Bidirectional Relationship Between Cancer and Heart Failure: Old and New Issues in Cardio-oncology

The main focus of cardio-oncology has been the prevention and treatment of the cardiac toxicity of chemotherapy and radiotherapy. Furthermore, several targeted therapies have been associated with unexpected cardiotoxic side-effects. Recently, epidemiological studies reported a higher incidence of cancer in patients with heart failure (HF) compared with individuals without HF. On this basis, it has been proposed that HF might represent an oncogenic condition. This hypothesis is supported by preclinical studies demonstrating that hyperactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which is a hallmark of HF, promotes cancer growth and dissemination. Another intriguing possibility is that the co-occurrence of HF and cancer is promoted by a common pathological milieu characterised by a state of chronic low-grade inflammation, which predisposes to both diseases. In this review, we provide an overview of the mechanisms underlying the bidirectional relationship between HF and cancer

Background Evidence and Research Perspectives

Recent epidemiological analyses suggest that incident cancer may be more common among patients with preexisting heart failure (HF) than in patients without HF. Arguments against this notion have been the increased chance of co-occurrence of 2 high-prevalence conditions and increased tumor detection in patients with HF because of intensified medical observation. However, biological data lend support to the hypothesis that HF is an oncogenic condition. Neurohormonal activation has been related to cancer initiation, progression, and dissemination by studies not specifically focusing on HF, which are now reappraised in the light of the emerging evidence that tumors are diagnosed more often in HF than control cohorts. Furthermore, a thought-provoking scenario to be considered is that a systemically perturbed milieu, where low-grade inflammation plays a primary role, leads to both HF and malignancy, thus connecting 1 disease to another. Postischemic HF has been shown to promote tumor growth in an animal model. Exploring these and other pathways potentially linking HF to malignancy is a new and exciting field of research, with the ultimate goal of answering the question of whether HF does promote cancer

Parallel Computation of Piecewise Linear Morse-Smale Segmentations

This paper presents a well-scaling parallel algorithm for the computation of Morse-Smale (MS) segmentations, including the region separators and region boundaries. The segmentation of the domain into ascending and descending manifolds, solely defined on the vertices, improves the computational time using path compression and fully segments the border region. Region boundaries and region separators are generated using a multi-label marching tetrahedra algorithm. This enables a fast and simple solution to find optimal parameter settings in preliminary exploration steps by generating an MS complex preview. It also poses a rapid option to generate a fast visual representation of the region geometries for immediate utilization. Two experiments demonstrate the performance of our approach with speedups of over an order of magnitude in comparison to two publicly available implementations. The example section shows the similarity to the MS complex, the useability of the approach, and the benefits of this method with respect to the presented datasets. We provide our implementation with the paper.Comment: Journal: IEEE Transactions on Visualization and Computer Graphics / Submitted: 22-Jun-2022 / Accepted: 13-Mar-202

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling

While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28~days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3~days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling

Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease

The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca2+) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca2+ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca2+, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF