Dataset Information

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

ABSTRACT: Background: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.

Methods and findings: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ? 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.

Conclusions: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

SUBMITTER: Chan XHS

PROVIDER: S-EPMC7058280 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

Chan Xin Hui S XHS Win Yan Naung YN Haeusler Ilsa L IL Tan Jireh Y JY Loganathan Shanghavie S Saralamba Sompob S Chan Shu Kiat S SKS Ashley Elizabeth A EA Barnes Karen I KI Baiden Rita R Bassi Peter U PU Djimde Abdoulaye A Dorsey Grant G Duparc Stephan S Hanboonkunupakarn Borimas B Ter Kuile Feiko O FO Lacerda Marcus V G MVG Nasa Amit A Nosten François H FH Onyeji Cyprian O CO Pukrittayakamee Sasithon S Siqueira André M AM Tarning Joel J Taylor Walter R J WRJ Valentini Giovanni G van Vugt Michèle M Wesche David D Day Nicholas P J NPJ Huang Christopher L-H CL Brugada Josep J Price Ric N RN White Nicholas J NJ

PLoS medicine 20200305 3

<h4>Background</h4>Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise th ...[more]

PMID: 32134952

Similar Datasets

Project description:ContextDisturbances in 25-hydroxyvitamin D, calcium, and phosphorus concentrations have been associated with increased risks of total and cardiovascular mortality. It is possible that changes in electrocardiographic QT interval duration may mediate these effects, but the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration has not been evaluated in general population samples.ObjectiveThe objective of the study was to evaluate the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration in two large samples of the U.S. general population.DesignThis study included cross-sectional analyses the Third National Health and Nutrition Survey (NHANES III) and the Atherosclerosis Risk in Communities (ARIC) study.SettingThe study was conducted in the general community.Patients or other participantsPatients included 7,312 men and women from NHANES III and 14,825 men and women from the ARIC study.InterventionsSerum 25-hydroxyvitamin D, total and ionized calcium, and inorganic phosphorus were measured in NHANES III, and serum total calcium and inorganic phosphorus were measured in ARIC.Main outcome measureQT interval duration was obtained from standard 12-lead electrocardiograms.ResultsIn NHANES III, the multivariate adjusted differences in average QT interval duration comparing the highest vs. the lowest quartiles of serum total calcium, ionized calcium, and phosphorus were -3.6 msec (-5.8 to -1.3; P for trend = 0.005), -5.4 msec (-7.4 to -3.5; P for trend <0.001), and 3.9 msec (2.0-5.9; P for trend <0.001), respectively. The corresponding differences in ARIC were -3.1 msec (-4.3 to -2.0; P for trend <0.001), -2.9 msec (-3.8 to -1.9; P for trend <0.001), and 2.3 msec (1.3-3.3; P for trend <0.001). No association was found between 25-hydroxyvitamin D concentrations and QT interval duration.ConclusionsIn two large samples of the general population, QT interval duration was inversely associated with the serum total and ionized calcium and positively associated with serum phosphorus.

Project description:BackgroundFour studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW; <2,500 g) may depend upon maternal nutritional status. We investigated this dependence further using a large, diverse study population.Methods and findingsWe evaluated the interaction between maternal malaria infection and maternal anthropometric status on the risk of LBW using pooled data from 14,633 pregnancies from 13 studies (6 cohort studies and 7 randomized controlled trials) conducted in Africa and the Western Pacific from 1996-2015. Studies were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability of treatment-weighted linear and log-binomial regression models and pooled using a random-effects model. The adjusted risk of delivering a baby with LBW was 8.8% among women with malaria infection at antenatal enrollment compared to 7.7% among uninfected women (adjusted risk ratio [aRR] 1.14 [95% confidence interval (CI): 0.91, 1.42]; N = 13,613), 10.5% among women with malaria infection at delivery compared to 7.9% among uninfected women (aRR 1.32 [95% CI: 1.08, 1.62]; N = 11,826), and 15.3% among women with low mid-upper arm circumference (MUAC <23 cm) at enrollment compared to 9.5% among women with MUAC ? 23 cm (aRR 1.60 [95% CI: 1.36, 1.87]; N = 9,008). The risk of delivering a baby with LBW was 17.8% among women with both malaria infection and low MUAC at enrollment compared to 8.4% among uninfected women with MUAC ? 23 cm (joint aRR 2.13 [95% CI: 1.21, 3.73]; N = 8,152). There was no evidence of synergism (i.e., excess risk due to interaction) between malaria infection and MUAC on the multiplicative (p = 0.5) or additive scale (p = 0.9). Results were similar using body mass index (BMI) as an anthropometric indicator of nutritional status. Meta-regression results indicated that there may be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies.ConclusionsPregnant women with malnutrition and malaria infection are at increased risk of LBW compared to women with only 1 risk factor or none, but malaria and malnutrition do not act synergistically.

Project description:Genome-wide association studies (GWAS) have suggested that sequence variation in cis-regulatory elements (CREs) modulate common disease risk and trait variation. However, identification of the majority of these causal variants and their mechanism of action have remained significant challenges. We used reporter assays for all common variants at the QT interval associated SCN5A GWAS locus with the goal of identifying causal variants for the association. A target region of ~500kb containing SCN5A was defined based on recombination hotspots (rate>10cM/Mb; estimated from HapMap) flanking the 5 independent QT interval GWAS hits. Within this region, all common variants (minor allele frequency >5%), from the 1000 Genomes European ancestry populations, in moderate linkage disequilibrium (LD; r2>0.3) with any of the 5 sentinel hits, were selected for analyses. Of a total 121 variants selected, 112 variants in 104 amplicons passed primer design (amplicon size 256-617bp; median 397bp), with both alleles of 106 variants successfully cloned along with flanking sequences into 98 amplicons upstream of a minimal promoter-driven firefly luciferase gene in pGL4.23. Cardiomyocyte cells, AC16 (human) and HL1 (mouse), were transfected with test constructs and Renilla luciferase vector (for transfection normalization) in triplicate; luciferase assays were performed 24h later. All cloning and reporter assays were performed in 96- and 24-well plates. In reporter assays across the two cell lines, compared to empty vector, 37 amplicons showed enhancer activity (z-score>99 %tile), with a concordance rate of ~70%. Of these 37 enhancer CREs, 9 overlapped open chromatin regions (DNase-seq peaks) observed in adult human heart tissue, largest among all human tissues evaluated by the RoadMap Epigenomics project. Of these 37 enhancer CREs, 12 showed allelic difference in reporter activity (P<0.05), thus identifying at least one enhancer CRE variant in high-to-moderate LD with each of the 5 sentinel hits. Using GTEx heart left ventricle (n=190) gene expression data, we showed correlation between SCN5A expression and the number of QT interval prolonging alleles across the 5 index SNPs. We are currently assessing the binding of cardiac nuclear factors at the 12 enhancer CRE variants by gel-shift assays and the effect of CRISPR-Cas9 mediated CRE deletion on SCN5A expression in AC16 and HL1 cells, an analyses helped by evaluation of AC16 and HL1 cells by RNA-seq, ATAC-seq and karyotyping. Thus, independent of the publicly available epigenomic data, which are of limited cell-type relevance, an unbiased in vitro reporter screen for CREs overlapping all common variants associated with QT interval at the SCN5A GWAS locus identified 12 common cis-regulatory variants that map to cardiac open chromatin regions and correlate with SCN5A cardiac expression.

Dataset Information

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

Publications

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets