Donald Bers

Intracellular fibroblast growth factors (iFGFs) are key regulators of voltage-gated sodium channels. In heart failure (HF), the late sodium current (I NaL) is markedly enhanced and contributes to arrhythmogenic action potentials (APs). However, I NaL regulation by iFGFs and its therapeutic targeting in HF have not been previously studied. We aimed to investigate the expression of iFGF11-14 splice isoforms and tested for the effects of an iFGF12 A-mimicking inhibitory peptide (FixR) on I NaL magnitude and AP duration in rabbit and murine HF ventricular myocytes. We found that the expression of long iFGF isoforms (eg, iFGF12 A and iFGF13 S), which can inhibit I NaL, was markedly reduced both in a pressure/volume-overload induced HF rabbit model and in a transverse aortic constriction (TAC) induced murine HF model. I NaL density was significantly increased in HF myocytes, and importantly, cell pretreatment …

Aim Sex-differences in heart failure with preserved ejection fraction (HFpEF) are important, but key mechanisms involved are incompletely understood. While animal models can inform about sex-dependent cellular and molecular changes, many previous preclinical HFpEF models have failed to recapitulate sex-dependent characteristics of human HFpEF. We tested for sex-differences in HFpEF using a two-hit mouse model (leptin receptor-deficient db/db mice plus aldosterone infusion for 4 weeks; db/db+Aldo). Methods and Results We performed echocardiography, electrophysiology, intracellular Ca2+ imaging, and protein analysis. Female HFpEF mice exhibited more severe diastolic dysfunction in line with increased titin N2B isoform expression and PEVK element phosphorylation, and reduced troponin-I phosphorylation. Female HFpEF mice had lower BNP levels than …

386a Tuesday, February 13, 2024 expressed in the LM and ID, with low expression at the t-tubules. A similar pattern is observed for iFGF13, the predominant iFGF in the murine heart, and iFGF14. iFGF11 was not detected in murine myocytes, while iFGF12s were found throughout the cells but at a much lower expression. The expression of NaV1. 1 was evenly distributed to the t-tubules, while NaV1. 6 and NaV1. 8 were concentrated in the t-tubules close to the LM. These results suggest various subpopulations of NaV channel and iFGF complexes within each subcellular microdomain. In the future, we will study how different NaV channels and iFGFs colocalize and whether their interactions are altered in diseased cardiomyocytes.

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial …

Women have a higher susceptibility to drug-induced long-QT syndrome (LQTS) and torsade the pointes (TdP) than men, potentially due to both chronic and acute hormonal effects on electrophysiological properties and variances in autonomic tone. Yet the mechanisms underlying the sex differences are not fully understood. Murine models have been used as valuable tools to investigate and understand the underlying mechanisms influenced by sex-related factors. Young female mice display longer action potential (AP) duration than males. Ion conductance differences such as lower I Kur and I tof and increased I NaL expression are thought to be responsible for these effects. Nevertheless, ion transporters such as the Na/Ca exchanger and lower phosphodiesterase expression in females have also been implicated. We tested whether the differences in repolarizing K currents are sufficient to explain female …

Currently, heart failure with preserved ejection fraction (HFpEF) is a human disease with increasing incidence, high mortality rates, and a narrow set of existing effective therapeutics. This disease has shown key sex-differences in which females present with higher prevalence, worse prognosis, and more severe diastolic dysfunction. The mechanisms that explain these differences are poorly understood, and this leads to inefficient drug development. Additionally, females are still underrepresented in both clinical trials and preclinical research. Many previous animal models of HFpEF failed to recapitulate key sex-differences of human HFpEF. Therefore, we proposed a preclinical HFpEF model that synergistically combines leptin receptor-deficient db/db mice with continuous 4-week aldosterone (Aldo) infusion. The HFpEF phenotype was confirmed using morphometry, echocardiography, and intracellular Ca imaging …

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome that drastically reduces patients' quality of life and increases the propensity for lethal ventricular arrhythmias. Importantly, patients' survival rate after first hospitalization is very limited, as most pharmacological options for HFpEF are currently inadequate. Functional changes of ion channels and transporters within the cardiomyocyte can induce both contractile dysfunction and arrhythmias, but exactly how excitation-contraction coupling is altered in HFpEF is still unclear. To address this gap, we implemented an integrative computational/experimental approach aiming at identifying the key disease-associated alterations in ventricular myocytes isolated from our two-hit mouse model of HFpEF (ie, leptin receptor-deficient db/db mice+ aldosterone infusion, db/db+ Aldo). We developed a preliminary parameterization of the mathematical model of …

Using fluorescence lifetime FRET-based high-throughput screening (HTS) assays, we have identified compounds that modulate the sarcoplasmic reticulum's (SR) Ca 2+ gatekeeper, the ryanodine receptor (RyR) channel. Intracellular Ca 2+ regulation is critical for striated muscle function, and SR Ca 2+ release via opening of RyR is essential for triggering muscle contraction. Under cellular rest, increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, and neurodegenerative diseases. Thus, this leaky state of the RyR is a high-value pharmacological target for treating such pathologies. Our FRET-based HTS detects the RyR leaky state by monitoring binding of the accessory proteins calmodulin, FKBP12. 0, FKBP12. 6, and DPc10. Under conditions that mimic a pathological state, we have screened two distinct 50,000 compound libraries for …