Heart failure (HF) is a clinical syndrome with various etiologies and heterogeneous clinical manifestations in patients. It can be classified into three groups based on ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range EF (HFmrEF), and heart failure with preserved EF (HFpEF) [1]. HFrEF is marked by cardiomyocyte loss resulting in systolic dysfunction, often preceded by ischemic events. By contrast, HFpEF is characterized by structural and cellular changes leading to impaired left ventricular relaxation, usually preceded by chronic comorbidities like hypertension and diabetes. Patients with HFrEF are more likely to be men with ischemic heart disease while patients with HFpEF are typically older and more often are women. Patients with HFpEF have a higher burden of medical comorbidities such as hypertension and atrial fibrillation. The term HFmrEF refers to an intermediate heart failure phenotype between HFrEF and HFpEF, sharing similarities with both groups in terms of clinical characteristics and risk factors [2,3].

To decipher the intricate interplay of molecular mechanisms and causal factors that lead to the progression of heart failure, an array of experimental models have been developed over many decades. Heart failure models span a diverse array of living organisms, ranging from unicellular yeast to the higher-order physiological intricacies of rodents, sheep, and goats. In 1979, Pfeffer et al. created the first animal model of heart failure in rats by surgically occluding the left coronary artery. In this model, they demonstrated the cardioprotective effects and survival benefit of the class of cardiovascular drugs termed angiotensin converting enzyme (ACE) inhibitors [4,5]. ACE inhibitors have become standard therapy in patients with myocardial infarction or heart failure. Another heart failure model used was established by Rockman et al., in 1991 [6], and involved inducing pressure overload of the heart using microsurgical techniques to band the thoracic aorta of mice. Over the years, heart failure has been studied in experimental models of hypertension via renal embolization or pharmacologic treatments [[7], [8], [9], [10]]Click or tap here to enter text.; induction of metabolic syndrome through diets high in fat and or sugar [11,12]Click or tap here to enter text.; and monogenic cardiomyopathy models utilizing knockout mice [13,14].Click or tap here to enter text. Multi-hit approaches that combine factors like aging, diet, and pharmacological interventions have also been developed [15,16].Click or tap here to enter text.

Each of these models has its advantages, particularly in studying the impact of specific interventions in heart failure, such as gene knockout or dietary modifications. Despite their merits, no single experimental model can replicate the complexity inherent to human heart failure. Oxidative stress has been implicated in the pathogenesis of heart failure in many experimental animal models as well as in human heart failure. Chemogenetic techniques have emerged as a promising avenue to elucidate the roles of redox regulation and dysregulation in the pathophysiology of heart failure. Recently, new animal models have shown that chemogenetic oxidative stress can lead to myriad new and surprising phenotypes. This review aims to discuss the current landscape of chemogenetic approaches and experimental systems deployed to probe the intricacies of redox dynamics and offer insight into potential therapeutic targets in the changing landscape of heart failure.