The intersection of heart failure and cancer in women: a review.

Cancer and cardiovascular disease represent the two leading causes of morbidity and mortality worldwide. Women continue to enjoy a greater life expectancy than men. However, this comes at a cost with more women developing diabetes, hypertension and coronary artery disease as they age. These traditional cardiovascular risk factors not only increase their lifetime risk of heart failure but also their overall risk of cancer. In addition to this, many of the cancers with female preponderance are treated with potentially cardiotoxic therapies, adding to their increased risk of developing heart failure. As a result, we are faced with a higher risk population, potentially suffering from both cancer and heart failure simultaneously. This is of particular concern given the coexistence of heart failure and cancer can confer a worse prognosis than either a single diagnosis of heart failure or cancer alone. This review article explores the intersection of heart failure and cancer in women at multiple levels, including traditional cardiovascular risk factors, cardiovascular toxicity derived from antineoplastic and radiation therapy, shared pathophysiology and HF as an oncogenic process. This article further identifies opportunities and strategies for intervention and optimisation, whilst highlighting the need for contemporary guidelines to better inform clinical practice.

Non-Vitamin K Antagonist Oral Anticoagulants versus Low Molecular Weight Heparin for Cancer-Related Venous Thromboembolic Events: Individual Patient Data Meta-Analysis.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan-Meier curves. Shared frailty, stratified Cox and Royston-Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan-Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50-0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40-0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49-0.86) for VTE recurrence. Stratified Cox and Royston-Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding.

Global Registry of Acute Coronary Events Score Underestimates Post-Acute Coronary Syndrome Mortality among Cancer Patients.

Background Patients with prior cancer are at increased risk of acute coronary syndrome (ACS) with poorer post-ACS outcomes. We aimed to ascertain if the Global Registry of Acute Coronary Events (GRACE) score accurately predicts mortality risk among patients with ACS and prior cancer. Methods We linked nationwide ACS and cancer registries from 2007 to 2018 in Singapore. A total of 24,529 eligible patients had in-hospital and 1-year all-cause mortality risk calculated using the GRACE score (2471 prior cancer; 22,058 no cancer). Results Patients with prior cancer had two-fold higher all-cause mortality compared to patients without cancer (in-hospital: 22.8% versus 10.3%, p < 0.001; 1-year: 49.0% vs. 18.7%, p < 0.001). Cardiovascular mortality did not differ between groups (in-hospital: 5.2% vs. 4.8%, p = 0.346; 1-year: 6.9% vs. 6.1%, p = 0.12). The area under the receiver operating characteristic curve of the GRACE score for prediction of all-cause mortality was less for prior cancer (in-hospital: 0.64 vs. 0.80, p < 0.001; 1-year: 0.66 vs. 0.83, p < 0.001). Among patients with prior cancer and a high-risk GRACE score > 140, in-hospital revascularization was not associated with lower cardiovascular mortality than without in-hospital revascularization (6.7% vs. 7.6%, p = 0.50). Conclusions The GRACE score performs poorly in risk stratification of patients with prior cancer and ACS.

Rationale and Design of the Cessation Of Pharmacotherapy In Recovered Chemotherapy-induced cardioToxicity (COP-RCT): A Pilot Study.

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.

Comparing Renin-Angiotensin-Aldosterone Blockade Regimens for Long-Term Chemotherapy-Related Cardiac Dysfunction: A Network Meta-Analysis.

PURPOSE: Cancer therapies including trastuzumab and anthracyclines are cardiotoxic and cause cardiac dysfunction. To prevent cardiotoxicity, pharmacological agents used in heart failure have been administered concomitantly with cardiotoxic cancer therapy, but few studies to date have performed a head-to-head comparison of these different agents. This systematic review and network meta-analysis of randomized-controlled trials aims to evaluate the efficacy of renin-angiotensin-aldosterone system (RAAS) blockers, namely angiotensin-converting enzyme inhibitors (ACE-Is), aldosterone receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), in primary prevention against chemotherapy-related cardiac dysfunction in patients receiving anthracyclines and/or trastuzumab. METHODS: A systematic search was performed in major web databases for studies from inception to 15 September 2022. A Bayesian network meta-analysis model was used to assess the relative effects of competing treatments on the primary outcomes of risk of significant decline in left ventricular ejection fraction (LVEF) and mean LVEF decline. Secondary outcomes included left ventricular diastolic function, global longitudinal strain, and cardiac biomarkers. This study is registered with PROSPERO, CRD42022357980. RESULTS AND CONCLUSION: Nineteen studies reported the effects of 13 interventions (N = 1905 patients). Only enalapril (RR 0.05, 95% CI 0.00-0.20) was associated with reduced risk of patients developing significant decline in LVEF relative to placebo. Subgroup analysis showed that the beneficial effect of enalapril was driven by protection against anthracycline-associated toxicity. In addition, no RAAS-inhibiting agents showed efficacy in protection against treatment with both anthracycline and trastuzumab. The use of RAAS inhibition therapy did not conclusively impact on other markers of cardiac function, including left ventricular diastolic function and cardiac biomarkers.

Advancing Cardio-Oncology in Asia.

Cardio-oncology is an emerging multi-disciplinary field, which aims to reduce morbidity and mortality of cancer patients by preventing and managing cancer treatment-related cardiovascular toxicities. With the exponential growth in cancer and cardiovascular diseases in Asia, there is an emerging need for cardio-oncology awareness among physicians and country-specific cardio-oncology initiatives. In this state-of-the-art review, we sought to describe the burden of cancer and cardiovascular disease in Asia, a region with rich cultural and socio-economic diversity. From describing the uniqueness and challenges (such as socio-economic disparity, ethnical and racial diversity, and limited training opportunities) in establishing cardio-oncology in Asia, and outlining ways to overcome any barriers, this article aims to help advance the field of cardio-oncology in Asia.

Natural Progression of Left Ventricular Function following Anthracyclines without Cardioprotective Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Anthracyclines form the backbone of many systemic chemotherapy regimens but are accompanied by dose-limiting cardiotoxicity. We elucidate the progression and severity of cardiac function over time, in the absence of cardioprotection, which less is known about. METHODS: This PRISMA-guideline-adherent review was registered on PROSPERO (CRD42022373496). RESULTS: 26 studies met the eligibility criteria including a total of 910 patients. The overall reduction in post-anthracycline pooled mean left ventricular ejection fraction (LVEF) in placebo arms of the included randomised-controlled trials was 4.5% (95% CI, 2.6 to 6.4). The trend in LVEF showed a progressive decline until approximately 180 days, after which there was no significant change. Those receiving a cumulative anthracycline dose of 300 mg/m2 experienced a more profound reduction. The overall pooled risk of a 10% absolute decline in LVEF from baseline, or a decline to an LVEF below 50%, was 17% (95% CI: 11 to 24; I2 = 71%). Sensitivity analyses of baseline LVEF and trastuzumab treatment status did not yield significant differences. CONCLUSION: While the mean LVEF decline in patients without cardioprotective therapy was clinically small, a vulnerable subset experienced significant impairment. Further research to best identify those who benefit most from cardioprotective therapies when receiving anthracyclines is required.

Prior Cancer Is Associated with Lower Atherosclerotic Cardiovascular Disease Risk at First Acute Myocardial Infarction.

Background: Patients with cancer are at increased risk of acute myocardial infarction (AMI). It is unclear if the Atherosclerotic Cardiovascular Disease (ASCVD) risk score at incident AMI is reflective of this higher risk in patients with prior cancer than those without. Methods: We linked nationwide AMI and cancer registries from 2008 to 2019. A total of 18,200 eligible patients with ASCVD risk score calculated at incident AMI were identified (1086 prior cancer; 17,114 no cancer). Results: At incident AMI, age-standardized mean ASCVD risk was lower in the prior cancer group (18.6%) than no cancer group (20.9%) (p < 0.001). Prior to incident AMI, smoking, hypertension, hyperlipidemia and diabetes mellitus were better controlled in the prior cancer group. However post-AMI, prior cancer was associated with lower guideline-directed medical therapy usage and higher all-cause mortality (adjusted hazard ratio 1.85, 95% confidence interval 1.66−2.07). Conclusions: AMI occurred despite better control of cardiovascular risk factors and lower age-standardized estimated mean 10-year ASCVD risk among patients with prior cancer than no cancer. Prior cancer was associated with lower guideline-directed medical therapy post-AMI and higher mortality.

Lipid profiles and outcomes of patients with prior cancer and subsequent myocardial infarction or stroke.

Patients with cancer are at increased risk of myocardial infarction (MI) and stroke. Guidelines do not address lipid profile targets for these patients. Within the lipid profiles, we hypothesized that patients with cancer develop MI or stroke at lower low density lipoprotein cholesterol (LDL-C) concentrations than patients without cancer and suffer worse outcomes. We linked nationwide longitudinal MI, stroke and cancer registries from years 2007-2017. We identified 42,148 eligible patients with MI (2421 prior cancer; 39,727 no cancer) and 43,888 eligible patients with stroke (3152 prior cancer; 40,738 no cancer). Median LDL-C concentration was lower in the prior cancer group than the no cancer group at incident MI [2.43 versus 3.10 mmol/L, adjusted ratio 0.87 (95% CI 0.85-0.89)] and stroke [2.81 versus 3.22 mmol/L, adjusted ratio 0.93, 95% CI 0.91-0.95)]. Similarly, median triglyceride and total cholesterol concentrations were lower in the prior cancer group, with no difference in high density lipoprotein cholesterol. Prior cancer was associated with higher post-MI mortality [adjusted hazard ratio (HR) 1.48, 95% CI 1.37-1.59] and post-stroke mortality (adjusted HR 1.95, 95% CI 1.52-2.52). Despite lower LDL-C concentrations, patients with prior cancer had worse post-MI and stroke mortality than patients without cancer.

Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study.

The utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) utility in predicting immune-related adverse events (irAEs) and survival have not been well studied in the context of treatment with immune checkpoint inhibitors (ICIs). We performed a case-control study of cancer patients who received at least one dose of ICI in a tertiary hospital. We examined NLR and PLR in irAE cases and controls. Logistic and Cox regression models were used to identify independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). The study included 91 patients with irAEs and 56 controls. Multiple logistic regression showed that NLR < 3 at baseline was associated with higher occurrence of irAEs. Multivariate Cox regression showed that development of irAEs and reduction in NLR from baseline to week 6 were associated with longer PFS. Higher NLR values at baseline and/or week 6 were independently associated with shorter OS. A reduction in NLR from baseline to week 6 was associated with longer OS. In this study of cancer patients treated with ICIs, NLR has a bidirectional relationship with adverse outcomes. Lower NLR was associated with increased occurrence of irAEs while higher NLR values were associated with worse clinical outcomes.

Chemotherapy and adverse cardiovascular events in colorectal cancer patients undergoing surgical resection.

BACKGROUND: Colorectal cancer patients undergoing surgical resection are at increased short-term risk of post-operative adverse events. However, specific predictors for long-term major adverse cardiac and cerebrovascular events (MACCE) are unclear. We hypothesised that patients who receive chemotherapy are at higher risk of MACCE than those who did not. METHODS: In this retrospective study, 412 patients who underwent surgical resection for newly diagnosed colorectal cancer from January 2013 to April 2015 were grouped according to chemotherapy status. MACCE was defined as a composite of cardiovascular death, myocardial infarction, stroke, unplanned revascularisation, hospitalisation for heart failure or angina. Predictors of MACCE were identified using competing risks regression, with non-cardiovascular death a competing risk. RESULTS: There were 200 patients in the chemotherapy group and 212 patients in the non-chemotherapy group. The overall prevalence of prior cardiovascular disease was 20.9%. Over a median follow-up duration of 5.1 years from diagnosis, the incidence of MACCE was 13.3%. Diabetes mellitus and prior cardiovascular disease were associated with an increased risk of MACCE (subdistribution hazard ratio, 2.56; 95% CI, 1.48-4.42) and 2.38 (95% CI, 1.36-4.18) respectively. The chemotherapy group was associated with a lower risk of MACCE (subdistribution hazard ratio, 0.37; 95% CI, 0.19-0.75) compared to the non-chemotherapy group. CONCLUSIONS: Amongst colorectal cancer patients undergoing surgical resection, there was a high incidence of MACCE. Diabetes mellitus and prior cardiovascular disease were associated with an increased risk of MACCE. Chemotherapy was associated with a lower risk of MACCE, but further research is required to clarify this association.

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.

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.

Activity and outcomes of a cardio-oncology service in the United Kingdom-a five-year experience.

AIMS: Cardio-oncology clinics optimise the cardiovascular status of cancer patients but there is a limited description of their structure, case mix, activity and results. The purpose of this paper is to describe the activity and outcomes of a cardio-oncology service, particularly with respect to supporting optimal cancer treatment and survival. METHODS AND RESULTS: We prospectively studied patients referred to our service from February 2011 to February 2016. New York Heart Association (NYHA) class and parameters of cardiac function were measured at baseline and after optimisation by our service. Up-titration of cardiac treatment, continuation of cancer therapy and mortality were used as outcome measures. Of the 535 patients (55.8% females) referred, rates of cardiotoxicity for anthracyclines, anti-HER2 agents and tyrosine kinase inhibitors were 75.8%, 69.8% and 62.1%, respectively. Patients with left ventricular systolic dysfunction (LVSD) (n =128) were younger, had higher rates of hypertension and previous exposure to chemotherapy/radiotherapy (P < 0.001). At a median follow-up of 360 days, 93.8% of the patients with LVSD showed improvement in left ventricular ejection fraction (45% pre vs. 53% post; P < 0.001) and NYHA class (NYHA III-IV in 22% pre vs. 10% post; P = 0.01). All patients with normal left ventricular ejection fraction and biochemical or functional myocardial toxicity and 88% of patients with LVSD were deemed fit for continuation of cancer therapy after cardiovascular optimisation. CONCLUSIONS: Through the establishment of a cardio-oncology service, it is feasible to achieve high rates of cardiac optimisation and cancer treatment continuation.

Role of Biomarkers in Prediction of Cardiotoxicity During Cancer Treatment.

PURPOSE OF REVIEW: As cancer survivor rates improve with early screening and modern treatment options, cardiotoxicity is becoming an increasing problem. It is imperative for physicians to recognize adverse events early so that appropriate measures can be taken before advanced and permanent cardiac dysfunction ensues. In this review, we will evaluate the literature surrounding current cardiac biomarkers in the detection of cardiotoxicity during cancer treatment as well as discuss the role of emerging novel biomarkers. RECENT FINDINGS: Troponin and brain natriuretic peptides show promise in the detection of subclinical cardiotoxicity during cancer treatment. In addition to identifying late complications among cancer survivors, they have the potential to predict patients who are at risk of developing cardiotoxicity prior to the initiation of cancer therapy. However, there are also conflicting data due to varying study design. Although biomarkers are an attractive option in the detection of cardiotoxicity among cancer patients, current recommendations surrounding its role are based on expert consensus opinion. Further research with appropriately designed prospective trials is required to guide optimal clinical practice.

Analysis of long non-coding RNA expression profiles in clear cell renal cell carcinoma.

To investigate the expression patterns of long non-coding RNAs (lncRNAs) in clear cell renal cell carcinoma (ccRCC) and in metastatic renal cell carcinoma (RCC), the present study downloaded three human exon arrays available from the public Gene Expression Omnibus. The probes of the human exon arrays were re-annotated and the probes uniquely mapping to lncRNAs were retained at the gene level. Following the analysis of GSE53757 and GSE46699, which contained paired ccRCC cancer and normal adjacent tissue samples, 32 differentially expressed lncRNAs (adjusted P<0.01) in ccRCC were identified. Various lncRNAs, including ENSG00000177133, NR_024418, T-cell leukemia/lymphoma 6 (TCL6), growth arrest-specific transcript 5, deleted in lymphocytic leukemia 2, colorectal neoplasia differentially expressed (CRNDE) and MIR155HG, have been reported to be abnormally expressed in cancers. Of these genes, NR_24418 and TCL6 have been reported to be associated with ccRCC. Following analysis of GSE47352, which contained 4 primary metastatic and 5 non-metastatic tumor samples, the 50 top differentially expressed lncRNAs were identified in metastatic ccRCC (Mann-Whitney U test, P<0.05). Comparison with the ccRCC associated lncRNAs revealed that the lncRNA CRNDE demonstrated an increased expression in ccRCC and metastatic ccRCC samples, which suggested that CRNDE is important in the progression of ccRCC. The lncRNA ENSG00000244020 was decreased in ccRCC and metastatic ccRCC, suggesting that silencing of ENSG00000244020 may be important in ccRCC development. Overall, a set of lncRNAs was identified as differentially expressed in ccRCC and metastatic ccRCC, providing potential candidates for the discovery of novel cancer biomarkers and therapeutic targets to improve diagnosis and therapy in RCC.