RESUMO
During the COVID-19 pandemic, the American Heart Association created a new 2024 Impact Goal with health equity at its core, in recognition of the increasing health disparities in our country and the overwhelming evidence of the damaging effect of structural racism on cardiovascular and stroke health. Concurrent with the announcement of the new Impact Goal was the release of an American Heart Association presidential advisory on structural racism, recognizing racism as a fundamental driver of health disparities and directing the American Heart Association to advance antiracist strategies regarding science, business operations, leadership, quality improvement, and advocacy. This policy statement builds on the call to action put forth in our presidential advisory, discussing specific opportunities to leverage public policy in promoting overall well-being and rectifying those long-standing structural barriers that impede the progress that we need and seek for the health of all communities. Although this policy statement discusses difficult aspects of our past, it is meant to provide a forward-looking blueprint that can be embraced by a broad spectrum of stakeholders who share the association's commitment to addressing structural racism and realizing true health equity.
Assuntos
Equidade em Saúde , Racismo , Estados Unidos , Humanos , Racismo Sistêmico , American Heart Association , Pandemias/prevenção & controle , Racismo/prevenção & controle , Política PúblicaRESUMO
Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.
Assuntos
Cardiotoxicidade/epidemiologia , Cardiotoxinas/toxicidade , Educação/normas , Relatório de Pesquisa/normas , United States Food and Drug Administration/normas , Animais , Cardiotoxicidade/prevenção & controle , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/tendências , Educação/tendências , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Relatório de Pesquisa/tendências , Estados Unidos/epidemiologia , United States Food and Drug Administration/tendênciasRESUMO
The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia. A variety of scientific topics were presented by speakers, covering a broad variety of topics in the fields of safety risk assessment; from pro-arrhythmia and contractility risk evaluation, to models of heart failure and seizure in-a-dish; and discovery sciences; from stem cells and precision medicine, to models of inherited cardiomyopathy and precision cut tissue slices. The present review summarizes the highlights of the presentations and provides an overview of the high level of innovation currently underlying many frontiers in safety pharmacology.
Assuntos
Indústria Farmacêutica/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Farmacologia/métodos , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Medição de Risco , Sociedades FarmacêuticasRESUMO
PURPOSE: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. METHODS: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. RESULTS: We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. CONCLUSIONS: The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Desenho de Fármacos , Animais , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica , HumanosAssuntos
Temas Bioéticos , Quimera , Células-Tronco Pluripotentes/transplante , Pesquisa com Células-Tronco/ética , Animais , Blastocisto , Administração Financeira/ética , Humanos , Camundongos , National Institutes of Health (U.S.)/economia , National Institutes of Health (U.S.)/ética , Pesquisa com Células-Tronco/economia , Estados UnidosRESUMO
RATIONALE: Thousands of mutations across >50 genes have been implicated in inherited cardiomyopathies. However, options for sequencing this rapidly evolving gene set are limited because many sequencing services and off-the-shelf kits suffer from slow turnaround, inefficient capture of genomic DNA, and high cost. Furthermore, customization of these assays to cover emerging targets that suit individual needs is often expensive and time consuming. OBJECTIVE: We sought to develop a custom high throughput, clinical-grade next-generation sequencing assay for detecting cardiac disease gene mutations with improved accuracy, flexibility, turnaround, and cost. METHODS AND RESULTS: We used double-stranded probes (complementary long padlock probes), an inexpensive and customizable capture technology, to efficiently capture and amplify the entire coding region and flanking intronic and regulatory sequences of 88 genes and 40 microRNAs associated with inherited cardiomyopathies, congenital heart disease, and cardiac development. Multiplexing 11 samples per sequencing run resulted in a mean base pair coverage of 420, of which 97% had >20× coverage and >99% were concordant with known heterozygous single nucleotide polymorphisms. The assay correctly detected germline variants in 24 individuals and revealed several polymorphic regions in miR-499. Total run time was 3 days at an approximate cost of $100 per sample. CONCLUSIONS: Accurate, high-throughput detection of mutations across numerous cardiac genes is achievable with complementary long padlock probe technology. Moreover, this format allows facile insertion of additional probes as more cardiomyopathy and congenital heart disease genes are discovered, giving researchers a powerful new tool for DNA mutation detection and discovery.
Assuntos
Análise Custo-Benefício , Cardiopatias/economia , Cardiopatias/genética , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequência de Bases , Marcação de Genes/economia , Marcação de Genes/métodos , Cardiopatias/diagnóstico , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Fatores de TempoRESUMO
OBJECTIVES: The purpose of this study was to evaluate whether radiation exposure from cardiac computed tomographic angiography (CTA) is associated with deoxyribonucleic acid (DNA) damage and whether damage leads to programmed cell death and activation of genes involved in apoptosis and DNA repair. BACKGROUND: Exposure to radiation from medical imaging has become a public health concern, but whether it causes significant cell damage remains unclear. METHODS: We conducted a prospective cohort study in 67 patients undergoing cardiac CTA between January 2012 and December 2013 in 2 U.S. medical centers. Median blood radiation exposure was estimated using phantom dosimetry. Biomarkers of DNA damage and apoptosis were measured by flow cytometry, whole genome sequencing, and single cell polymerase chain reaction. RESULTS: The median dose length product was 1,535.3 mGy·cm (969.7 to 2,674.0 mGy·cm). The median radiation dose to the blood was 29.8 mSv (18.8 to 48.8 mSv). Median DNA damage increased 3.39% (1.29% to 8.04%, p < 0.0001) and median apoptosis increased 3.1-fold (interquartile range [IQR]: 1.4- to 5.1-fold, p < 0.0001) post-radiation. Whole genome sequencing revealed changes in the expression of 39 transcription factors involved in the regulation of apoptosis, cell cycle, and DNA repair. Genes involved in mediating apoptosis and DNA repair were significantly changed post-radiation, including DDB2 (1.9-fold [IQR: 1.5- to 3.0-fold], p < 0.001), XRCC4 (3.0-fold [IQR: 1.1- to 5.4-fold], p = 0.005), and BAX (1.6-fold [IQR: 0.9- to 2.6-fold], p < 0.001). Exposure to radiation was associated with DNA damage (odds ratio [OR]: 1.8 [1.2 to 2.6], p = 0.003). DNA damage was associated with apoptosis (OR: 1.9 [1.2 to 5.1], p < 0.0001) and gene activation (OR: 2.8 [1.2 to 6.2], p = 0.002). CONCLUSIONS: Patients exposed to >7.5 mSv of radiation from cardiac CTA had evidence of DNA damage, which was associated with programmed cell death and activation of genes involved in apoptosis and DNA repair.
Assuntos
Apoptose , Biomarcadores/análise , Angiografia Coronária/efeitos adversos , Dano ao DNA , Coração/efeitos da radiação , Tomografia Computadorizada por Raios X/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Anexina A5/análise , Proteínas Mutadas de Ataxia Telangiectasia/análise , Estudos de Coortes , Reparo do DNA , Proteínas de Ligação a DNA/análise , Feminino , Citometria de Fluxo , Histonas/análise , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Reação em Cadeia da Polimerase , Estudos Prospectivos , Análise de Sequência de DNA , Análise de Sequência de RNA , Proteína X Associada a bcl-2/análiseAssuntos
Sistema Cardiovascular/diagnóstico por imagem , Imagem Molecular/métodos , Cardiologia/métodos , Cardiologia/tendências , Doenças Cardiovasculares/diagnóstico por imagem , Circulação Coronária , Países em Desenvolvimento , Custos de Cuidados de Saúde , Coração/diagnóstico por imagem , Coração/fisiologia , Humanos , Isquemia Miocárdica/patologia , CintilografiaRESUMO
There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.