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Heart Failure (HF) continues to be a complex public health issue with increasing world population prevalence. Although overall mortality has decreased for HF and hypertrophic cardiomyopathy (HCM), a precursor for HF, their prevalence continues to increase annually. Because the etiology of HF and HCM is heterogeneous, it has been difficult to identify novel therapies to combat these diseases. Isoproterenol (ISP), a non-selective β-adrenoreceptor agonist, is commonly used to induce cardiotoxicity and cause acute and chronic HCM and HF in mice. However, the variability in dose and duration of ISP treatment used in studies has made it difficult to determine the optimal combination of ISP dose and delivery method to develop a reliable ISP-induced mouse model for disease. Here we examined cardiac effects induced by ISP via subcutaneous (SQ) and SQ-minipump (SMP) infusions across 3 doses (2, 4, and 10mg/kg/day) over 2 weeks to determine whether SQ and SMP ISP delivery induced comparable disease severity in C57BL/6J mice. To assess disease, we measured body and heart weight, surface electrocardiogram (ECG), and echocardiography recordings. We found all 3 ISP doses comparably increase heart weight, but these increases are more pronounced when ISP was administered via SMP. We also found that the combination of ISP treatment and delivery method induces contrasting heart rate, RR interval, and R and S amplitudes that may place SMP treated mice at higher risk for sustained disease burden. Mice treated via SMP also had increased heart wall thickness and LV Mass, but mice treated via SQ showed greater increase in gene markers for hypertrophy and fibrosis. Overall, these data suggest that at 2 weeks, mice treated with 2, 4, or 10mg/kg/day ISP via SQ and SMP routes cause similar pathological heart phenotypes but highlight the importance of drug delivery method to induce differing disease pathways.

Background Transforming growth factor beta (TGF‐β) is an important cytokine in mediating the cardiac fibrosis that often accompanies pathogenic cardiac remodeling. Cardiomyocyte‐specific expression of a mutant αB‐crystallin (CryABR120G), which causes human desmin‐related cardiomyopathy, results in significant cardiac fibrosis. During onset of fibrosis, fibroblasts are activated to the so‐called myofibroblast state and TGF‐β binding mediates an essential signaling pathway underlying this process. Here, we test the hypothesis that fibroblast‐based TGF‐β signaling can result in significant cardiac fibrosis in a disease model of cardiac proteotoxicity that has an exclusive cardiomyocyte‐based etiology. Methods and Results Against the background of cardiomyocyte‐restricted expression of CryABR120G, we have partially ablated TGF‐β signaling in cardiac myofibroblasts to observe whether cardiac fibrosis is reduced despite the ongoing pathogenic stimulus of CryABR120G production. Transgenic CryABR120G mice were crossed with mice containing a floxed allele of TGF‐β receptor 2 (Tgfbr2f/f). The double transgenic animals were subsequently crossed to another transgenic line in which Cre expression was driven from the periostin locus (Postn) so that Tgfbr2 would be ablated with myofibroblast conversion. Structural and functional assays were then used to determine whether general fibrosis was affected and cardiac function rescued in CryABR120G mice lacking Tgfbr2 in the myofibroblasts. Ablation of myofibroblast specific TGF‐β signaling led to decreased morbidity in a proteotoxic disease resulting from cardiomyocyte autonomous expression of CryABR120G. Cardiac fibrosis was decreased and hypertrophy was also significantly attenuated, with a significant improvement in survival probability over time, even though the primary proteotoxic insult continued. Conclusions Myofibroblast‐targeted knockdown of Tgfbr2 signaling resulted in reduced fibrosis and improved cardiac function, leading to improved probability of survival.

BackgroundCardiac stress can trigger production of a 40‐kDa peptide fragment derived from the amino terminus of the cardiac myosin‐binding protein C. Cardiac stress, as well as cMyBP‐C mutations, can trigger production of 1 such truncated protein fragment, a 40‐kDa peptide fragment derived from the amino terminus of cMyBP‐C. Genetic expression of this 40‐kDa fragment in mouse cardiomyocytes (cMyBP‐C40k) leads to cardiac disease, fibrosis, and death within the first year. Fibrosis can occur in many cardiovascular diseases, and mitogen‐activated protein kinase––activated protein kinase‐2 signaling has been implicated in a variety of fibrotic processes. Recent studies demonstrated that mitogen‐activated protein kinase––activated protein kinase‐2 inhibition using the cell‐permeant peptide inhibitor MMI‐0100 is protective in the setting of acute myocardial infarction. We hypothesized that MMI‐0100 might also be protective in a chronic model of fibrosis, produced as a result of cMyBP‐C40k cardiomyocyte expression. Methods and ResultsNontransgenic and cMyBP‐C40k inducible transgenic mice were given MMI‐0100 or PBS daily for 30 weeks. In control groups, long‐term MMI‐0100 was benign, with no measurable effects on cardiac anatomy, function, cell viability, hypertrophy, or probability of survival. In the inducible transgenic group, MMI‐0100 treatment reduced cardiac fibrosis, decreased cardiac hypertrophy, and prolonged survival. ConclusionsPharmaceutical inhibition of mitogen‐activated protein kinase––activated protein kinase‐2 signaling via MMI‐0100 treatment is beneficial in the context of fibrotic cMyBPC40k disease.

The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents. [ABSTRACT FROM AUTHOR]