Biology subjects

Haq, K.

Publications and source records attributed to Haq, K..

4 recordsLinked to original sources

bioRxiv2024

Validation of a Demography-Based Adaptive QTc Formula using Pediatric and Adult Datasets Acquired from Humans and Guinea Pigs

IntroductionA variety of QT rate-correction (QTc) formulae have been utilized for both clinical and research purposes. However, these formulae are not universally effective, likely due to significant influences of demographic diversity on the QT-HR relationship. To address this limitation, we proposed an adaptive QTc (QTcAd) formula that adjusts to subject demographics (i.e., age). Further, we compared the efficacy and accuracy of the QTcAd formula to other widely used alternatives. MethodUsing age as a demographic parameter, we tested the QTcAd formula across diverse age groups with different heart rates (HR) in both humans and guinea pigs. Utilizing retrospective human (n=1360) and guinea pig electrocardiogram (ECG) data from in-vivo (n=55) and ex-vivo (n=66) settings, we evaluated the formulas effectiveness. Linear regression fit parameters of HR-QTc (slope and R{superscript 2}) were utilized for performance assessment. To evaluate the accuracy of the predicted QTc, we acquired epicardial electrical and optical voltage data from Langendorff-perfused guinea pig hearts. ResultsIn both human subjects and guinea pigs, the QTcAd formula consistently outperformed other formulae across all age groups. For instance, in a 20-year-old human group (n=300), the QTcAd formula successfully nullified the inverse HR-QT relationship (R{superscript 2}=5.1E-09, slope=-3.5E-05), while the Bazett formula (QTcB) failed to achieve comparable effectiveness (R{superscript 2}= 0.20, slope=0.91). Moreover, the QTcAd formula exhibited better accuracy than the age-specific Benatar formula (QTcBe), which overcorrected QTc (1-week human QT: 263.8{+/-}14.8 ms, QTcAd: 263.8{+/-}7.3 ms, p=0.62; QTcBe: 422.5{+/-}7.3 ms, p<0.0001). The optically measured pseudo-QT interval (143{+/-}22.5 ms, n=44) was better approximated by QTcAd (180.6{+/-}17.0 ms) compared to all other formulae. Furthermore, we demonstrated that the QTcAd formula was not inferior to individual-specific QTc formulae. ConclusionThe demography-based QTcAd formula showed superior performance across human and guinea pig age groups, which may enhance the efficacy of QTc for cardiovascular disease diagnosis, risk stratification, and drug safety testing. What is knownCorrected QT (QTc) is a well-known ECG biomarker for cardiovascular disease risk stratification and drug safety testing. Various QT rate-correction formulae have been developed, but these formulae do not perform consistently across diverse datasets (e.g., sex, age, disease, species). What the study addsWe introduce a novel QTc formula (QTcAd) that adapts to demographic variability, as the parameters can be modified based on the characteristics of the study population. The formula (QTcAd = QT + (|m|*(HR-HRmean)) - includes the absolute slope (m) of the linear regression of QT and heart rate (HR) and the mean HR of the population (HRmean) as population characteristics parametersUsing datasets from both pediatric and adult human subjects and an animal model, we demonstrate that the QTcAd formula is more effective at eliminating the QT-HR inverse relationship, as compared to other commonly used correction formulae.

physiology↗

bioRxiv2023

Toxins in plastic: Evidence for the cardiodepressive effects of di-2-ethylhexylphthalate (DEHP)

Di-2-ethylhexylphthalate (DEHP) is commonly used in the manufacturing of plastic materials, including intravenous bags, blood storage bags, and medical-grade tubing. DEHP can leach from plastic medical products, which can result in inadvertent patient exposure. DEHP concentrations were measured in red blood cell (RBC) units stored between 7-42 days (23-119 g/mL). Using these concentrations as a guide, Langendorff-perfused rat heart preparations were acutely exposed to DEHP. Sinus activity remained stable with lower doses of DEHP (25-50 g/mL), but sinus rate declined by 43% and sinus node recovery time prolonged by 56.5% following 30-minute exposure to 100 g/ml DEHP. DEHP exposure also exerted a negative dromotropic response, as indicated by a 69.4% longer PR interval, 108.5% longer Wenckebach cycle length, and increased incidence of atrioventricular uncoupling. Pretreatment with doxycycline partially rescued the effects of DEHP on sinus activity, but did not ameliorate the effects on atrioventricular conduction. DEHP exposure also prolonged the ventricular action potential and effective refractory period, but had no measurable effect on intracellular calcium transient duration. Follow-up studies using hiPSC-CM confirmed that DEHP slows electrical conduction in a time (15 min - 3 hours) and dose-dependent manner (10-100 g/mL). Previous studies have suggested that phthalate toxicity is specifically attributed to metabolites of DEHP, including mono-2-ethylhexyl phthalate (MEHP). This study demonstrates that DEHP exposure also contributes to cardiac dysfunction in a dose- and time-dependent manner. Future work is warranted to investigate the impact of DEHP (and its metabolites) on human health, with special consideration for clinical procedures that employ plastic materials.

pharmacology and toxicology↗

bioRxiv2023

KairoSight-3.0: Validated Optical Mapping Software to Characterize Cardiac Electrophysiology, Excitation-Contraction Coupling, and Alternans

BackgroundCardiac optical mapping is an imaging technique that measures fluorescent signals across a cardiac preparation. Dual optical mapping of voltage-sensitive and calcium-sensitive probes allow for simultaneous recordings of cardiac action potentials and intracellular calcium transients with high spatiotemporal resolution. The analysis of these complex optical datasets is both time intensive and technically challenging; as such, we have developed a software package for semi-automated image processing and analysis. Herein, we report an updated version of our software package (KairoSight-3.0) with features to enhance characterization of cardiac parameters using optical signals. MethodsTo test software validity and applicability, we used Langendorff-perfused heart preparations to record transmembrane voltage and intracellular calcium signals from the epicardial surface. Isolated hearts from guinea pigs and rats were loaded with a potentiometric dye (RH237) and/or calcium indicator dye (Rhod-2AM) and fluorescent signals were acquired. We used Python 3.8.5 programming language to develop the KairoSight-3.0 software. Cardiac maps were validated with a user-specified manual mapping approach. ResultsManual maps of action potential duration (30 or 80% repolarization), calcium transient duration (30 or 80% reuptake), action potential and calcium transient alternans were constituted to validate the accuracy of software-generated maps. Manual and software maps had high accuracy, with >97% of manual and software values falling within 10 ms of each other and >75% within 5 ms for action potential duration and calcium transient duration measurements (n=1000-2000 pixels). Further, our software package includes additional cardiac metric measurement tools to analyze signal-to-noise ratio, conduction velocity, action potential and calcium transient alternans, and action potential-calcium transient coupling time to produce physiologically meaningful optical maps. ConclusionsKairoSight-3.0 has enhanced capabilities to perform measurements of cardiac electrophysiology, calcium handling, and the excitation-contraction coupling with satisfactory accuracy. Graphical Abstract Demonstrating Experimental and Data Analysis WorkflowCreated with Biorender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/538926v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@619850org.highwire.dtl.DTLVardef@156cd35org.highwire.dtl.DTLVardef@1ba772aorg.highwire.dtl.DTLVardef@e57084_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Does Sex Modify an Association of Electrophysiological Substrate with Sudden Cardiac Death? The Atherosclerosis Risk in Communities (ARIC) Study

BackgroundSex is a well-recognized risk factor for sudden cardiac death (SCD). Sex differences in electrophysiological (EP) substrate of SCD are known. However, it remains unknown whether sex can modify an association of EP substrate with SCD.\n\nMethodsParticipants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,725; age, 54.2{+/-}5.8 yrs; 55% female, 74% white) were included. EP substrate was characterized by traditional 12-lead ECG (heart rate, QRS, QTc, Cornell voltage), spatial ventricular gradient (SVG) and sum absolute QRST integral (SAI QRST) metrics. Two competing outcomes were adjudicated SCD and nonSCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Relative hazard ratio (RHR) and relative sub-hazard ratio (RSHR) with a 95% confidence interval for SCD and nonSCD risk for women relative to men were calculated. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD.\n\nResultsOver a median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72 (1.58-1.88)/1000 person-years) and 2,178 nonSCDs (incidence 7.09; (6.80-7.39)/ 1000 person-years). Women experienced a greater than men risk of SCD associated with Cornell voltage (RHR 1.18(1.06-1.32); P=0.003), SAI QRST (RHR 1.16(1.04-1.30); P=0.007), area SVG magnitude (RHR 1.24(1.05-1.45); P=0.009), and peak SVG magnitude (RHR 1.22(1.04-1.44); P=0.018), independently from incident CVD. Greater risk of SCD for women than men associated with QRS duration (RHR 1.24(1.07-1.44); P=0.004) and QTc (RSHR 1.15(1.02-1.30); P=0.025) was explained by incident CVD. Furthermore, women had greater odds of SCD associated with heart rate (RSHR 1.19(1.01-1.40); P=0.036), independently of incident CVD.\n\nConclusionsSex modifies an association of EP substrate with SCD. In women, global EP substrate is associated with up to 27% greater risk of SCD than in men. Development of sex-specific risk scores of SCD is necessary. Further studies of mechanisms behind sex differences in EP substrate of SCD are warranted.

epidemiology↗