How good are our models of cardiovascular disease? Introducing our themed issue on preclinical models for cardiovascular disease research

Cardiovascular disease (CVD) is an enormous health challenge that remains a major contributor to global morbidity and mortality. The World Health Organization (WHO) reports that nearly one-third of all deaths in 2019 were directly attributable to myocardial or vascular disease (myocardial infarction and stroke account for nearly 85% of all CVD-related deaths) (WHO, 2021). Although several modifiable risk factors are known (e.g., hypertension, smoking, diabetes and poor diet), our understanding of precise cellular and molecular mechanisms of cardiovascular pathology is minimal, and hence, many of our current therapies still merely treat the symptoms of cardiovascular disease. In order to more effectively intervene to halt or reverse cardiovascular disease progression, we first need to gain a greater understanding of those complex underlying pathologies. Animal models have been, and will continue to be, vital for increasing our understanding of both physiology and cardiovascular disease development in humans. This themed issue on Preclinical Models for Cardiovascular Disease Research comprises 11 reviews by leading cardiovascular research groups that describe and update current models for studying key features of human cardiovascular pathologies. Since the major therapeutic approach in tackling CVD remains drug-based, articles in this Themed Issue provide important context on how the model in question can be used to develop new drugs to treat, and even perhaps, prevent CVD. Animal models are critical for the improved understanding and treatment of several contributors to cardiovascular morbidity and mortality associated with systemic, peripheral or vascular disorders, such as hypertension, diabetes and vascular rupture. Hypertension is the main risk factor for cardiovascular disease and, as it involves multiple organs and systems, remains a challenging disease for the discovery of underlying molecular targets and testing new treatments. For several decades, rodent models of hypertension have proven to be highly valuable for advancing the field, and here, Jama et al. (2021) discuss their strengths and weaknesses, highlighting how specific target organs and systems influence blood pressure in the major rodent models. Diabetes is also a major risk factor for the development of numerous vascular complications that represent significant causes of mortality and morbidity. Choi et al. review our current understanding of mechanisms of diabetes-driven vascular complications and the therapies arising from studies of animal models (Choi et al., 2021). Consideration is given to the choice of appropriate models to study vascular pathogenesis to identify novel mechanism-based targeted therapies to reduce the burden of diabetic complications. Abdominal aortic aneurysm (AAA) rupture is typically life-threatening, with surgical repair of large asymptomatic aneurysms being the only current treatment. As this procedure is itself associated with a risk of serious perioperative complications, patients with small aneurysms are treated conservatively despite 70% of small aneurysms continuing to grow with an increased risk of rupture. There is clearly an urgent need to develop drug therapies effective at slowing AAA growth, and the review by Golledge et al. describes the commonly used mouse models for AAA that are being used in this research (Golledge et al., 2022). Another prevalent type of vascular injury that results in significant cardiovascular morbidity and mortality is the rupture of unstable or vulnerable atherosclerotic plaques. However, it has been extremely challenging to study unstable plaque pathology so as to effectively prevent plaque rupture, and most atherosclerosis research has utilised preclinical animal models exhibiting stable atherosclerosis. Here, Noonan et al. describe their novel Tandem Stenosis mouse model that reflects plaque instability and rupture as seen in patients, exhibiting key characteristics of human unstable plaques (Noonan et al., 2021). This model appears to represent an ideal preclinical tool for improving our understanding of human plaque instability/rupture, developing imaging technologies to identify unstable plaques and testing plaque-stabilising therapeutics. Furthermore, animal models of overt cardiac dysfunction and disease are vital for progress in research with larger species than rats or mice playing prominent roles. For example, rabbit models have made a significant contribution to cardiac disease research, and Hornyik et al. review their advantages and also their limitations (Hornyik et al., 2021). In particular, they address methodological approaches for the generation of transgenic rabbits for cardiac disease research and introduce currently available transgenic rabbit models for monogenic cardiac diseases. Models in even larger animal species, such as pigs, goats, dogs and horses, can accurately reflect human phenotypes of atrial fibrillation, an increasing health problem in the aging population. Animal models are needed to understand the mechanisms of AF, as well as to test new pharmacological interventions. The review by Saljic et al. focuses on antiarrhythmic investigations in large animals, including spontaneous atrial fibrillation in small and large mammals followed by a short presentation of frequently used methods for inducing short- and long-term atrial fibrillation with a major focus on antiarrhythmic compounds used in the human clinic or promising new candidates (Saljic et al., 2021). Moreover, Loen et al. provide us with a description of the canine model of ventricular cardiac arrhythmia by chronic atrioventricular block and its value for preclinical drug research (Loen et al., 2021). Those authors provide an explanation of the structural, contractile and electrical remodelling processes following atrioventricular block and thus offer insight into several factors contributing to drug-induced arrhythmia. However, in addition to their higher cost, large animal models are not without significant ethical challenges that have become more acute and prohibitive for researchers in this century. Regulatory requirements for continual reduction, refinement and replacement of animals in research are ever present and can limit the excellence of the scientific insight obtainable. Thus, at the other end of the spectrum of animal models, Bowley et al. review the utility of zebrafish to model accurately important aspects of human cardiovascular development and disease (Bowley et al., 2021). They compare the anatomy and physiology of zebrafish and mammalian cardiovascular systems and describe zebrafish models for studying the mechanisms of a range of cardiac and vascular pathologies, pharmacological responses to cardiovascular drugs and the in vivo screening of compounds for the treatment of cardiovascular diseases. Acute myocardial infarction is the most severe consequence of coronary artery disease and is the leading cause of cardiovascular mortality. Animal models have played an important role in advancing our understanding of myocardial infarction and enabling the development of therapeutic strategies currently used to treat patients with myocardial infarction and heart failure. Nevertheless, pre-clinical models do not fully recapitulate the complexity of myocardial infarction in humans, and so the model must be selected carefully to maximise the translational relevance of results. Martin et al. describe current models of myocardial infarction and consider their usefulness for understanding drug mechanisms of action and developing translational medicines (Martin et al., 2021). Furthermore, a common consequence of myocardial infarction is cardiac fibrosis or scarring, due to the deposition of extracellular matrix proteins, which contributes to the progression of heart failure. It is therefore likely that the development of interventions to inhibit cardiac fibrosis could improve patient outcomes. Many preclinical approaches have been used to study cardiac fibrosis, and here, Wang et al. discuss commonly used rodent models, also providing context for the use of specific heart failure models (Wang et al., 2021). Finally, but importantly, pulmonary hypertension is a fatal condition that may occur due to the development of right ventricular failure. However, there are still no therapies targeted to right ventricular failure, and right ventricular function is not always addressed in the preclinical evaluation of new therapeutics. Dignam et al. describe several small animal models used to study pulmonary hypertension, including classical models involving exposure to hypoxia or monocrotaline, newer combinational and genetic models and a surgical model of pulmonary artery banding to produce right ventricular pressure overload (Dignam et al., 2021). Recapitulation by these models of clinical features (structural remodelling and functional decline) have provided valuable insight into the pathophysiology of right ventricular failure. However, the challenge of reversing remodelling and improving right ventricular function remains an obstacle, with emerging animal models likely to reveal mechanisms and druggable molecular targets in the transition from adaptive remodelling to a failing right ventricle. We trust that our readers will find the breadth and depth of information provided in this Themed Issue on Preclinical Models for Cardiovascular Disease Research to be valuable for providing context for published cardiovascular findings in animal models of disease and for guiding high-quality future preclinical cardiovascular research.