Professor Aaron Sverdlov

Background: The mechanisms contributing to impaired neurocognitive performance in adults born with congenital heart disease (ACHD) are incompletely defined. Objectives: The authors performed a pilot study measuring novel biomarkers of blood-brain barrier integrity, angiogenesis, and endothelial function in patients with ACHD. Methods: Adults with congenital heart disease underwent biomarker assessment. Plasma levels of asymmetric dimethyl arginine, as a marker of endothelial dysfunction, vascular endothelial growth factor A, as a measure of angiogenesis, and S100B, as a biomarker of the integrity of the blood-brain barrier, were assayed. Results: A total of 70 patients were recruited with the average age of 43.6 years with 54% patients female. The majority of patients were considered to have moderate severity ACHD (43/70). S100B levels were undetectable in patients with mild ACHD and highest in the cohort with severe ACHD (4,551.9 pg/mL; P = 0.24). Patients with Fontan palliation (1,383.89 pg/mL) and those having undergone atrial switch repair (14,845.78 pg/mL) had the highest mean levels of S100B. Mean asymmetric dimethyl arginine levels were particularly elevated in patients with aortic coarctation surgery (358.10 ng/UL). Mean vascular endothelial growth factor levels were elevated across the spectrum of patients with ACHD, most notably in patients with moderate severity ACHD incorporating repaired tetralogy of Fallot (306.2 pg/mL vs 177.9 pg/mL [severe] and 145.0 pg/mL [mild]; P = 0.01). Conclusions: In a pilot study across the spectrum of ACHD, we note elevated levels of biomarkers that may improve the ability to more accurately identify neurological injury and impaired vascular function, which in turn may have implications with respect to cognitive function and cardiovascular sequelae.

The Internet of Medical Things (IoMT) is a network of interconnected medical devices and applications aiming to facilitate real-time data sharing and personalised patient care. IoMT devices collect vast amounts of data, which are then analysed using advanced computational methods. Real-time patient monitoring is crucial, particularly for people with chronic diseases and older adults. Moreover, traditional in-person monitoring by healthcare providers can be resource-intensive and time-consuming. By leveraging IoMT technology for remote patient monitoring (RPM), healthcare providers can improve service quality, reduce costs and enhance patient care. To evaluate the current state of knowledge and address research gaps in IoMT adoption for RPM, we conducted a thorough systematic literature review (SLR). This SLR aims to provide a comprehensive overview of existing research, identify knowledge gaps, and analyse the factors that influence IoMT adoption. It follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocol. PRISMA guidelines allow us to systematically evaluate and synthesise the current state of relevant literature. After analysing the theoretical models used in previous studies on IoMT adoption for RPM, UTAUT2 was identified as the most effective framework for technology adoption in this area. Additionally, this SLR has identified the key factors influencing the adoption of IoMT technology, including privacy, trust, security, and perceived risk, and suggested their inclusion in future studies by analysing and integrating the findings of other studies. As much of the current research focuses solely on patient viewpoints, our SLR points to the necessity of giving equal weight to the opinions of both patients and healthcare professionals. To create IoMT systems that are more effective and inclusive, these deficiencies must be filled. This study will benefit researchers, healthcare professionals, policymakers and technology developers by offering insights to inform decision-making, guide future research and aid the development of effective IoMT solutions for RPM.

Cancer and cardiovascular disease (CVD) commonly coexist, with increasing evidence that long-term cancer survivors are more likely to die from CVD than the general population. Effective management of CVD and its risk factors requires identification of patients at increased risk who may benefit from early intervention and their appropriate monitoring across the disease trajectory. Improving outcomes requires new models of multidisciplinary cancer care supported by care pathways. Such pathways require a clear delineation of the roles and responsibilities of all team members and provision of appropriate enablers for their delivery. These include accessible point-of-care tools/risk calculators, patient resources, and the provision of tailored training opportunities for health care providers.

Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality and residing in a rural and remote region is associated with an increased risk. The impact of rurality on CVD outcomes needs to be fully elucidated. Objectives: The purpose of this study was to assess the difference in mortality, readmission within 30 days, total readmissions, survival, and total emergency department (ED) presentations following an index CVD admission among patients from rural or remote areas as compared to metropolitan areas. Methods: This retrospective observational study included all index hospitalizations with heart failure (HF), atrial fibrillation (AF), or acute coronary syndrome (ACS) within the Hunter New England region of Australia, between January 1, 2008, and December 31, 2021. Results: There were 27,995 ACS admissions, 15,586 HF admissions, and 16,935 AF admissions. Patients from a rural or remote area presenting with CVD presentations had increased 30-day readmission (OR: 1.19; P < 0.001), an increased number of readmissions (incident rate ratio: 1.19; P < 0.001), and more ED presentations (incident rate ratio: 1.39; P < 0.001) as compared to patients from metropolitan areas. This was consistent across patients presenting with ACS, HF, and AF. There was no difference in mortality (HR: 1.01; P = 0.515). However, in the ACS subgroup, there was increased mortality in the rural and remote population (HR: 1.05; P = 0.015). Conclusions: This study highlights the increased incidence of ED presentations and hospital readmissions, for those living in rural Australia, illustrating the disparity in health care provided, and the ongoing need for interventions that address poorer access to specialized health care in the early discharge phase of hospitalization.

Background: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). Methods: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. Results: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041). Conclusions: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. Clinicaltrials.gov registration: NCT02600234, NCT03088033.

Background: Cancer therapeutics-related cardiac dysfunction (CTRCD) is a well-recognised complication of cancer treatment. Treatment of CTRCD involves cardioprotective therapy (CPT) which can lead to a recovery of CTRCD with normalisation of the left ventricular ejection fraction (LVEF). As a result, there are potentially millions of cancer survivors with recovered CTRCD on CPT. Cardioprotective therapy can be associated with an undesirable long-term pill burden, financial costs, and side effects. Cancer survivorship is anticipated to increase significantly by the end of this decade. To date, there is no evidence of the safety of stopping CPT in this setting. This study seeks to evaluate the hypothesis that ceasing cardioprotective medication is a feasible and safe option without significant impact on LVEF in low-risk patients who have recovered from CTRCD. Methods and Analysis: We will perform a multicentre prospective open-label randomised controlled trial with blinded endpoint (PROBE) of supervised CPT cessation compared to continuing CPT (control). The primary study end point is the change in LVEF by cardiac magnetic resonance imaging at 6 months of enrolment between the two groups. Secondary end points include changes in quality-of-life questionnaires, other cardiac imaging parameters, and recurrence of heart failure. Conclusion: Cessation Of Pharmacotherapy In Recovered Chemotherapy-induced cardioToxicity (COP-RCT) is one of the first studies currently underway to evaluate the safety of ceasing CPT in recovered CTRCD. The results will inform clinical practice in this evidence-free zone.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Background: Cancer and heart disease are the two most common health conditions in the world, associated with high morbidity and mortality, with even worse outcomes in regional areas. Cardiovascular disease is the leading cause of death in cancer survivors. We aimed to evaluate the cardiovascular outcomes of patients receiving cancer treatment (CT) in a regional hospital. Methods: This was an observational retrospective cohort study in a single rural hospital over a ten-year period (17th February 2010 to 19th March 2019). Outcomes of all patients receiving CT during this period were compared to those who were admitted to the hospital without a cancer diagnosis. Results: 268 patients received CT during the study period. High rates of cardiovascular risk factors: hypertension (52.2%), smoking (54.9%), and dyslipidaemia (38.4%) were observed in the CT group. Patients who had CT were more likely to be readmitted with ACS (5.9% vs. 2.8% p = 0.005) and AF (8.2% vs. 4.5% p = 0.006) when compared to the general admission cohort. There was a statistically significant difference observed for all cause cardiac readmission, with a higher rate observed in the CT group (17.1% vs. 13.2% p = 0.042). Patients undergoing CT had a higher rate of mortality (49.5% vs. 10.2%, p = 0.001) and shorter time (days) from first admission to death (401.06 vs. 994.91, p = 0.001) when compared to the general admission cohort, acknowledging this reduction in survival may be driven at least in part by the cancer itself. Conclusion: There is an increased incidence of adverse cardiovascular outcomes, including higher readmission rate, higher mortality rate and shorter survival in people undergoing cancer treatment in rural environments. Rural cancer patients demonstrated a high burden of cardiovascular risk factors.

Aims To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. Methods and results We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. Conclusion We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.

Australia's First Nations Peoples, Aboriginal and Torres Strait Islanders, have reduced life expectancy compared to the wider community. Cardiovascular diseases, mainly driven by ischaemic heart disease, are the leading contributors to this disparity. Despite over a third of First Nations Peoples living in New South Wales, the bulk of the peer-reviewed literature is from Central Australia and Far North Queensland. Regardless of the site of publication, First Nations Peoples are significantly younger at disease onset and have higher rates of comorbidities, in turn driving adverse health events. On top of this, very few First Nations Peoples specific cardiovascular interventions or programs have been shown to improve outcomes. The traditional biomedical model of care is less efficacious and non-traditional models of communication such as clinical yarning may benefit both clinicians and patients. The key purpose of this review is to highlight the deficiencies of our knowledge of cardiovascular burden of disease for First Nations Peoples; and to serve as a catalyst for more dedicated research. We need to have relationships with communities and concentrate on community improvement and partnerships. By involving First Nations Peoples researchers in collaboration with local communities in all levels of health care design and intervention will improve outcomes.

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1 -/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3¿6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Background: Given chronic disease is increasing among young women and unintended pregnancies among these women are associated with poor maternal and fetal outcomes, these women would benefit from effective preconception care. However, there is a lack of understanding of how these women use or don't use contraception to inform such interventions. This study examined patterns of contraceptive use among an Australian cohort of young women and investigated the influence of chronic disease on contraceptive use over time. Methods: Using data from 15,244 young women from the Australian Longitudinal Study on Women's Health (born 1989¿1995), latent transition analysis was performed to identify distinct contraceptive patterns among women who were at risk of an unintended pregnancy. Multinomial mixed-effect models were used to evaluate the relationship between contraceptive combinations and chronic disease. Results: Contraceptive use for women with cardiac and autoinflammatory diseases differed to women without chronic disease over the observation period. Compared to women without chronic disease using the pill, women with cardiac disease had double the odds of using 'other' contraception and condoms (OR = 2.20, 95% CI 1.34, 3.59) and a modest increase in the odds of using the combined oral contraceptive pill and condoms (OR = 1.39, 95% CI 1.03, 1.89). Compared to women without chronic disease who used the pill, women with autoinflammatory disease had increased odds of using LARC and condoms (OR = 1.58, 95% CI 1.04, 2.41), using 'other' contraception and condoms (OR = 1.69, 95% CI 1.11, 2.57), and using the¿combined oral contraceptive pill and condoms (OR = 1.38, 95% CI 1.09, 1.75). No differences in contraceptive patterns over the observation period were found for women with asthma or diabetes when compared to women without chronic disease. Conclusion: The findings identified a need for effective contraceptive counselling as part of routine chronic disease care and improved communication between health¿care providers and women with chronic disease to improve young women's contraceptive knowledge and agency in contraceptive choice, particularly for those with cardiac or autoinflammatory conditions. This may be the key to reducing high-risk unintended pregnancies among this vulnerable population.

Background: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. Methods: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II¿IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as ß blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. Findings: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65¿0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69¿1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52¿0·88]; pinteraction=0·18). A similar result was seen for ß blockers at doses of less than 50% of the target dose (HR 0·66 [0·54¿0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66¿1·00]; pinteraction=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus ß blocker plus MRA (given combination HR 0·73 [0·61¿0·88]; not given combination HR 0·76 [0·62¿0·94]; pinteraction=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. Interpretation: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. Funding: Boehringer Ingelheim and Eli Lilly and Company.

Background Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) is now the standard of care, but whether the demonstrated benefits of RM translate into improvements in heart failure (HF) management is controversial. This systematic review addresses the role of RM in patients with HF with a CIED. Methods and results A systematic search of the literature for randomised clinical trials in patients with HF and a CIED assessing efficacy/effectiveness of RM was performed using MEDLINE, PubMed and Embase. Meta-analysis was performed on the effects of RM of CIEDs in patients with HF on mortality and readmissions. Effects on implantable cardiac defibrillator (ICD) therapy, healthcare costs and clinic presentations were also assessed. 607 articles were identified and refined to 10 studies with a total of 6579 patients. Implementation of RM was not uniform with substantial variation in methodology across the studies. There was no reduction in mortality or hospital readmission rates, while ICD therapy findings were inconsistent. There was a reduction in patient-associated healthcare costs and reduction in healthcare presentations. Conclusion RM for patients with CIEDs and HF was not uniformly performed. As currently implemented, RM does not provide a benefit on overall mortality or the key metric of HF readmission. It does provide a reduction in healthcare costs and healthcare presentations. PROSPERO REGISTRATION NUMBER CRD42019129270.

Aims This study aims to (1) define the characteristics of patients with a first admission for heart failure (HF), stratified by type (reduced (HFrEF) vs preserved (HFpEF) ejection fraction) in a regional Australian setting; (2) compare the outcomes in terms of mortality and rehospitalisation and (3) assess adherence to the treatment guidelines. Methods We identified all index hospitalisations with HF to John Hunter Hospital and Tamworth Rural Referral Hospital in the Hunter New England Local Health District over a 12 months. We used the recent Australian HF guidelines to classify HFrEF and HFpEF and assess adherence to guideline-directed therapy. The primary outcome of the study was to compare short-term (1 year) and long-term all-cause mortality and the composite of all-cause hospitalisation or all-cause mortality of patients with HFrEF and HFpEF. Results There were 664 patients who had an index HF admission to John Hunter and Tamworth hospitals in 2014. The median age was 80 years, 47% were female and 22 (3%) were Aboriginal. In terms of HF type, 29% had HFrEF, 37% had HFpEF, while the remainder (34%) did not have an echocardiogram within 1 year of admission and could not be classified. The median follow-up was 3.3 years. HFrEF patients were predominantly male (64%) and in 48% the aetiology was ischaemic heart disease. The 1-year all-cause mortality was 23% in HFpEF subgroup and 29% in HFrEF subgroup (p=0.15). Five-year mortality was 61% in HFpEF and HFrEF patients. Of the HFrEF patients, only 61% were on renin-angiotensin-aldosterone blockers, 74% were on ß-blockers and 39% were on aldosterone antagonist. Conclusion HF patients are elderly and about evenly split between HFrEF and HFpEF. In this regional cohort, both HF types are associated with similar 1-year and 5-year mortality following incident HF hospitalisation. Echocardiography and guideline-directed therapies were underused.

Objective To assess the changes in cardiac hospitalisations, acute coronary syndromes (ACS) and out-of-hospital cardiac arrest (OOHCA) during COVID-19 isolation compared with prior time periods in an area of low COVID-19 disease incidence. Methods Review of all cardiology admissions, non-ST segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI) requiring urgent catheter laboratory activation and OOHCA. The 10-week period of government-imposed social isolation (23 March-31 May 2020) was compared with the same period in 2018, 2019 and a 10-week period prior to social isolation (6 January-15 March 2020). Incidence rate ratios were calculated. Symptom to balloon time was also compared for those requiring catheterisation laboratory activation for STEMI. Results The incidence of COVID-19 in the health district was 0.14 per 100 000 per day during the isolation period. There was a significant reduction in cardiology hospitalisations, NSTEMI and STEMI presentations without changes in OOHCA or symptom to balloon time for STEMI. Conclusions We observed a significant decline in cardiology presentations during social isolation without widespread COVID-19 disease. This provides further evidence for the important influence of social and behavioural factors on coronary event rates.

Purpose of Review: Breast cancer survival rate has greatly improved in the last two decades due to the emergence of next-generation anti-cancer agents. However, cardiotoxicity remains a significant adverse effect arising from traditional and emerging chemotherapies as well as targeted therapies for breast cancer patients. In this review, we will discuss cardiotoxicities of both traditional and emerging therapies for breast cancer. We will discuss current practices to detect cardiotoxicity of these therapies with the focus on new and emerging biomarkers. We will then focus on 'omics approaches, especially the use of epigenetics to discover novel biomarkers and therapeutics to mitigate cardiotoxicity. Recent Findings: Significant cardiotoxicities of conventional chemotherapies remain and new and unpredictable new forms of cardiac and/or vascular toxicity emerge with the surge in novel and targeted therapies. Yet, there is no clear guidance on detection of cardiotoxicity, except for significant left ventricular systolic dysfunction, and even then, there is no uniform definition of what constitutes cardiotoxicity. The gold standard for detection of cardiotoxicity involves a serial echocardiography in conjunction with blood-based biomarkers to detect early subclinical cardiac dysfunction. However, the ability of these tests to detect early disease remains limited and not all forms of toxicity are detectable with these modalities. Summary: There is an unprecedented need to discover novel biomarkers that are sensitive and specific for early detection of subclinical cardiotoxicity. In that space, novel echocardiographic techniques, such as strain, are becoming more common-place and new biomarkers, discovered by epigenetic approaches, seem to become promising alternatives or adjuncts to conventional non-specific cardiac biomarkers.

Radiation therapy is a key component of modern-day cancer therapy and can reduce the rates of recurrence and death from cancer. However, it can increase risk of cardiovascular (CV) events, and our understanding of the timeline associated with that risk is shorter than previously thought. Risk mitigation strategies, such as different positioning techniques, and breath hold acquisitions as well as baseline cardiovascular risk stratification that can be undertaken at the time of radiotherapy planning should be implemented, particularly for patients receiving chest radiation therapy. Primary and secondary prevention of cardiovascular disease (CVD), as appropriate, should be used before, during, and after radiation treatment in order to minimize the risks. Opportunistic screening for subclinical coronary disease provides an attractive possibility for primary/secondary CVD prevention and thus mitigation of long-term CV risk. More data on long-term clinical usefulness of this strategy and development of appropriate management pathways would further strengthen the evidence for the implementation of such screening. Clear guidelines in initial cardiovascular screening and cardiac aftercare following radiotherapy need to be formulated in order to integrate these measures into everyday clinical practice and policy and subsequently improve post-treatment morbidity and mortality for these patients.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Background: Ibrutinib increases the risk of atrial fibrillation (AF) and is associated with bleeding tendencies. Reported rates of arrhythmia are variable in different studies. The aim of the current analysis was to evaluate the incidence of AF in a single-center cohort of patients. Methods: This analysis was conducted at Hunter New England Local Health District, Australia between April 1, 2015 and June 30, 2017. We included all consecutive patients commenced on ibrutinib for hematological malignancies. Patients with a history of paroxysmal AF were excluded. The primary end point was incidence of AF. Time to diagnosis and management were secondary outcomes of interest. Results: A total of 24 patients (age 73¿±¿9 years, males n¿=¿16 [67%]) were commenced on ibrutinib treatment during the study period with chronic lymphocytic leukemia (n¿=¿21, 88%) as the main indication. During a median follow-up of 12 months, four (17%) patients were diagnosed with AF with increasing age, duration of ibrutinib treatment as associations. The median time to AF diagnosis was 9 (interquartile range [IQR]: 7-18) months. All patients were managed with a rate control strategy with beta blockers as the preferred agents. Three (75%) patients were commenced on anticoagulation for stroke prevention. During a follow-up of 18 (IQR: 17-23) months following AF onset, one patient required hospitalization for AF. There were no bleeding complications reported. Conclusions: In conclusion, this series noted a higher incidence of AF than previously reported. Oncologists and cardiologists need to be aware of the increased risk of AF in patients receiving ibrutinib.

Obesity, particularly visceral adiposity, has been linked to mitochondrial dysfunction and increased oxidative stress, which have been suggested as mechanisms of insulin resistance. The mechanism(s) behind this remains incompletely understood. In this study, we hypothesized that mitochondrial complex II dysfunction plays a role in impaired insulin sensitivity in visceral adipose tissue of subjects with obesity. We obtained subcutaneous and visceral adipose tissue biopsies from 43 subjects with obesity (body mass index = 30 kg/m 2 ) during planned bariatric surgery. Compared with subcutaneous adipose tissue, visceral adipose tissue exhibited decreased complex II activity, which was restored with the reducing agent dithiothreitol (5 mM) (P < 0.01). A biotin switch assay identified that cysteine oxidative posttranslational modifications (OPTM) in complex II subunit A (succinate dehydrogenase A) were increased in visceral vs. subcutaneous fat (P < 0.05). Insulin treatment (100 nM) stimulated complex II activity in subcutaneous fat (P < 0.05). In contrast, insulin treatment of visceral fat led to a decrease in complex II activity (P < 0.01), which was restored with addition of the mitochondria-specific oxidant scavenger mito-TEMPO (10 µ M). In a cohort of 10 subjects with severe obesity, surgical weight loss decreased OPTM and restored complex II activity, exclusively in the visceral depot. Mitochondrial complex II may be an unrecognized and novel mediator of insulin resistance associated with visceral adiposity. The activity of complex II is improved by weight loss, which may contribute to metabolic improvements associated with bariatric surgery.

Aims: Metabolic syndrome is associated with metabolic heart disease (MHD) that is characterized by left ventricular (LV) hypertrophy, interstitial fibrosis, contractile dysfunction, and mitochondrial dysfunction. Overexpression of catalase in mitochondria (transgenic expression of catalase targeted to the mitochondria [mCAT]) prevents the structural and functional features of MHD caused by a high-fat, high-sucrose (HFHS) diet for =4 months. However, it is unclear whether the effect of mCAT is due to prevention of reactive oxygen species (ROS)-mediated cardiac remodeling, a direct effect on mitochondrial function, or both. To address this question, we measured myocardial function and energetics in mice, with or without mCAT, after 1 month of HFHS, before the development of cardiac structural remodeling. Results: HFHS diet for 1 month had no effect on body weight, heart weight, LV structure, myocyte size, or interstitial fibrosis. Isolated cardiac mitochondria from HFHS-fed mice produced 2.2- to 3.8-fold more H2O2, and 16%-29% less adenosine triphosphate (ATP). In isolated beating hearts from HFHS-fed mice, [phosphocreatine (PCr)] and the free energy available for ATP hydrolysis (¿G~ATP) were decreased, and they failed to increase with work demands. Overexpression of mCAT normalized ROS and ATP production in isolated mitochondria, and it corrected myocardial [PCr] and ¿G~ATP in the beating heart. Innovation: This is the first demonstration that in MHD, mitochondrial ROS mediate energetic dysfunction that is sufficient to impair contractile function. Conclusion: ROS produced and acting in the mitochondria impair myocardial energetics, leading to slowed relaxation and decreased contractile reserve. These effects precede structural remodeling and are corrected by mCAT, indicating that ROS-mediated energetic impairment, per se, is sufficient to cause contractile dysfunction in MHD.

Background: Postoperative atrial fibrillation (POAF) is a frequent complication of coronary artery bypass graft (CABG) surgery. This arrhythmia occurs more frequently among patients who receive perioperative inotropic therapy (PINOT). Administration of nitrates with antiplatelet agents reduces the conversion rate of cyclic guanosine monophosphate to guanosine monophosphate. This process is associated with increased concentrations of free radicals, catecholamines, and blood plasma volume. We hypothesized that patients undergoing CABG surgery who receive PINOT may be more susceptible to POAF when nitrates are administered with antiplatelet agents. Methods: Clinical records were examined from a prospectively maintained cohort of 4,124 patients undergoing primary isolated CABG surgery to identify POAF-associated factors. Results: POAF risk was increased among patients receiving PINOT, and the greatest effect was observed when nitrates were administered with antiplatelet therapy. Adjustment for comorbidities did not substantively change the study results. Conclusions: Administration of nitrates with certain antiplatelet agents was associated with an increased POAF risk among patients undergoing CABG surgery. Additional studies are needed to determine whether preventive strategies such as administration of antioxidants will reduce this risk.