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1.
Occurrence of early afterdepolarization under healthy or hypertrophic cardiomyopathy conditions in the human ventricular endocardial myocyte: In silico study using 109 torsadogenic or non-torsadogenic compounds.
Christophe, B
Toxicology and applied pharmacology. 2022;:115914
Abstract
The goal of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) was to assess a more accurate prediction of new drug candidate proarrhythmic severe liabilities such as torsades de pointes, for example. This new CiPA paradigm was partly based on in silico reconstruction of human ventricular cardiomyocyte action potential useful to identify repolarization abnormalities such early afterdepolarization (EAD), for example. Using the ToR-ORd algorithm (Tomek-Rodriguez-O'Hara-Rudy dynamic model), the aim of the present work was (i) to identify intracellular parameters leading to EAD occurrence under healthy and hypertrophic cardiomyopathy (HCM) conditions and (ii) to evaluate the prediction accuracy of compound torsadogenic risk based on EAD occurrence using a large set of 109 torsadogenic and non-torsadogenic compounds under both experimental conditions. In silico results highlighted the crucial involvement of Ca++ handling in the ventricular cardiomyocyte intracellular subspace compartment for the initiation of EAD, demonstrated by a higher amplitude of Ca++ release from junctional sarcoplasmic reticulum to subspace compartments (Jrel) measured at EAD take-off voltage in the presence vs. the absence of EAD initiated either by high IKr inhibition or by high enough concentration of a torsadogenic compound under both experimental conditions. Under healthy or HCM conditions, the prediction accuracy of the torsadogenic risk of compound based on EAD occurrence was observed to be 61 or 92%, respectively. This high accuracy under HCM conditions was discussed regarding its usefulness for cardiac safety pharmacology at least at early drug screening/preclinical stage of the drug development process.
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2.
The interaction among OSA, CPAP, and medications in patients with comorbid OSA and cardiovascular/cerebrovascular disease: a randomized controlled trial.
Lao, M, Cheng, Y, Gao, X, Ou, Q
BMC pulmonary medicine. 2022;(1):99
Abstract
BACKGROUND Most patients with comorbid sleep apnea (OSA), cardiovascular (CV) disease, and/or cerebrovascular (CeV) disease simultaneously take medications. Whether OSA and continuous positive airway pressure (CPAP) interact with CV/CeV medications remains unknown. This study aimed to determine the interaction among OSA, CPAP, and CV/CeV medications; the effects of medications on major adverse cardiac and cerebrovascular events, and survival in patients with comorbid OSA and CV/CeV. METHODS This was a post hoc analysis of the data from one center of the Sleep Apnea Cardiovascular Endpoints Study. Participants (aged 45-75 years) with comorbid OSA and CV/CeV were randomized to receive usual care with or without CPAP from December 2008 to November 2013. The primary endpoint was death and the secondary endpoint was a composite of death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, and transient ischemic attack. RESULTS In total, 131 patients were analyzed. Sixty-three were in the CPAP group and 68 were in the usual care group, 41 had good adherence to CPAP (65.1%), and the median follow-up time was 43.0 (35.0, 54.0) months. In Cox regression analysis, ACE inhibitors and nitrates were independent factors for decreased survival in patients with comorbid OSA and CV/CeV (chi-square = 22.932, P = 0.003; ACE inhibitors: OR 7.241, P = 0.048, 95% CI 1.016-51.628; nitrates: OR 18.012, P = 0.011, 95% CI 1.923-168.750). ACE inhibitors increased mortality and secondary endpoints in the CPAP group (chi-square = 4.134, P = 0.042) but not in patients with good CPAP adherence. Clopidogrel and nitrates decreased survival in usual care group (clopidogrel: chi-square = 5.312, P = 0.021; nitrates: chi-square = 6.417, P = 0.011), but not in CPAP group. CONCLUSIONS OSA may predispose patients with CV/CeV and CV/CeV medications to a negative effect. CPAP treatment may neutralize the negative effects of OSA by relieving chronic intermittent hypoxia. Trial registration ClinicalTrials.gov (NCT00738179, first registration date: 20/08/2008).
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3.
The Potential Role of Creatine in Vascular Health.
Clarke, H, Hickner, RC, Ormsbee, MJ
Nutrients. 2021;(3)
Abstract
Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to the abundance of evidence supporting the ergogenic benefits of creatine supplementation, recent evidence suggests a far broader application for creatine within various myopathies, neurodegenerative diseases, and other pathologies. Furthermore, creatine has been found to exhibit non-energy related properties, contributing as a possible direct and in-direct antioxidant and eliciting anti-inflammatory effects. In spite of the new clinical success of supplemental creatine, there is little scientific insight into the potential effects of creatine on cardiovascular disease (CVD), the leading cause of mortality. Taking into consideration the non-energy related actions of creatine, highlighted in this review, it can be speculated that creatine supplementation may serve as an adjuvant therapy for the management of vascular health in at-risk populations. This review, therefore, not only aims to summarize the current literature surrounding creatine and vascular health, but to also shed light onto the potential mechanisms in which creatine may be able to serve as a beneficial supplement capable of imparting vascular-protective properties and promoting vascular health.
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4.
Impact of the presence of heart disease, cardiovascular medications and cardiac events on outcome in COVID-19.
Cabezón Villalba, G, Amat-Santos, IJ, Dueñas, C, Lopez Otero, D, Catala, P, Aparisi, A, López-Pais, J, Cacho Antonio, CE, Candela, J, Antúnez Muiños, P, et al
Cardiology journal. 2021;(3):360-368
Abstract
BACKGROUND Cardiovascular risk factors and usage of cardiovascular medication are prevalent among coronavirus disease 2019 (COVID-19) patients. Little is known about the cardiovascular implications of COVID-19. The goal herein, was to evaluate the prognostic impact of having heart disease (HD) and taking cardiovascular medications in a population diagnosed of COVID-19 who required hospitalization. Also, we studied the development of cardiovascular events during hospitalization. METHODS Consecutive patients with definitive diagnosis of COVID-19 made by a positive real time- -polymerase chain reaction of nasopharyngeal swabs who were admitted to the hospital from March 15 to April 14 were included in a retrospective registry. The association of HD with mortality and with mortality or respiratory failure were the primary and secondary objectives, respectively. RESULTS A total of 859 patients were included in the present analysis. Cardiovascular risk factors were related to death, particularly diabetes mellitus (hazard ratio in the multivariate analysis: 1.810 [1.159- -2.827], p = 0.009). A total of 113 (13.1%) patients had HD. The presence of HD identified a group of patients with higher mortality (35.4% vs. 18.2%, p < 0.001) but HD was not independently related to prognosis; renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, diuretics and beta-blockers did not worsen prognosis. Statins were independently associated with decreased mortality (0.551 [0.329-0.921], p = 0.023). Cardiovascular events during hospitalization identified a group of patients with poor outcome (mortality 31.8% vs. 19.3% without cardiovascular events, p = 0.007). CONCLUSIONS The presence of HD is related to higher mortality. Cardiovascular medications taken before admission are not harmful, statins being protective. The development of cardiovascular events during the course of the disease is related to poor outcome.
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5.
A Novel Approach to Medical Management of Heart Failure With Reduced Ejection Fraction.
Miller, RJH, Howlett, JG, Fine, NM
The Canadian journal of cardiology. 2021;(4):632-643
Abstract
The advent of newly available medical therapies for heart failure with reduced ejection fraction (HFrEF) has resulted in many potential therapeutic combinations, increasing treatment complexity. Publication of expert consensus guidelines and initiatives aimed to improve implementation of treatment has emphasized sequential stepwise initiation and titration of medical therapy, which is labour intensive. Data taken from heart failure registries show suboptimal use of medications, prolonged titration times, and consequently little change in dose intensity, all of which indicate therapeutic inertia. Recently published evidence indicates that 4 medication classes-renin-angiotensin-neprilysin inhibitors, β-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter inhibitors-which we refer to as Foundational Therapy, confer rapid and robust reduction in both morbidity and mortality in most patients with HFrEF and that they work in additive fashion. Additional morbidity and mortality may be observed following addition of several personalized therapies in specific subgroups of patients. In this review, we discuss mechanisms of action of these therapies and propose a framework for their implementation, based on several principles. These include the critical importance of rapid initiation of all 4 Foundational Therapies followed by their titration to target doses, emphasis on multiple simultaneous drug changes with each patient encounter, attention to patient-specific factors in choice of medication class, leveraging inpatient care, use of the entire health care team, and alternative (ie, virtual visits) modes of care. We have incorporated these principles into a Cluster Scheme designed to facilitate timely and optimal medical treatment for patients with HFrEF.
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6.
Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.
Liu, J, Li, DD, Dong, W, Liu, YQ, Wu, Y, Tang, DX, Zhang, FC, Qiu, M, Hua, Q, He, JY, et al
Signal transduction and targeted therapy. 2021;(1):329
Abstract
It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).
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7.
Cardiovascular Drug Therapy during Interstage After Hybrid Approach: A Single-Center Experience in 51 Newborns with Hypoplastic Left Heart.
Mienert, T, Esmaeili, A, Steinbrenner, B, Khalil, M, Müller, M, Akintuerk, H, Kerst, G, Schranz, D
Paediatric drugs. 2021;(2):195-202
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Abstract
BACKGROUND Newborns with hypoplastic left heart (HLH) are usually palliated with the Norwood procedure or a hybrid stage I procedure. Hybrid is our preferred approach. Given the critical relationship between stage I, interstage, and comprehensive stage II or advanced biventricular repair, we hypothesized that appropriate drug treatment is a significant therapeutic cornerstone, especially for the management of the high-risk interstage. METHODS We report a single-center observational study addressing the cardiovascular effects of, in particular, oral β-blockers and the additional use of angiotensin-converting enzyme (ACE) and mineralocorticoid inhibitors. RESULTS In total, 51 newborns-30 with HLH syndrome (HLHS) and 21 with HLH complex (HLHC)-with a median bodyweight of 3.0 kg (range 1.9-4.4; nine with bodyweight ≤ 2500 g) underwent an uneventful "Giessen hybrid approach" using a newly approved duct stent. All patients were discharged home with a single, double or triple therapy consisting of ß-blockers, ACE and mineralocorticoid inhibitors; 90% of the patients received bisoprolol, 10% received propranolol, 72% received lisinopril, and 78% received spironolactone. Resting heart rate decreased from 138 bpm (range 112-172; n = 51) at admission to 123 bpm (range 99-139; n = 51) at discharge and 110 bpm before stage II/biventricular repair/heart transplantation (range 90-140; n = 37) accompanied by favorable bodyweight gain. No side effects were evident. CONCLUSION In view of drug risk/benefit profiles, as well as the variable morphology and hemodynamics, the highly selective β1-adrenoceptor blocker bisoprolol is our preferred drug for treatment of HLHS/HLHC in the interstage. We avoid using ACE inhibitor monotherapy and exclude potential risks for coronary and cerebral perfusion pressure beforehand.
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CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction.
McDonald, M, Virani, S, Chan, M, Ducharme, A, Ezekowitz, JA, Giannetti, N, Heckman, GA, Howlett, JG, Koshman, SL, Lepage, S, et al
The Canadian journal of cardiology. 2021;(4):531-546
Abstract
In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.
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The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta-analysis.
Jiang, F, Hu, X, Jiang, K, Pi, H, He, Q, Chen, X
Taiwanese journal of obstetrics & gynecology. 2021;(1):1-8
Abstract
To assess the roles of the low molecular weight heparin (LMWH) on recurrent pregnancy loss (RPL). The relevant studies of all randomized controlled trials (RCTs) were retrieved, and the systematic evaluation was conducted. PubMed, Embase, and Cochrane library databases were searched by using keywords, including low-molecular-weight heparin or LMWH, and recurrent miscarriage or recurrent pregnancy loss in pregnant women from their earliest data to February 2020. Two investigators independently evaluated eligibility. Risk ratios (RRs) and their corresponding 95% confidence interval (CI) were determined. To pool the results, this meta-analysis was performed using random-effect model due to the high heterogeneity among these eight studies. A total of eight RCTs involving 1854 participants were included in the meta-analysis involving 963 patients with RPL who were prescribed LMWH (enoxaparin, tinzaparin, or dalteparin) alone and 891 patients who were treated with no LMWH interventions (placebo, folic acid or non-treatment) were compared. Pooled data from the remaining eight RCTs showed the differences between intervention groups and control groups. Compared with control groups, LMWH had significantly improved live births (RR,1.19; 95%CI, 1.03 to 1.38; P = 0.02), and reduced miscarriage rates (RR, 0.62; 95%CI, 0.43 to 0.91; P = 0.01). The study suggested that LMWH could improve the live births and reduce the miscarriage rates of RPL. Therefore, LMWH might be a good treatment choice for women with unexplained PRL.
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Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development.
Holmes, MV, Richardson, TG, Ference, BA, Davies, NM, Davey Smith, G
Nature reviews. Cardiology. 2021;(6):435-453
Abstract
Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.