Biology subjects

Swift, L. M.

Publications and source records attributed to Swift, L. M..

3 recordsLinked to original sources

bioRxiv2026

Postnatal Development Shapes the Cardiac Response to Milrinone

Background: Milrinone, a phosphodiesterase-3 (PDE-3) inhibitor, is widely used to improve cardiac output in pediatric and adult patients. Yet, developmental differences in myocardial responsiveness to milrinone remain incompletely understood. In this study, we examined the impact of postnatal maturation on the acute cardiac effects of milrinone using an intact guinea pig heart model. Methods: Neonatal (0-2 days), juvenile (4-10 days), and adult (> 6 months) guinea pig hearts were excised, Langendorff-perfused, and cardiac metrics were evaluated under basal conditions and in response to acute milrinone treatment (15 minutes, 10 and 100 M sequential concentrations). Pseudo-electrocardiograms were recorded continuously and left ventricular pressure measurements were performed under sinus rhythm and in response to external pacing. Post-rest potentiation was used to assess contractile reserve, and optical action potentials and calcium transients were recorded. Results: Baseline left ventricular developed pressure (LVDP), action potential duration (APD), and calcium transient duration (CaD) increased with postnatal maturation, consistent with developmental cardiomyocyte remodeling and refinement of excitation-contraction coupling. Milrinone increased heart rate in all age groups, with the greatest chronotropic response at 100 M. Milrinone also increased ventricular contractility and relaxation across developmental stages, but the magnitude of the response varied with age and was attenuated during high frequency pacing. Adult hearts had the greatest increase in LVDP during sinus rhythm and robust post-rest potentiation, which were less pronounced in neonatal hearts. APD and CaD were shortened in neonatal and adult hearts, but were minimally affected in juveniles, indicating a non-linear developmental pattern. Conclusions: Milrinone exerts positive chronotropic, inotropic, and lusitropic effects throughout development, but the magnitude and frequency dependence of these responses vary with age. These findings suggest that postnatal maturation influences the cardiac response to PDE3 inhibition. These developmental differences highlight the importance of considering age as a biological factor in pediatric drug selection and dosing.

pharmacology and toxicology↗

bioRxiv2024

Electroanatomical Adaptations in the Guinea Pig Heart from Neonatal to Adulthood

BackgroundElectroanatomical adaptations during the neonatal to adult phase have not been comprehensively studied in preclinical animal models. To explore the impact of age as a biological variable on cardiac electrophysiology, we employed neonatal and adult guinea pigs, which are a recognized animal model for developmental research. MethodsHealthy guinea pigs were categorized into three age groups (neonates, n=10; younger adults, n=13; and older adults, n=26). Electrocardiogram (ECG) recordings were collected in vivo from anesthetized animals (2-3% isoflurane). A Langendorff-perfusion system was employed for optical assessment of epicardial action potentials and calcium transients, using intact excised heart preparations. Optical data sets were analyzed and metric maps were constructed using Kairosight 3.0. ResultsThe allometric relationship between heart weight and body weight diminishes with age, as it is strongest at the neonatal stage (R2 = 0.84) and completely abolished in older adults (R2 = 1E-06). Neonatal hearts exhibit circular activation waveforms, while adults show prototypical elliptical shapes. Neonatal conduction velocity (40.6{+/-}4.0 cm/s) is slower than adults (younger adults: 61.6{+/-}9.3 cm/s; older adults: 53.6{+/-}9.2 cm/s). Neonatal hearts have a longer action potential duration (APD) and exhibit regional heterogeneity (left apex; APD30: 68.6{+/-}5.6 ms, left basal; APD30: 62.8{+/-}3.6), which was absent in adult epicardium. With dynamic pacing, neonatal hearts exhibit a flatter APD restitution slope (APD70: 0.29{+/-}0.04) compared to older adults (0.49{+/-}0.04). Similar restitution characteristics are observed with extrasystolic pacing, with a flatter slope in neonatal hearts (APD70: 0.54{+/-}0.1) compared to adults (Younger adults: 0.85{+/-}0.4; Older adults: 0.95{+/-}0.7). Finally, neonatal hearts display unidirectional excitation-contraction coupling, while adults exhibit bidirectionality. ConclusionThe transition from neonatal to adulthood in guinea pig hearts is characterized by transient changes in electroanatomic properties. Age-specific patterns can influence cardiac physiology, pathology, and therapies for cardiovascular diseases. Understanding postnatal heart development is crucial to evaluating therapeutic eligibility, safety, and efficacy. What is KnownAge-specific cardiac electroanatomical characteristics have been documented in humans and some preclinical animal models. These age-specific patterns can influence cardiac physiology, pathology, and therapies for cardiovascular diseases. What the Study AddsCardiac electroanatomical characteristics are age-specific in guinea pigs, a well-known preclinical model for developmental studies. Age-dependent adaptations in cardiac electrophysiology are readily observed in the electrocardiogram recordings and via optical mapping of epicardial action potentials and calcium transients. Our findings reveal unique activation and repolarization characteristics between neonatal and adult animals. Graphical AbstractAge-dependent adaptations in the guinea pig heart include adjustments in allometric scaling and cardiac electrophysiology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/577234v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@5fcdaforg.highwire.dtl.DTLVardef@1b8acc3org.highwire.dtl.DTLVardef@1567089org.highwire.dtl.DTLVardef@1f63c4a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗