction (LVEF) measurements, and detection of cardiac dysfunction (defined as >5% LVEF decrement from baseline by three-dimensional [3D]-LVEF). A secondary end point was accuracy of global longitudinal strain in predicting cardiac dysfunction. RESULTS: In total, 35 patients were recruited, including 15 with breast cancer, 19 with haematological malignancy, and one with gastric cancer. MUGA and echocardiographic LVEF measurements correlated poorly with limits of agreement of 30% between 3D-LVEF and MUGA-LVEF and 37% for 3D-LVEF and MUGA-LVEF. Only one case (2.9%) of CTRCD was diagnosed by MUGA, compared with 12 (34.2%) cases by echocardiography. Four (4) patients had >10% decrement in 3D-LVEF that was not detected by MUGA. Global longitudinal strain at 2 months displayed significant ability to predict CTRCD (area under the curve, 0.75, 95% confidence interval, 0.55-0.94). CONCLUSIONS: The MUGA correlates poorly with echocardiographic assessment with substantial discrepancy between MUGA and echocardiography in CTRCD diagnosis. Echocardiographic and MUGA imaging strategies should not be considered equivalent for imaging cancer patients, and a single imaging modality should ideally be used per patient to prevent misdiagnosis by inter-modality variation These findings should be considered hypothesis-generating and require confirmation with larger studies.

Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

Five-membered ring systems are ubiquitous throughout natural products and synthetic therapeutics, and thus, efficient methods to access this essential scaffold are required. Herein, we report the thioacid-mediated, 5-exo-trig cyclization of various 1,6-dienes, with high yields of up to 98%. The labile thioester functionality can be exploited to generate a free thiol residue which can be used as a functional handle or removed entirely to provide the traceless cyclized product.

Cost-effectiveness of screening for paroxysmal atrial fibrillation in patients undergoing echocardiography.

BACKGROUND: Screening for atrial fibrillation is recommended for patients > 65 years on current guidelines. Targeted screening may be more efficient, however the appropriate location for screening programs has not been well defined. Our aim was to compare the cost-effectiveness of unselected electrocardiographic (ECG) screening for atrial fibrillation (AF), and selective screening based on an abnormal echocardiogram. METHODS: Two strategies of portable ECG screening for AF were compared in the base case of a hypothetical asymptomatic 65-year-old man (CHA2 DS2 -VASC = 3 based on hypertension and diabetes mellitus) with previous echocardiography but without a cause for AF (e.g. mitral valve disease, left ventricular (LV) dysfunction). With age-based screening (AgeScreen; 3% AF detection rate) all patients underwent ECG. With imaging-guided screening (ImagingScreen; 5% detection rate), only patients with left atrial (LA) volume ≥34 mL/m2 and LA reservoir strain <34% or LV global longitudinal strain > -18% underwent ECG screening. A Markov model was informed by published transition probabilities, costs and quality-adjusted life years (QALY). Costs, effects and incremental cost-effectiveness ratio were assessed for each screening strategy over a 20-year period. The willingness-to-pay threshold was $53 000/QALY. RESULTS: ImagingScreen dominated AgeScreen, with a lower cost ($54 823 vs $57842) and better outcome (11.56 vs 11.52 QALY over 20 years). Monte Carlo simulation demonstrated that 61% of observations were more efficacious with ImagingScreen, with cost below willingness to pay. The main cost determinants were annual costs of stroke or heart failure and AF detection rates. ImagingScreen was more cost-effective for AF detection rates up to 14%, and more cost-effective across a range of annual stroke ($24 000-$102 000) and heart failure ($4000-$12 000) costs. CONCLUSION: In patients with a previous echocardiogram, AF screening of those with baseline clinical and imaging risk parameters is more cost-effective than age-based screening.

At the heart of sentencing: exploring whether more compassionate delivery of sentencing remarks increases public concern for people who offend.

Compassion has the capacity to change how we think and feel about people who offend, enabling us to understand individual and systemic causes of criminality and whether, and in what circumstances, desistance is possible. Across two experiments, our research examined whether a more compassionate sentencing delivery, firstly, in written sentencing remarks and, secondly, in videoed sentencing remarks, stimulated more concern for sentenced offenders amongst members of the Australian public. Our results suggest that it is possible to alter the features of a written or orally-delivered sentence, so that it is recognisably more compassionate. Further, engagement with compassion-enhanced sentencing remarks altered criminal justice spending preferences, reducing the proportion of the criminal justice budget that the public believed should be spent on imprisonment and increasing that to be spent on rehabilitation.

Thioether analogues of the pituitary neuropeptide oxytocin via thiol-ene macrocyclisation of unprotected peptides.

Disulfide bonds are an essential feature of many bioactive peptides, however, they are labile to reducing conditions which can limit therapeutic application. Herein, we report an efficient methodology for peptide macrocyclisation, furnishing thioether mimetics of disulfide linkages via thiol-ene click chemistry. Furthermore, this methodology is applied to the efficient synthesis of analogues of the neuropeptide oxytocin and in a highly efficient route to the clinical therapeutic carbetocin.

Cysteinyl radicals in chemical synthesis and in nature.

Nature harnesses the unique properties of cysteinyl radical intermediates for a diverse range of essential biological transformations including DNA biosynthesis and repair, metabolism, and biological photochemistry. In parallel, the synthetic accessibility and redox chemistry of cysteinyl radicals renders them versatile reactive intermediates for use in a vast array of synthetic applications such as lipidation, glycosylation and fluorescent labelling of proteins, peptide macrocyclization and stapling, desulfurisation of peptides and proteins, and development of novel therapeutics. This review provides the reader with an overview of the role of cysteinyl radical intermediates in both chemical synthesis and biological systems, with a critical focus on mechanistic details. Direct insights from biological systems, where applied to chemical synthesis, are highlighted and potential avenues from nature which are yet to be explored synthetically are presented.

Cost-effectiveness of combined catheter ablation and left atrial appendage closure for symptomatic atrial fibrillation in patients with high stroke and bleeding risk.

BACKGROUND: Combined catheter ablation (CA) and left atrial appendage closure (LAAC) have been proposed for management of symptomatic atrial fibrillation (AF) in patients with high stroke and bleeding risk. We assessed the cost-effectiveness of combined CA and LAAC compared with CA and standard oral anticoagulation (OAC) in symptomatic AF. METHODS: A Markov model was developed to assess total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio among 2 post-CA strategies: (1) standard OAC and (2) LAAC (combined CA and LAAC procedure). The base-case used a 10-year time horizon and consisted of a hypothetical cohort of patients aged 65 years with symptomatic AF, with high thrombotic (CHA2DS2-VASc = 3) and bleeding risk (HAS-BLED = 3), and planned for AF ablation. Values for transition probabilities, utilities, and costs were derived from the literature. Costs were converted to 2020 US dollars. Half-cycle correction was applied, and costs and QALYs were discounted at 3% annually. Sensitivity analyses were performed for significant variables and scenario analyses for higher embolic risk. RESULTS: In the base-case cohort of 10,000 patients followed for 10 years, total costs for the LAAC strategy were $29,027 and for OAC strategy were $27,896. The LAAC strategy was associated with 122 fewer disabling strokes and 203 fewer intracranial hemorrhages per 10,000 patients compared with the OAC strategy. The LAAC strategy had an incremental cost-effectiveness ratio of $11,072/QALY. In sensitivity analyses, although cost-effectiveness was highly dependent on the risk of intracranial hemorrhage in the LAAC strategy and the cost of the combined procedure, LAAC was superior to OAC under the most circumstances. Scenario analyses demonstrated that the combined procedure was more cost-effective in patients with higher stroke risk. CONCLUSIONS: In symptomatic AF patients with high stroke and bleeding risk who are planned for CA, the combined CA and LAAC procedure may be a cost-effective therapeutic option and be more beneficial to patients with CHA2DS2-VASc risk score ≥3.

Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes.

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Jury decision-making: the impact of engagement and perceived threat on verdict decisions.

The present study examined the role of political orientation and task engagement in juror decision-making. The study was conducted as a 2 (mode: laboratory versus online) × 2 (role: juror, observer) × 3 (evidence: admissible, inadmissible, control) between-subjects experiment, with participants (N = 157) recruited from a mid-sized Australian university. Findings supported our predictions that political conservatism is associated with convictions, and that university students endorse a wide range of political orientations. Participants who were more engaged in the study perceived more threat in the defendant, and threat, in turn, led to higher conviction rates; furthermore, the effect of participation mode on verdict decisions was completely mediated by perceptions of the threat posed by the defendant. Findings are discussed in terms of their implications for jury decision-making research and its relevance to actual juror decisions.

Association of depression with evolution of heart failure in patients with type 2 diabetes mellitus.

BACKGROUND: Depression is a prevalent, independent predictor of mortality in patients with heart failure (HF). Depression is also common in type 2 diabetes mellitus (T2DM), which is itself an important risk factor for HF. However, association of depression with incident HF in T2DM is undefined. The aim of the present study was to evaluate the predictive value of depression in predicting incident HF in a community-based cohort of asymptomatic patients with T2DM. METHODS: We prospectively recruited 274 asymptomatic T2DM patients ≥ 65 years (age 71 ± 4 year, 56% men) with preserved EF and no ischemic heart disease from a community-based population. The Patient Health Questionnaire 9 (PHQ-9) was used to detect depression, and LV dysfunction was sought with a comprehensive echocardiogram, including LV hypertrophy (LVH) and subclinical diastolic function (E/e'). Over a median follow-up of 1.5 years (range 0.5-3), 20 patients were lost to follow-up and 254 individuals were followed for outcomes. RESULTS: At baseline, depression was present in 9.5%, LVH was identified in 26% and reduced E/e' in 11%. Over a median follow-up of 1.5 years, 37 of 245 patients developed new-onset HF and 3 died, giving an event rate of 107/1000 person-years. In a competing-risks regression analysis, depression (adjusted HR 2.54, 95% CI 1.18-5.46; p = 0.017) was associated with incident HF and had incremental predictive power to clinical, biochemical and echocardiographic variables. CONCLUSION: Depression is prevalent in asymptomatic elderly patients with T2DM, and depression independently and incrementally predicts incident HF.

An emerging epidemic: cancer and heart failure.

Heart disease and cancer are the two leading causes of mortality globally. Cardiovascular complications of cancer therapy significantly contribute to the global burden of cardiovascular disease. Heart failure (HF) in particular is a relatively common and life-threatening complication. The increased risk is driven by the shared risk factors for cancer and HF, the direct impact of cancer therapy on the heart, an existing care gap in the cardiac care of patients with cancer and the increasing population of adult cancer survivors. The clear relationship between cancer treatment initiation and the potential for myocardial injury makes this population attractive for prevention strategies, targeted cardiovascular monitoring and treatment. However, there is currently no consensus on the optimal strategy for managing this at-risk population. Uniform treatment using cardioprotective medications may reduce the incidence of HF, but would impose frequently unnecessary and burdensome side effects. Ideally we could use validated risk-prediction models to target HF-preventive strategies, but currently no such models exist. In the present review, we focus on evidence and rationales for contemporary clinical decision-making in this novel field and discuss issues, including the burden of HF in patients with cancer, the reasons for the elevated risk and potential prevention strategies.

Blood Pressure Lowering in Patients With Central Hypertension: A Randomized Clinical Trial.

BACKGROUND: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. METHODS: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. RESULTS: At 24-months, there was a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m2; P=0.001) with intervention compared with control. Cuff and central BPs were lowered by a similar magnitude across all BP measurement modes (eg, clinic cuff systolic BP, -6.16 [-9.60 to -2.72] mm Hg and clinic central systolic BP, -4.96 [-8.06 to -1.86] mm Hg; P≥0.48 all). Secondary analyses found that changes in left ventricular mass index correlated to changes in BP, with the magnitude of effect nearly identical for BP measured by cuff (eg, 24-hour systolic BP, ß, 0.17 [0.02-0.31] g/m2) or centrally (24-hour systolic BP, ß, 0.16 [0.01-0.32] g/m2). CONCLUSIONS: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729.