Search

The article focuses on the trends in cardiovascular system education and training in the U.S. Topics discussed include the future of pediatric cardiology training, the measurement of training outcomes, the environment of the training, the cardiovascular training, and the predicted adult cardiovascular medicine training.

The article projects the future of cardiovascular genomics and genetics in the U.S. Topics discussed include an overview of cardiovascular genetics, the gap of phenotype in precision medicine, the impact of cardiovascular genomics and genetics on health, and the genetic architecture of cardiovascular system.

The article projects the future of cardiovascular treatment options in the U.S. Topics discussed include the concepts of cardiovascular disease and their association with therapy, the target population of cardiovascular community, various drug discovery approaches and their driving factors, and the emergence of different classes of therapeutics.

An editorial is presented which discusses the state-of-the-art strategies to assess the causality of newly identified variants in potential cardiovascular disease genes. It mentions the discovery of numerous disease genes for cardiomyopathies, arrhythmias, aortopathies, and other disorders through genetic and genomic studies which demontsrate complex relationships between genotype and phenotype.

The article presents the case study of a 34-year-old female who is 4 months postpartum after a nocturnal seizure having epileptic-type movements before spontaneously recovering. Topics discussed include Long QT syndrome (LQTS) inherited cardiac condition, Genetic and Molecular Mechanism of LQTS, and correlation between Genotype and Phenotype characteristics of patients suffering from LQTS.

The authors reflect on the insights from genome-wide associations (GWAs). Topics include correlation between common variants and peripheral or tissue-specific expression quantitative trait loci (eQTL), a study by N. A. M. Almontashiri and colleagues on disruption of specific transcription factor (TF) binding sites, and a phenotype gap in modern human genetics.

The author reflects on the need for a new phenotypic lexicon to accelerate translation from mechanistic discoveries to new drug entities. He cites the challenge of finding new drugs and argues that the conventional drug discovery and development sequence remains the basis of most industrial programs. The author also discusses complementary approaches to drug discovery and a study on the benefits of drug discovery and translational science.

The article reports that patient care and biomedical research will undoubtedly be increasingly influenced by genomic medicine efforts in the coming years. In his 2016 budget proposal, former U.S. President Barack Obama allocated $215 million to fund the Precision Medicine Initiative. Some groups have already taken steps to develop and implement genomics training into various medical education paths.

The article focuses on the projected future of the U.S. cardiovascular biomedicine. Topics discussed include the application of molecular medicine and its mechanistic insights to clinical medicine, the generation of recombinant proteins, and the significance of cardiovascular biomedicine in transformation biomedicine.

The article discusses research concerning the need for quantitative tools in clinical genomic studies to determine the association of genotype to phenotype. An overview on the establishment of initial disease gene in segregation studies of multiple independent families and specific variant in the gene, is provided. Also outlined is the opportunities for genomic medicine and the hurdles with combination of remarkable degradation in pedigree information.

The article comments on the impact of pharmacotherapy on mortality and morbidity in cardiovascular disease and also refers to an article published within the issue related to the same.

Background: Novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy (HCM) detection. However, its low prevalence (0.5%) and resemblance to common diseases present challenges that may benefit from automated machine learning-based approaches. We aimed to develop machine learning models to detect HCM and to differentiate it from other cardiac conditions using ECGs and echocardiograms, with robust generalizability across multiple cohorts.Methods: Single-institution HCM ECG models were trained and validated on external data. Multi-institution models for ECG and echocardiogram were trained on data from 3 academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held-out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of HCM from aortic stenosis, hypertension, and cardiac amyloidosis. Last, automated detection was compared with manual interpretation by 3 cardiologists on a data set with a realistic HCM prevalence.Results: We identified 74 376 ECGs for 56 129 patients and 8392 echocardiograms for 6825 patients at the 4 academic medical centers. Although ECG models trained on data from each institution displayed excellent discrimination of HCM on internal test data (C statistics, 0.88-0.93), the generalizability was limited, most notably for a model trained in Japan and tested in the United States (C statistic, 0.79-0.82). When trained in a federated manner, discrimination of HCM was excellent across all institutions (C statistics, 0.90-0.96 and 0.90-0.96 for ECG and echocardiogram model, respectively), including for phenotypic subgroups. The models further discriminated HCM from hypertension, aortic stenosis, and cardiac amyloidosis (C statistics, 0.84, 0.83, and 0.88, respectively, for ECG and 0.93, 0.94, 0.85, respectively, for echocardiogram). Analysis of electrocardiography-echocardiography paired data from 11 823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists (0.98 versus 0.81 at a positive predictive value of 0.01 for ECG and 0.78 versus 0.59 at a positive predictive value of 0.24 for echocardiogram).Conclusions: Federated learning improved the generalizability of models that use ECGs and echocardiograms to detect and differentiate HCM from other causes of hypertrophy compared with training within a single institution. [ABSTRACT FROM AUTHOR]

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models.Methods: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations.Results: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models.Conclusions: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia. [ABSTRACT FROM AUTHOR]

DOI: 10.1161/CIRCULATIONAHA.120.051913 February 2, 2021 509 CORRESPONDENCE The Table presents LDL-C changes in all patients enrolled and in those patients who entered the maintenance phase of the program after active titration. Of the 3939 patients enrolled in the cholesterol program, 1385 (35%) had established atherosclerotic cardiovascular disease group, 995 (25%) had diabetes but no atherosclerotic cardiovascular disease, 1247 (32%) had LDL-C >190 mg/dL group, and 312 (8%) were primary prevention patients at elevated cardiovascular risk. Nonlicensed navigators were the primary communication channel with patients, ordering laboratory tests and providing education at preset intervals until treatment targets (LDL-C guideline-directed thresholds 3 and average home blood pressure <130/80 mm Hg) were achieved. [Extracted from the article]

Background: Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration.Methods: Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control.Results: Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1.Conclusions: These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 52-year-old woman with scleroderma and a medical history of acute coronary syndrome (ACS). Topics include the woman having a medical history of ACS managed with percutaneous coronary intervention (PCI) and scleroderma presented to outpatient cardiology clinic with chest discomfort, her treatment with heparin, aspirin, and clopidogre, and coronary angiography performed on her.

The Precision Medicine Initiative recently announced by President Barack Obama seeks to move the field of precision medicine more rapidly into clinical care. Precision medicine revolves around the concept of integrating individual-level data including genomics, biomarkers, lifestyle and other environmental factors, wearable device physiological data, and information from electronic health records to ultimately provide better clinical care to individual patients. The Precision Medicine Initiative as currently structured will primarily fund efforts in cancer genomics with longer-term goals of advancing precision medicine to all areas of health, and will be supported through creation of a 1 million person cohort study across the United States. This focused effort on precision medicine provides scientists, clinicians, and patients within the cardiovascular community an opportunity to work together boldly to advance clinical care; the community needs to be aware and engaged in the process as it progresses. This article provides a framework for potential involvement of the cardiovascular community in the Precision Medicine Initiative, while highlighting significant challenges for its successful implementation. [ABSTRACT FROM AUTHOR]

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care. [ABSTRACT FROM AUTHOR]

Background—Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor-like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG. Methods and Results—NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7±0.6% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 50.9±2.6%, P=0.813). Conclusions—NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines. [ABSTRACT FROM AUTHOR]

The article presents information on the application of human genome mapping and specific genetic tests in analyzing the genetic predisposition of diseases which in turn helps in improving human health. It presents information on the use of genetic information in clinical medicine and new policy recommendations designed to facilitate the safe incorporation of the latest technologies and research findings into the clinical domain.

Introduction: Genetically induced cardiomyopathy and heart failure are frequent and life-threatening conditions. Recently, we linked genetic deactivation or mutation of the gene PR/SET domain 16 (PRDM16) to cardiomyopathy in patients. Moreover, ablation or mutation of Prdm16 in zebrafish leads to cardiac dysfunction, diminished cardiomyocyte proliferation and increased cardiomyocyte apoptosis. Hypothesis: Here, we explore the molecular mechanisms underlying the PRDM16 associated cardiomyopathy with human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Methods: We established a cellular cardiomyopathy model of mono- or biallelic PRDM16 ablation in hiPSC by using the CRISPR/Cas approach. By using a chemical differentiation protocol hiPSC were differentiated into hiPSC derived cardiomyocytes (hiPSC-CM). Functional analysis of hiPSC-CM occurred with the engineered heart tissue (EHT) system. For molecular analysis, we performed a high-throughput mRNA expression screen with RNAseq and subsequent bioinformatics evaluation. Results: Efficient PRDM16 deactivation was confirmed on genomic, mRNA, and protein level. Analysis of hiPSC-CM_PRDM16_hom with the EHT system revealed a ~20% reduction of the maximal beating force but normal beating frequency compared to controls. EHT analysis further showed diminished maximal force development during stimulation with increased calcium concentrations in hiPSC-CM_PRDM16_hom. A high throughput RNAseq screen revealed in hiPSC-CM_PRDM16_hom approx. 500 down-regulated and 350 up-regulated genes compared to controls. Among these, we detected genes related to cell stress and TGF-beta signaling. This observation is in line with previous findings in csp1 mice, which is a hypomorphic Prdm16 mutant model, showing reduced TGF-beta signaling activity in cartilage. Interestingly, other genes that have already been linked to PRDM16 function in adipocytes are not differentially regulated. Conclusions: Our work establishes hiPSC models to explore the function of PRDM16 in cardiomyocytes and other cell types. Initial functional analysis reveals diminished cardiomyocyte beating force and altered TGF-beta signaling after loss of PRDM16. [ABSTRACT FROM AUTHOR]