How good are our models of cardiovascular disease?

Cardiovascular disease (CVD) is an enormous health challenge that remains a major contributor to global morbidity and mortality. The World Health Organisation (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 cardiovascular disease 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 cardiovascular disease 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 cardiovascular disease. 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. (2021) review our current understanding of mechanisms of diabetes-driven vascular complications and the therapies arising from studies of animal models. 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 abdominal aortic aneurysm growth, and the review by Golledge et al. (2021) describes the commonly used mouse models for abdominal aortic aneurysm that are being used in this research. 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. (2021) describe their novel Tandem Stenosis mouse model that reflects plaque instability and rupture as seen in patients, exhibiting key characteristics of human unstable plaques. 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. (2021) review their advantages and also their limitations. 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, LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley. com/doi/10.1111/bph.v179. 5/issuetoc DOI: 10.1111/bph.15761