Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as for example acute myocardial infarction and postischemic heart failure, heart failure of additional etiologies, and cardiac arrhythmias, belong to the leading causes of death. In contrast, the cardioprotective part of TRPV1 receptors after adenoviral delivery of the NGF gene was supported in normal and combined streptozotocin- and high extra fat diet-induced diabetic mouse hearts subjected to I/R injury ex vivo. Elevated levels of CGRP, but not SP, were 5-Methylcytidine found, which was accompanied by improved cardiac functions in both organizations . A recent study showed that in the heart of normal rats treated with the antidiabetic drug dipeptidyl peptidase 4 inhibitor sitagliptin orally for 2 weeks, TRPV1 and also CGRP protein levels were improved. Moreover, capsazepine co-administered with sitagliptin orally for 2 weeks 5-Methylcytidine abolished the cardioprotective effect of DPP-4 inhibition when rat hearts were subjected to I/R injury . Morphine, a major analgesic drug used to alleviate severe pain accompanied with AMI, was KMT6 shown to protect the heart against I/R injury, and this protection was partially mediated by TRPV1 receptors since TRPV1 receptor antagonists (capsazepine or P5, a peptide analgesic and TRPV1 inhibitor), prior to coronary occlusion, abrogated the cardioprotective effects of morphine . 4.2.2. Ischemic ConditioningThe endogenous ischemic adaptation phenomena, including different forms of ischemic pre- and postconditioning, may involve capsaicin-sensitive nerve- or TRPV1-mediated cardioprotection. In ischemic preconditioning (IPC), the critical role of TRPV1 receptors was demonstrated by TRPV1 gene deletion, which abolished SP- and CGRP-mediated cardioprotection evoked by IPC . Sensory Nerve DesensitizationOur research group has shown for the first time in the literature that capsaicin-sensitive sensory nerves are involved in preconditioning-induced cardioprotection evoked by rapid ventricular pacing. Preconditioning stimuli facilitated the release of CGRP and nitric oxide from capsaicin-sensitive nerves [40,90], which was abolished by systemic capsaicin treatment-induced sensory desensitization. Later on, a research group from the Hunan Medical University, China, demonstrated that systemic high dose (50 mg/kg) capsaicin treatment abrogates the cardioprotective effects of ischemia-, CGRP-, bradykinin-, and monophosphoryl lipid A-induced early or delayed preconditioning, respectively [91,92,93,94]. They have shown a significant decrease in the number of CGRP positive neurons, as well as decreased plasma CGRP levels, in the capsaicin-treated groups in each experimental setup. TRPV1 ModulationRemote IPC triggered by short episodes of hindlimb ischemia in rats was shown to be transferred at least partially by TRPV1 channels, since elevated left ventricular TRPV1 expression was measured after remote IPC as compared to control ischemic animals . TRPV1 activation-induced CGRP release have been shown to participate in sensory nerve-mediated cardioprotection. The cardioprotective effect of limb ischemia-induced remote ischemic postconditioning was shown to 5-Methylcytidine be abrogated by capsazepine, the CGRP antagonist CGRP8C37, and the SP antagonist RP67580, respectively, as administered IV separately to rats . Moreover, decreased myocardial TRPV1 expression was accompanied by reduced CGRP and SP release into coronary effluent after myocardial ischemia in 5-Methylcytidine the isolated hearts of type I diabetic rats as compared to nondiabetic ones, leading to the loss of ischemic postconditioning-induced cardioprotection and impaired myocardial function . 4.2.3. SummaryThese experimental data show predominantly protective roles of cardiac capsaicin-sensitive afferents and sensory TRPV1 receptors in myocardial protection through the release of sensory neuropeptides. However, involvement of TRPV1 receptors expressed by cardiomyocytes [43,98] and endothelial cells has not been investigated. Although several studies have been performed to investigate the alterations in proteomics or transcriptomics, including microRNA (miRNA)-omics, related to myocardial I/R injury or cardioprotective maneuvers like ischemic conditionings, surprisingly, involvement of TRPV1 or capsaicin-sensitive sensory nerves in such studies is still an unmet need. 4.3. Center Failure Heart failing (HF) can be a complex medical syndrome caused by the reduced function of the proper, remaining, or both ventricles. The symptoms are based on an insufficient cardiac output, because the faltering center struggles to match the needs . Three main phenotypes describe HF.