CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who ...receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype‐guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).
Abstract
Cardiovascular diseases are among the main causes of morbidity and mortality in Western countries and considered as a leading public health issue. Therefore, there is a strong need for new ...disease models to support the development of novel therapeutics approaches. The successive improvement of genome editing tools with zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and more recently with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) has enabled the generation of genetically modified cells and organisms with much greater efficiency and precision than before. The simplicity of CRISPR/Cas9 technology made it especially suited for different studies, both in vitro and in vivo, and has been used in multiple studies evaluating gene functions, disease modelling, transcriptional regulation, and testing of novel therapeutic approaches. Notably, with the parallel development of human induced pluripotent stem cells (hiPSCs), the generation of knock-out and knock-in human cell lines significantly increased our understanding of mutation impacts and physiopathological mechanisms within the cardiovascular domain. Here, we review the recent development of CRISPR–Cas9 genome editing, the alternative tools, the available strategies to conduct genome editing in cardiovascular cells with a focus on its use for correcting mutations in vitro and in vivo both in germ and somatic cells. We will also highlight that, despite its potential, CRISPR/Cas9 technology comes with important technical and ethical limitations. The development of CRISPR/Cas9 genome editing for cardiovascular diseases indeed requires to develop a specific strategy in order to optimize the design of the genome editing tools, the manipulation of DNA repair mechanisms, the packaging and delivery of the tools to the studied organism, and the assessment of their efficiency and safety.
Graphical Abstract
Graphical Abstract
Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is ...increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure-lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure-lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.
Coronavirus disease-2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders.
To explore the coagulopathy and endothelial dysfunction in COVID-19 patients.
The ...study analyzed clinical and biological profiles of patients with suspected COVID-19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs).
Among 96 consecutive COVID-19-suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS-CoV-2. COVID-19-positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission. Prevalence of D-dimer >500 ng/mL was higher in COVID-19-positive patients (74.2% versus 43.3%; P = .007). No sign of disseminated intravascular coagulation were identified. Adding D-dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID-19 diagnosis. COVID-19-positive patients had significantly more CECs at admission (P = .008) than COVID-19-negative ones. COVID-19-positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without. Interestingly, patients treated with curative anticoagulation and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007).
Curative anticoagulation could prevent COVID-19-associated coagulopathy and endothelial lesion.
Background
Ambulatory ECG monitoring is typically achieved using portable devices with limited number of surface leads, autonomy, and length of recording. Smart garments with multiple conductive ...textile electrodes provide great promise to perform continuous and comfortable ECG monitoring.
Methods
We evaluated the ECG signal quality measured on healthy subjects with a smart 12‐lead ECG acquisition T‐shirt or a 12‐lead Holter recording. ECG signals were recorded during 3 min with both techniques in three resting positions (supine, seated, standing) and while walking. Three readers independently assessed ECG patterns and evaluated the denoising of the isoelectric line, the distinction of p waves, R peaks and RR intervals, and the possible appreciation of cardiac rhythm in at least 3 leads.
Results
Thirty healthy subjects (70% males, 29.5 ± 7.8 years) were enrolled in the study. For all three resting conditions, cardiac rhythm was appreciated in 100% of recordings with distinction of p waves, R peaks, and isoelectric line in >97% of recordings. Appreciation of cardiac rhythm was lower in the walking conditions with both techniques (53.3% vs. 46.7%, Holter vs. smart T‐shirt, p = .60) mainly due to difficulties to distinguish p waves. These results were consistent across both genders. All ECG parameters (heart rate, PR, QRS and QTC intervals) were comparable between both techniques. No skin irritation was seen with the textile electrodes.
Conclusions
A smart T‐shirt with 13 textiles electrodes allows short‐duration 12‐lead ECG acquisition with quality levels comparable to Holter recordings. The novel device should now be evaluated for long‐term non‐invasive ECG monitoring.
Heart failure (HF) in young adults is uncommon, and changes in its incidence and prognosis in recent years are poorly described.
The incidence and prognosis of HF in young adults (1850 years) were ...characterized using nationwide medico-administrative data from the French National Hospitalization Database (period 20132018). A total of 1,486 877 patients hospitalized for incident HF were identified, including 70 075 (4.7) patients aged 1850 years (estimated incidence of 0.44 for this age group). During the study period, the overall incidence of HF tended to decrease in the overall population but significantly increased by 0.041 in young adults (P 0.001). This increase was notably observed among young men (from 0.51 to 0.59, P 0.001), particularly those aged 3650 years. In these young men, ischaemic heart disease (IHD) was the most frequently reported cause of HF, whereas non-ischaemic HF was mainly observed in patients 35 years old. In contrast to non-ischaemic HF, the incidence of IHD increased over the study period, which suggests that IHD-related HF is progressively affecting younger patients. Concordantly, young HF patients presented with high rates of traditional IHD risk factors, including obesity, smoking, hypertension, dyslipidaemia, or diabetes. Lastly, the rates of re-hospitalization (for HF or for any cause) within two years after the first HF event and in-hospital mortality were high in all groups, indicating a poor-prognosis population.
Strategies for the prevention of HF risk factors should be strongly considered for patients under 50 years old.
Cardiac experimental biology and translational research would benefit from an in vitro surrogate for human heart muscle. This study investigated structural and functional properties and ...interventional responses of human engineered cardiac tissues (hECTs) compared to human myocardium. Human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs, >90% troponin‐positive) were mixed with collagen and cultured on force‐sensing elastomer devices. hECTs resembled trabecular muscle and beat spontaneously (1.18±0.48 Hz). Microstructural features and mRNA expression of cardiac‐specific genes (α‐MHC, SERCA2a, and ACTC1) were comparable to human myocardium. Optical mapping revealed cardiac refractoriness with loss of 1:1 capture above 3 Hz, and cycle length dependence of the action potential duration, recapitulating key features of cardiac electrophysiology. hECTs reconstituted the Frank‐Starling mechanism, generating an average maximum twitch stress of 660 μN/mm2 at Lmax, approaching values in newborn human myocardium. Dose‐response curves followed exponential pharmacodynamics models for calcium chloride (EC50 1.8 mM) and verapamil (IC50 0.61 μM); isoproterenol elicited a positive chronotropic but negligible inotropic response, suggesting sarcoplasmic reticulum immaturity. hECTs were amenable to gene transfer, demonstrated by successful transduction with Ad.GFP. Such 3‐D hECTs recapitulate an early developmental stage of human myocardium and promise to offer an alternative preclinical model for cardiology research.—Turnbull, I. C., Karakikes, I., Serrao, G. W., Backeris, P., Lee, J.‐J., Xie, C., Senyei, G., Gordon, R. E., Li, R. A., Akar, F. G., Hajjar, R. J., Hulot, J.‐S., Costa, K. D. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEB J. 28, 644–654 (2014). www.fasebj.org
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