Cardiovascular disease and cancer are the two leading causes of morbidity and mortality in the world. The emerging field of cardio-oncology has revealed that these seemingly disparate disease processes are intertwined, owing to the cardiovascular sequelae of anticancer therapies, shared risk factors that predispose individuals to both cardiovascular disease and cancer, as well the possible potentiation of cancer growth by cardiac dysfunction. As a result, interest has increased in understanding the fundamental biological mechanisms that are central to the relationship between cardiovascular disease and cancer. Metabolism, appropriate regulation of energy, energy substrate utilization, and macromolecular synthesis and breakdown are fundamental processes for cellular and organismal survival. In this Review, we explore the emerging data identifying metabolic dysregulation as an important theme in cardio-oncology. We discuss the growing recognition of metabolic reprogramming in cardiovascular disease and cancer and view the novel area of cardio-oncology through the lens of metabolism.

AIMS: There are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF). METHODS AND RESULTS: Transcriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice. Based on this observation, serum levels of three well-known IC ligands (i.e. sPD-L1, sPD-L2 and galectin-9) were measured in stable HF patients from the Vitamin D Chronic Heart Failure (VitD-CHF) study (n = 101), as well as healthy individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (n = 58). sPD-L1, sPD-L2, and galectin-9 were all associated with New York Heart Association classification. In multivariate linear regression analyses, all three IC ligands were associated with galectin-3 (β = 0.230, β = 0.283, and β = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (β = 0.386 and β = 0.314). Regarding prognosis, higher serum levels of sPD-L1 and galectin-9 were significantly associated with increased risk for HF hospitalization and all-cause mortality [hazard ratio 1.69 (1.09-2.59) and hazard ratio 1.50 (1.06-2.12)]. Furthermore, the importance of IC ligands was tested in another stage of HF, namely worsening HF patients. In the worsening HF cohort (The BIOlogy Study to Tailored Treatment in Chronic Heart Failure) (n = 2032), sPD-L2 and galectin-9 were associated with New York Heart Association classification and significantly predicted outcome with an increased relative risk of 15% and 20%, after multivariable adjustment, respectively. CONCLUSIONS: IC ligands are expressed in cardiac disease models, and serum levels of IC ligands are elevated in HF patients, are associated with disease severity, and significantly predict prognosis. These data indicate a potential role for IC ligands in HF pathogenesis.

Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.

Aims

Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF.

Methods and results

The biological variability of established biomarkers [NT-proBNP and high-sensitivity troponin T (hsTnT)], novel biomarkers [galectin-3, suppression of tumorigenicity 2 (ST2), and growth differentiation factor 15 (GDF-15)], and renal/neurohormonal biomarkers (aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) was determined in 28 healthy subjects and 83 HF patients, over a period of 4 months and 6 weeks, respectively. The analytical (CV_a ), intraindividual (CV_i ), and interindividual (CV_g ) variations were calculated, as well as the reference change value (RCV), which reflects the percentage of change that may indicate a 'relevant' change. All crude biomarker levels were significantly increased or decreased in HF patients compared with controls (all P < 0.01). Variation indices were comparable in healthy individuals and HF patients. CV_i was not influenced by the individual levels of the biomarker itself. NT-proBNP and GDF-15 had relatively high CV_i (21.8% and 16.6%) and RCV (61.7% and 64.3%), whereas ST2 (CV_i , 15.0; RCV, 42.9%), hsTnT (CV_i , 11.1; RCV, 31.4%), and galectin-3 (CV_i , 8.1; RCV, 25.0%) had lower indices of variation.

Conclusion

Biological variation indices are comparable between healthy subjects and HF patients for a broad spectrum of biomarkers. NT-proBNP and GDF-15 have substantial variation, with lower variation for ST2, hsTnT, and galectin-3. These data are instrumental in proper interpretation of biomarker levels in HF patients.

Background

Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear.

Objectives

The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer.

Methods

FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models.

Results

Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all).

Conclusions

Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

Aims

While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

Methods and results

We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).

Conclusions

We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

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.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Background

The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods

Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results

We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.

Conclusions

Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.