Anthracyclines, such as doxorubicin, are the most potent and widely used chemotherapeutic agents for the treatment of a variety of human cancers, including solid tumors and hematological ...malignancies. However, their clinical use is hampered by severe cardiotoxic side effects and cancer therapy-related heart disease has become a leading cause of morbidity and mortality among cancer survivors. The identification of therapeutic strategies limiting anthracycline cardiotoxicity with preserved antitumor efficacy thus represents the current challenge of cardio-oncologists. Anthracycline cardiotoxicity has been originally ascribed to the ability of this class of drugs to disrupt iron metabolism and generate excess of reactive oxygen species (ROS). However, small clinical trials with iron chelators and anti-oxidants failed to provide any benefit and suggested that doxorubicin cardiotoxicity is not solely due to redox cycling. New emerging explanations include anthracycline-dependent regulation of major signaling pathways controlling DNA damage response, cardiomyocyte survival, cardiac inflammation, energetic stress and gene expression modulation. This review will summarize recent studies unraveling the complex web of mechanisms of doxorubicin-mediated cardiotoxicity, and identifying new druggable players for the prevention of heart disease in cancer patients. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
•Heart failure is a major complication of anticancer treatments, especially anthracyclines.•Strategies preventing anthracycline cardiotoxicity represent a so far unmet clinical need.•The molecular mechanisms underlying the cardiotoxicity of antitumor drugs are poorly understood.•Anthracycline cardiotoxicity has been traditionally ascribed to oxidative stress.•Emerging explanations include regulation of signaling networks which are central to cardiomyocyte survival.
Cardiac drug discovery is hampered by the reliance on non-human animal and cellular models with inadequate throughput and physiological fidelity to accurately identify new targets and test novel ...therapeutic strategies. Similarly, adverse drug effects on the heart are challenging to model, contributing to costly failure of drugs during development and even after market launch. Human induced pluripotent stem cell derived cardiac tissue represents a potentially powerful means to model aspects of heart physiology relevant to disease and adverse drug effects, providing both the human context and throughput needed to improve the efficiency of drug development. Here we review emerging technologies for high throughput measurements of cardiomyocyte physiology, and comment on the promises and challenges of using iPSC-derived cardiomyocytes to model disease and introduce the human context into early stages of drug discovery. This article is part of a Special Issue entitled: Cardiomyocyte biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
•High throughput physiological assays are at the forefront of new methods of drug discovery and safety pharmacology•This new technology offers unprecedented opportunities for personalized medicine•We discuss the challenges of reproducing human disease manifestions, and offers some solutions to advance the field.
After decades of directed research, no effective regenerative therapy is currently available to repair the injured human heart. The epicardium, a layer of mesothelial tissue that envelops the heart ...in all vertebrates, has emerged as a new player in cardiac repair and regeneration. The epicardium is essential for muscle regeneration in the zebrafish model of innate heart regeneration, and the epicardium also participates in fibrotic responses in mammalian hearts. This structure serves as a source of crucial cells, such as vascular smooth muscle cells, pericytes, and fibroblasts, during heart development and repair. The epicardium also secretes factors that are essential for proliferation and survival of cardiomyocytes. In this Review, we describe recent advances in our understanding of the biology of the epicardium and the effect of these findings on the candidacy of this structure as a therapeutic target for heart repair and regeneration.
Calcium (Ca) is a universal regulator of various cellular functions. In cardiomyocytes, Ca is the central element of excitation–contraction coupling, but also impacts diverse signaling cascades and ...influences the regulation of gene expression, referred to as excitation–transcription coupling. Disturbances in cellular Ca-handling and alterations in Ca-dependent gene expression patterns are pivotal characteristics of failing cardiomyocytes, with several excitation–transcription coupling pathways shown to be critically involved in structural and functional remodeling processes. Thus, targeting Ca-dependent transcriptional pathways might offer broad therapeutic potential. In this article, we (1) review cytosolic and nuclear Ca dynamics in cardiomyocytes with respect to their impact on Ca-dependent signaling, (2) give an overview on Ca-dependent transcriptional pathways in cardiomyocytes, and (3) discuss implications of excitation–transcription coupling in the diseased heart.
Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Cardiac pressure overload resulting from ...trans-aortic constriction in mice leads to cardiac fibrosis and increased Wnt/β-catenin signaling in cardiac fibroblasts. Here, we conditionally induce β-catenin loss of function in resident cardiac fibroblasts using Tcf21
or in activated cardiac fibroblasts using periostin (Postn)
. We show that β-catenin loss of function in cardiac fibroblasts after trans-aortic constriction significantly preserves cardiac function, and reduces interstitial fibrosis but does not alter the numbers of activated or differentiated cardiac fibroblasts in vivo. However, β-catenin is specifically required in resident cardiac fibroblasts for fibrotic excessive extracellular matrix gene expression and binds Col3a1 and Postn gene sequences in cultured cardiac fibroblasts after induction of Wnt signaling. Moreover, cardiomyocyte hypertrophy is blunted with cardiac fibroblast-specific loss of β-catenin after trans-aortic constriction in vivo. Thus, Wnt/β-catenin signaling in resident cardiac fibroblasts is required for excessive extracellular matrix gene expression and collagen deposition after trans-aortic constriction.Understanding the mechanisms causing cardiac fibrosis is key to prevention and therapy development of many heart diseases. Here, the authors show that Wnt/β-catenin signaling in resident cardiac fibroblasts is required for deposition of fibrotic extracellular matrix and the regulation of cardiomyocyte hypertrophy in a mouse model of heart fibrosis.
Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% ...of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
•hPSC-CM drug screening, disease modelling & Cas9/CRISPR engineering becoming routine.•hPSC-CMs used to refine patient treatment & assist in progressing drugs to clinic.•Transplantation into heart failure pigs and primates now translated to humans.•Barriers to progression include cost of goods, subtype specification & maturation.•2D and 3D hPSC-CM high content phenotyping platforms evolving rapidly.
Researchers have begun studying how accurately a new tool, known as the Predicting Risk of Cardiovascular Disease Events (PREVENT) calculator, estimates risk in people from different racial and ...ethnic backgrounds as well as from a range of ages, the American Heart Association announced. Three research teams will evaluate the new scores using larger databases and will assess PREVENT's fairness and cost-effectiveness compared with the Pooled Cohort Equations (PCEs).
Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival ...of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.
Abstract Background Wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure. Objectives The purpose of this study was to determine the ...natural history of ATTRwt and the predictors of survival. Methods We retrospectively reviewed patients diagnosed with ATTRwt at the Mayo Clinic through 2013 and recorded clinical data and survival data. Factors affecting overall survival (OS) were identified, and a prognostic staging system was developed. Results The median age of the 360 patients diagnosed before death was 75 years (range: 47 to 94 years), and 91% were male. Presenting signs and symptoms included dyspnea or heart failure in 67% and atrial arrhythmias in 62%. Median OS from diagnosis was 3.6 years and did not change over time. Multivariate predictors of mortality included age, ejection fraction, pericardial effusion, N-terminal pro–B-type natriuretic peptide, and troponin T. A staging system was developed that used thresholds of troponin T (0.05 ng/ml) and N-terminal pro–B-type natriuretic peptide (3,000 pg/ml). The respective 4-year OS estimates were 57%, 42%, and 18% for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively. Stage III patients were at an increased risk of mortality after adjustment for age and sex compared with stage I patients (hazard ratio: 3.6; p < 0.001). Conclusions The natural history of ATTRwt is poor. We report a novel cardiac biomarker staging system that enables risk stratification in an era of emerging treatment strategies.
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