Background: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the β-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. Methods: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, β3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). Results: In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the β3AR-agonist, BRL-37344, increased myocyte BDNF content, while β3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the β1AR blocker, metoprolol, via upregulated β3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. Conclusions: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac β3AR stimulation, or β-blockers (via upregulated β3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi‐hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP‐related, Ca ²⁺ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

Brain-derived neurotrophic factor (BDNF) impacts parasympathetic nervous system function by increasing the excitability of cardioinhibitory parasympathetic neurons in the brainstem, ultimately lowering heart rate (HR) and heightening resting parasympathetic tone. Yet, whether BDNF and its high-affinity receptor—tropomyosin receptor kinase B (TrkB)—also act more distally, i.e., at the level of cholinergic-sensitive intrinsic cardiac ganglia (ICGs), remains unclear. Hence, we conducted morphological and functional studies in neural crest-specific BDNF knockout mice (ncBDNF KO), a model that selectively ablates BDNF signaling in neural crest-derived autonomic structures, including the intrinsic cardiac nervous system. ncBDNF mice exhibited a significant rise in resting heart rate with unchanged baseline contractile performance, thus supporting the role of endogenous BDNF in maintaining physiological parasympathetic restraint. When examining the ICGs, immunofluorescence analysis revealed a highly compartmentalized organization, with BDNF being predominantly confined to cholinergic neuronal somata and TrkB mainly clustered instead in S100-positive satellite glial cells, thus unveiling a previously unrecognized neuron–glia BDNF/TrkB ICG pattern. Next, we directly infused BDNF in Langendorff-perfused isolated WT mouse hearts and observed a rapid and reproducible bradycardic response that was abrogated by atropine but potentiated by neostigmine, hence attesting to the cholinergic nature of such bradycardia. Of note, BDNF maintained its positive inotropic effects under muscarinic blockade, as witnessed by the enhanced left ventricular developed pressure, maximal dP/dt, and rate-pressure product, congruent with direct BDNF-evoked myocardial TrkB agonism. Thus, ICGs are additional relevant relay stations interposed between BDNF/TrkB signaling and parasympathetic modulation of heart function. Although through different molecular paths, BDNF-mediated modulation of ICG firing can coordinate with the previously reported BDNF positive inotropy/lusitropy to adapt cardiac performance to increased workload and/or stress conditions.

ID 24433 Poster Board 157 Rationale: Lack of brain-derived neurotrophic factor (BDNF) and/or inadequate expression/activity of its associated tropomyosin kinase receptor B (TrkB) account for brain and cardiac disorder. While β-adrenergic receptor (βAR) is responsible for the local expression of BDNF in neurons, whether a similar interaction is observed and pathophysiologically relevant in the cardiovascular system is unknown, especially in the post-ischemic myocardium with adrenergic desensitization. Moreover, it is unclear whether and how TrkB agonists counter chronic post-ischemic left ventricle (LV) decompensation. Methods: We conducted in vitro studies with neonatal rat (NRVM)/adult murine cardiomyocytes (CMs), SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed the degree of impact from ischemia-related injury via either in vivo coronary ligation (myocardial infarction, MI) or ex vivo isolated hearts with global ischemia-reperfusion injury (I/R) in WT, cardiomyocyte-selective BDNF KO (myoBDNF KO) or β3AR KO mice. Results: In WT hearts, early after MI (<24 hours), BDNF levels rose while dropping at four weeks together concomitant with LV dysfunction, adrenergic denervation, and compromised angiogenesis. In vitro, the TrkB agonist, LM22A-4 promoted neurite outgrowth and neovascularization. Moreover, LM22A-4 and another agonist, TrkB, 7,8-dihydroflavone enhanced myocyte contractility. When given to in vivo MI mice, LM22A-4 rescued, at least in part, LV dysfunction, denervation, and hypovascularity. Of note, when given to isolated myoBDNF KO hearts, it no longer benefited post-I/R LV structure and function. Superfusing isolated murine myocyte with the β3AR-agonist, BRL-37344 enriched these cells with BDNF. Moreover, BRL-37344 limited post-I/R injury in WT mice but not in myoBDNF KO ones. Finally, the β1AR blocker that upregulates β3AR, augmented BDNF levels in the ischemic myocardium, improving in vivo post-MI dysfunction. Conclusions: Lack of BDNF accounts, at least in part, for chronic post-ischemic LV decompensation. By extension, by restoring intracardiac BDNF levels, TrkB agonists can limit the extent of ischemic injury, both in vivo and ex-in vivo. Direct and indirect cardiac β3AR stimulation via BRL-37344 or β-blocker, metoprolol, respectively, show another BDNF-centered means to arrest chronic post-ischemic HF. These findings may have relevant pharmacological implications for the treatment of chronic post-ischemic LV decompensation.