o-ring-aortic-banding-versus-traditional-transverse-aortic

O-Ring Aortic Banding Versus Traditional Transverse Aortic Constriction for Modeling Pressure Overload-Induced Cardiac Hypertrophy

Aortic banding in mice is one of the most commonly used experimental models for cardiac pressure overload-induced cardiac hypertrophy and the induction of ...

University Hospital Heidelberg, Partner Site Heidelberg/Mannheim

IMAGE CARDIO MED. A patient with LEOPARD syndrome and PTPN11 mutation.

New treatment options for patients with metastatic Soft Tissue Sarcoma are urgently needed. Preclinical studies suggested activity of vorinostat, a histone deacetylase inhibitor.

Vorinostat in refractory soft tissue sarcomas - Results of a multi-centre phase II trial of the German Soft Tissue Sarcoma and Bone Tumour Working Group (AIO).

This article about the emerging field of cardio-oncology highlights typical side effects of oncological therapies in the cardiovascular system, cardiovascular complications of malignancies itself, and potential preventive or therapeutic modalities.

Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome.

Patients with oncological diseases frequently show cardiac arrhythmias. This is explained by an increased risk in this specific patient cohort and is frequently associated with specific oncological therapies. So far, it is unclear how to deal with the occurrence of arrhythmias diagnostically and therapeutically, since the current clinical data do not provide satisfying answers to these questions. Clinical care of high-risk patients in specialized teams with a focus on cardio-oncology is recommended. Based on the current clinical studies and the position papers of the European Society of Cardiology (ESC), we give a brief overview of arrhythmias in malignant diseases and their therapies.

[Cardiac arrhythmias in oncological diseases, during radiotherapy, chemotherapy].

Oncocardiology is an emerging field in cardiovascular healthcare. Besides establishing surveillance and follow-up strategies for cancer patients, it will be essential to set up specialized oncocardiology services. However, there is a lack of clinical studies to give evidence-based recommendations regarding cardiological diagnostic and therapeutic approaches for cancer patients. An oncocardiology service is a patient-centered structure that aims to integrate research and interdisciplinary patient care to bridge this gap. We discuss the current challenges in developing an oncocardiology service and review the literature on this topic. We further provide an overview of the essential diagnostic tools and upcoming ethical issues to be considered in the management of oncology patients.

Establishing an oncocardiology service.

Oncological therapies show a number of undesired adverse effects on the cardiovascular system. In particular, the side effects of recently established oncological therapies are incompletely understood and clinical data are lacking in the interpretation of novel cardiac complications.

[Mechanisms of cardiotoxicity of oncological therapies].

The Heidelberg cardio-oncology unit (COUNT)-a possible blueprint for improved care of cardio-oncological patients.

Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a 'repressive' to an 'active' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes ('first hit') plus a 'second hit' (e.g., exercise) determines the transcriptional response.

Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation.

Cancer patients are at risk of suffering from cardiovascular diseases (CVD). Nevertheless, the impact of cardiovascular comorbidity on all-cause mortality (ACM) in large clinical cohorts is not well investigated. In this retrospective cohort study, we collected data from 40,329 patients who were subjected to cardiac catherization from 01/2006 to 12/2017 at University Hospital Heidelberg. The study population included 3666 patients with a diagnosis of cancer prior to catherization and 3666 propensity-score matched non-cancer patients according to age, gender, diabetes and hypertension. 5-year ACM in cancer patients was higher with a reduced left ventricular function (LVEF < 50%; 68.0% vs 50.9%) or cardiac biomarker elevation (high-sensitivity cardiac troponin T (hs-cTnT; 64.6% vs 44.6%) and N-terminal brain natriuretic peptide (NT-proBNP; 62.9% vs 41.4%) compared to cancer patients without cardiac risk. Compared to non-cancer patients, NT-proBNP was found to be significantly higher (median NT-proBNP cancer: 881 ng/L, IQR [254; 3983 ng/L] vs non-cancer: 668 ng/L, IQR [179; 2704 ng/L]; p < 0.001, Wilcoxon-rank sum test) and turned out to predict ACM more accurately than hs-cTnT (NT-proBNP: AUC: 0.74; hs-cTnT: AUC: 0.63; p < 0.001, DeLong's test) in cancer patients. Risk factors for atherosclerosis, such as diabetes and age (> 65 years) were significant predictors for increased ACM in cancer patients in a multivariate analysis (OR diabetes: 1.96 (1.39-2.75); p < 0.001; OR age > 65 years: 2.95 (1.68-5.4); p < 0.001, logistic regression). Our data support the notion, that overall outcome in cancer patients who underwent cardiac catherization depends on cardiovascular comorbidities. Therefore, particularly cancer patients may benefit from standardized cardiac care.

Coronary artery disease, left ventricular function and cardiac biomarkers determine all-cause mortality in cancer patients-a large monocenter cohort study.

Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.

Article	Year
IMAGE CARDIO MED. A patient with LEOPARD syndrome and PTPN11 mutation. Circulation\| PubMed ID: 19273734	2009
Vorinostat in refractory soft tissue sarcomas - Results of a multi-centre phase II trial of the German Soft Tissue Sarcoma and Bone Tumour Working Group (AIO). European journal of cancer (Oxford, England : 1990)\| PubMed ID: 27367154	2016
Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome. Clinical research in cardiology : official journal of the German Cardiac Society\| PubMed ID: 29453595	2018
[Cardiac arrhythmias in oncological diseases, during radiotherapy, chemotherapy]. Herzschrittmachertherapie & Elektrophysiologie\| PubMed ID: 31463582	2019
Establishing an oncocardiology service. Herz\| PubMed ID: 32572500	2020
[Mechanisms of cardiotoxicity of oncological therapies]. Der Internist\| PubMed ID: 33034675	2020
The Heidelberg cardio-oncology unit (COUNT)-a possible blueprint for improved care of cardio-oncological patients. Clinical research in cardiology : official journal of the German Cardiac Society\| PubMed ID: 34181066	2022
Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation. Journal of molecular and cellular cardiology\| PubMed ID: 34492228	2022
Coronary artery disease, left ventricular function and cardiac biomarkers determine all-cause mortality in cancer patients-a large monocenter cohort study. Clinical research in cardiology : official journal of the German Cardiac Society\| PubMed ID: 35312818	2022
Cardio-oncology imaging tools at the translational interface. Journal of molecular and cellular cardiology\| PubMed ID: 35385715	2022

Lorenz Lehmann

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