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.

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

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.

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.

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.

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.

Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.

Men placed on waiting lists for psychiatric admission from Irish Prisons over five years: Clinical outcomes during a forensic "bed crisis".

BACKGROUND: Ireland has low provision rates of general and forensic beds compared with other western countries. In recent years there have been difficulties and delays in accessing forensic beds for prisoners with severe mental illness. AIMS: We aimed to determine clinical outcomes for male prisoners assessed as requiring psychiatric admission over an extended period, with time frames for admission and other outcomes. We aimed to determine whether admissions to forensic and non-forensic locations were risk-appropriate. METHODS: Participants included all male prisoners placed on psychiatric admission waiting lists in Ireland over five years 2015-2019. We described demographic, clinical and offending variables. We measured clinical outcomes including forensic admission, other admission and recovery with voluntary treatment in prison. We also measured times to clinical outcomes. Security requirements and clinical urgency were assessed using the DUNDRUM Toolkit scales 1 and 2. RESULTS: 541 male prisoners were placed on admission waiting lists and spent an aggregate of over 114 years on admission waiting lists during 2015-2019. Almost one quarter improved with voluntary treatment allowing removal from waiting lists, while over 75% did not. Admission was achieved for a majority of cases, albeit after lengthy delays for some. The most frequent outcome was diversion from remand to non-forensic inpatient settings. Non-forensic admissions arranged by the Prison Inreach and Court Liaison Service (PICLS) at Ireland's main remand prison at Cloverhill contributed 54% (179/332) of all admissions achieved and 76% (179/235) of all non-forensic admissions from prison waiting list. Median delay to admission was 59 days for forensic admissions and 69 days for admissions to non-forensic hospitals from sentenced settings, compared with 16.5 days for admissions to non-forensic hospitals from remand. CONCLUSIONS: Long delays for forensic admission during a five-year period of limited access to such beds were partly mitigated by transfers to non-forensic hospitals, mainly diversion of minor offenders from remand settings.

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.

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.

Screening for Coronary Artery Disease in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review.

Coronary artery disease (CAD) is an important contributor to the cardiovascular burden in cancer survivors. This review identifies features that could help guide decisions about the benefit of screening to assess the risk or presence of subclinical CAD. Screening may be appropriate in selected survivors based on risk factors and inflammatory burden. In cancer survivors who have undergone genetic testing, polygenic risk scores and clonal hematopoiesis markers may become useful CAD risk prediction tools in the future. The type of cancer (especially breast, hematological, gastrointestinal, and genitourinary) and the nature of treatment (radiotherapy, platinum agents, fluorouracil, hormonal therapy, tyrosine kinase inhibitors, endothelial growth factor inhibitors, and immune checkpoint inhibitors) are also important in determining risk. Therapeutic implications of positive screening include lifestyle and atherosclerosis interventions, and in specific instances, revascularization may be indicated.

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.

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.

Prognostic Value of Exercise Capacity in Kidney Transplant Candidates.

Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age- and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29-0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30-0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32-1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42-2.25], P=0.95). Conclusions Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

Novel Non-pharmaceutical Advancements in Heart Failure Management: The Emerging Role of Technology.

PURPOSE OF REVIEW: To summarise and discuss the implications of recent technological advances in heart failure care. RECENT FINDINGS: Heart failure remains a significant source of morbidity and mortality in the US population despite multiple classes of approved pharmacological treatments. Novel cardiac devices and technologies may offer an opportunity to improve outcomes. Baroreflex Activation Therapy and Cardiac Contractility Remodelling may improve myocardial contractility by altering neurohormonal stimulation of the heart. Implantable Pulmonary Artery Monitors and Biatrial Shunts may prevent heart failure admissions by altering the trajectory of progressive congestion. Phrenic Nerve Stimulation offers potentially effective treatment for comorbid conditions. Smartphone applications offer an intriguing strategy for improving medication adherence. SUMMARY: Novel heart failure technologies offer promise for reducing this public health burden. Randomized controlled studies are indicated for assessing the future role of these novel therapies.