Heart or cardiovascular diseases are said to be the principal cause of deaths in humans around the globe for many years. In this present era heart regeneration is said to be a better option for heart disease. Stem cell-based therapy for heart regeneration has long been seen as a potential application since the heart lacks adequate intrinsic regenerative potential. Innovations are new idea, device or process. Innovations are the application of better solutions that meet new requirements, inarticulated needs or existing market needs. It is proficient through more effective products, processes, services, technologies, or new ideas that are readily available to markets, governments and society. Innovations are something original and novel, as a significant, new that breaks into the market or society. Ischemic heart disease is the leading cause of death worldwide. The blockade of coronary arteries limits oxygen-rich blood to the heart and consequently there is cardiomyocyte (CM) cell death, inflammation, fibrotic scarring, and myocardial remodeling. Unfortunately, current therapeutics fail to effectively replace the lost cardiomyocytes or prevent fibrotic scarring, which results in reduced cardiac function and the development of heart failure (HF) in the adult mammalian heart. In contrast, neonatal mice are capable of regenerating their hearts following injury. However, this regenerative response is restricted to the first week of post-natal development. Recently, we identified that cholinergic nerve signaling is necessary for the neonatal mouse cardiac regenerative response. This demonstrates that cholinergic nerve stimulation holds significant potential as a bioelectronic therapeutic tool for heart disease. However, the mechanisms of nerve directed regeneration in the heart remain undetermined. In this review, we will describe the historical evidence of nerve function during regeneration across species. Specifically, we will focus on the emerging role of cholinergic innervation in modulating cardiomyocyte proliferation and inflammation during heart regeneration. Understanding the role of nerves in mammalian heart regeneration and adult cardiac remodeling can provide us with innovative bioelectronic-based therapeutic approaches for treatment of human heart disease.