Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

[BLITZ-AF Cancer study: an international observational research project on patients with atrial fibrillation and cancer]. / Studio BLITZ-AF Cancer: un progetto di ricerca osservazionale internazionale sui pazienti con fibrillazione atriale e cancro.

BACKGROUND: Cancer is an important condition associated with the development of atrial fibrillation (AF). The objectives of the BLITZ-AF Cancer study were to collect real-life information on the clinical profile and use of antithrombotic drugs in patients with AF and cancer to improve clinical management, as well as the evaluation of the association between different antithrombotic treatments (or their absence) and the main clinical events. METHODS: European multinational, multicenter, prospective, non-interventional study conducted in patients with AF (electrocardiographically confirmed) and cancer occurring within 3 years. The CHA2DS2-VASc and the HAS-BLED scores were calculated in all enrolled patients. RESULTS: From June 2019 to July 2021, 1514 patients were enrolled, 36.5% women, from 112 cardiology departments in 6 European countries (Italy, Belgium, the Netherlands, Spain, Portugal and Ireland). Italy enrolled 971 patients in 77 centers. Average age of patients was 74 ± 9 years, of which 20.9% affected by heart failure, 18.1% by ischemic heart disease, 9.8% by peripheral arterial disease and 38.5% by valvular diseases; 41.5% of patients had a CHA2DS2-VASc score ≥4. The most represented cancer sites were lung (14.9%), colorectal tract (14.1%), prostate (8.8%), or non-Hodgkin's lymphoma (8.1%). Before enrollment, 16.6% of patients were not taking antithrombotic therapy, while 22.7% were on therapy with antiplatelet agents and/or low molecular weight heparin. After enrollment these percentages decreased to 7.7% and 16.6%, respectively and, at the same time, the percentage of patients on direct oral anticoagulant (DOAC) therapy increased from 48.4% to 68.4%, also to the detriment of those on vitamin K antagonist therapy. CONCLUSIONS: The BLITZ-AF Cancer study, which enrolled patients diagnosed with AF and cancer, highlights that the use of DOACs by cardiologists in this clinical context has increased, even though the guidelines on AF do not give accurate indications about oral anticoagulant therapy in patients with cancer.

Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Association of inflammatory markers with incident heart failure or cancer in the HUNT3 and Health ABC population studies.

AIMS: To investigate the relationship between chronic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) levels, and incident heart failure (HF) or cancer. METHODS: We assessed the relationship between baseline hsCRP concentrations and subsequent HF or cancer in two community-based cohorts, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (ABC) study. In the latter, the analysis was replicated with interleukin (IL)-1, IL-6, or tumour necrosis factor (TNF)-α instead of hsCRP. RESULTS: In HUNT3, hsCRP was measured in 47,163 subjects (mean age 52.3 ± 15.8 years). During a median follow-up of 12.1 years, 2,034 (4.3%) individuals developed HF and 5,024 (10.7%) cancer, with 442 (0.9%) being diagnosed with both. After adjusting for age, male sex, diabetes, obesity, previous or current smoking, and comorbidities, elevated baseline hsCRP was associated with a higher risk of HF or cancer (HR 1.09; 95%CI, 1.07-1.10). In the Health ABC study, hsCRP levels were assessed in 2,803 participants, who had a mean age of 72.6 ± 2.9 years and a higher burden of comorbidities than in HUNT3. During a median follow-up of 8.2 years, HF and cancer were diagnosed in 346 (12.3%) and 776 (27.7%) subjects, respectively, with 77 (2.7%) having both conditions. After adjusting for the same variables used for the HUNT3 cohort, hsCRP remained significantly associated with incident HF or cancer (HR 1.11; 95%CI, 1.05-1.18), as were IL-1 (HR 1.15; 1.07-1.24), IL-6 (HR 1.09; 1.02-1.17), and TNF-α (HR 1.15; 1.07-1.24). CONCLUSIONS: A state of chronic, low-grade inflammation captured by an increase in hsCRP levels is associated with an increased risk of developing HF or cancer, with potential implications for clinical trials with anti-inflammatory therapies.

There is an increasing recognition that cardiovascular (CV) risk factors portend an increased risk of both heart failure (HF) and cancer. Chronic, low-grade inflammation might represent a shared pathogenic pathway underlying the association between these risk factors, HF, and malignancy. The biomarker high-sensitivity C-reactive protein (hsCRP) might add prognostic information on CV and cancer risk by capturing this inflammatory state. In this study we analysed the association of inflammation, as assessed by baseline measurement of hsCRP, and the risk of developing HF and cancer in two community-based prospective studies, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (Health ABC) study.In these cohorts, comprising more than 50,000 individuals, inflammation at baseline was associated with an increased risk of incident HF or cancer during a median follow-up of 8-12 years, after adjusting for traditional risk factors and comorbidities.In the Health ABC study sample, three inflammatory markers other than hsCRP, namely interleukin (IL)-1, IL-6, or tumour necrosis factor α, performed similarly to hsCRP in predicting the risk of incident HF or cancer. These results provide insights into the interconnection between HF and cancer and reinforce the concept that low-grade, chronic inflammation promotes the development of both HF and cancer and, thereby, might be targeted for prevention of either condition. Furthermore, our findings confirm the reliability of hsCRP as a biomarker to select individuals who may benefit from anti-inflammatory treatments to reduce CV and cancer events.

Ischaemic heart disease in patients with cancer.

Cardiologists are encountering a growing number of cancer patients with ischaemic heart disease (IHD). Several factors account for the interrelationship between these two conditions, in addition to improving survival rates in the cancer population. Established cardiovascular (CV) risk factors, such as hypercholesterolaemia and obesity, predispose to both IHD and cancer, through specific mechanisms and via low-grade, systemic inflammation. This latter is also fuelled by clonal haematopoiesis of indeterminate potential. Furthermore, experimental work indicates that IHD and cancer can promote one another, and the CV or metabolic toxicity of anticancer therapies can lead to IHD. The connections between IHD and cancer are reinforced by social determinants of health, non-medical factors that modify health outcomes and comprise individual and societal domains, including economic stability, educational and healthcare access and quality, neighbourhood and built environment, and social and community context. Management of IHD in cancer patients is often challenging, due to atypical presentation, increased bleeding and ischaemic risk, and worse outcomes as compared to patients without cancer. The decision to proceed with coronary revascularization and the choice of antithrombotic therapy can be difficult, particularly in patients with chronic coronary syndromes, necessitating multidisciplinary discussion that considers both general guidelines and specific features on a case by case basis. Randomized controlled trial evidence in cancer patients is very limited and there is urgent need for more data to inform clinical practice. Therefore, coexistence of IHD and cancer raises important scientific and practical questions that call for collaborative efforts from the cardio-oncology, cardiology, and oncology communities.

Mandatory role of endoplasmic reticulum and its pentose phosphate shunt in the myocardial defense mechanisms against the redox stress induced by anthracyclines.

Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD-/-). Twenty-eight wildtype (WT) and 32 H6PD-/- mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca2+-ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD-/- died. At microPET, DXR-H6PD-/- survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD-/- condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity.

European Society of Cardiology Core Curriculum for cardio-oncology.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.

Direct Oral Anticoagulants for Cancer-Associated Venous Thromboembolism.

PURPOSE OF REVIEW: To present the randomized controlled trial (RCT) evidence and highlight the areas of uncertainty regarding direct oral anticoagulants (DOAC) for cancer-associated venous thromboembolism (CAT). RECENT FINDINGS: In the last years, four RCTs have shown that rivaroxaban, edoxaban, and apixaban are at least as effective as low-molecular-weight heparin (LMWH) for the treatment of both incidental and symptomatic CAT. On the other hand, these drugs increase the risk of major gastrointestinal bleeding in patients with cancer at this site. Another two RCTs have demonstrated that apixaban and rivaroxaban also prevent CAT in subjects at intermediate-to-high risk commencing chemotherapy, albeit at the price of higher likelihood of bleeding. By contrast, data are limited about the use DOAC in individuals with intracranial tumors or concomitant thrombocytopenia. It is also possible that some anticancer agents heighten the effects of DOAC via pharmacokinetic interactions, up to making their effectiveness-safety profile unfavorable. Leveraging the results of the aforementioned RCTS, current guidelines recommend DOAC as the anticoagulants of choice for CAT treatment and, in selected cases, prevention. However, the benefit of DOAC is less defined in specific patient subgroups, in which the choice of DOAC over LMWH should be carefully pondered.

Differential expression of epigenetic modifiers in early and late cardiotoxic heart failure reveals DNA methylation as a key regulator of cardiotoxicity.

Background: Anthracycline-induced cardiotoxicity is a well-known serious clinical entity. However, detailed mechanistic insights on how short-term administration leads to late and long-lasting cardiotoxicity, are still largely undiscovered. We hypothesize that chemotherapy provokes a memory effect at the level of epigenomic DNA modifications which subsequently lead to cardiotoxicity even years after cessation of chemotherapy. Methods: We explored the temporal evolution of epigenetic modifiers in early and late cardiotoxicity due to anthracyclines by means of RNA-sequencing of human endomyocardial left ventricular biopsies and mass spectrometry of genomic DNA. Based on these findings, validation of differentially regulated genes was obtained by performing RT-qPCR. Finally, a proof-of-concept in vitro mechanistic study was performed to dissect some of the mechanistic aspects of epigenetic memory in anthracycline-induced cardiotoxicity. Results: Correlation of gene expression between late and early onset cardiotoxicity revealed an R 2 value of 0.98, demonstrating a total of 369 differentially expressed genes (DEGs, FDR < 0.05). of which 72% (n = 266) were upregulated, and 28% of genes, (n = 103) downregulated in later as compared to earlier onset cardiotoxicity. Gene ontology analysis showed significant enrichment of genes involved in methyl-CpG DNA binding, chromatin remodeling and regulation of transcription and positive regulation of apoptosis. Differential mRNA expression of genes involved in DNA methylation metabolism were confirmed by RT-qPCR in endomyocardial biopsies. In a larger biopsy cohort, it was shown that Tet2 was more abundantly expressed in cardiotoxicity biopsies vs. control biopsies and vs. non-ischemic cardiomyopathy patients. Moreover, an in vitro study was performed: following short-term doxorubicin treatment, H9c2 cells were cultured and passaged once they reached a confluency of 70%-80%. When compared to vehicle-only treated cells, in doxorubicin-treated cells, three weeks after short term treatment, Nppa, Nppb, Tet1/2 and other genes involved in active DNA demethylation were markedly upregulated. These alterations coincided with a loss of DNA methylation and a gain in hydroxymethylation, reflecting the epigenetic changes seen in the endomyocardial biopsies. Conclusions: Short-term administration of anthracyclines provokes long-lasting epigenetic modifications in cardiomyocytes both in vivo and in vitro, which explain in part the time lapse between the use of chemotherapy and the development of cardiotoxicity and, eventually, heart failure.

Inside the Mechanism of Action of Three Pyrazole Derivatives in Human Platelets and Endothelial Cells.

In the effort to obtain multitarget compound interfering with inflammation, oxidative stress, and tumorigenesis, we synthesized a small library of pyrazole compounds, selecting 4a, 4f, and 4g as the most noteworthy being IC50 against platelet ROS production induced by thrombin of about 10 µM. The in vitro antioxidant potential of the three molecules was evaluated, and since they show a remarkable antioxidative activity, their effect on several parameter indicative of oxidative status and on the efficiency of the aerobic metabolism was tested. The three molecules strongly inhibit superoxide anion production, lipid peroxidation, NADPH oxidase activity and almost restore the oxidative phosphorylation efficiency in thrombin-stimulated platelet, demonstrating a protective effect against oxidative stress. This effect was confirmed in endothelial cell in which 4a, 4f, and 4g show an interesting inhibition activity on H2O2-stimulated EA.hy926 cells. At last, antiproliferative activity of 4a, 4f, and 4g was submitted to a large screening at the NCI. The molecules show interesting anticancer activity, among them the most remarkable is 4g able to strongly inhibit the proliferation of both solid tumor and leukemia cells lines. In conclusion, all the three newly synthetized pyrazoles show remarkable antioxidant and antiproliferative effect worthy of further study.

Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings: JACC: CardioOncology State-of-the-Art Review.

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.

Exploring the influence of takotsubo syndrome on oncologic patients' mortality.

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients.

The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism.

Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia.