Are the Lessons Learned From Animal Models of Hypertension Applicable to the Clinical Condition of Hypertension in Humans?

One in three adults in the United States has diagnosed high blood pressure (1). However, taking into consideration the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults by the American Heart Association and American College of Cardiology, 130/80 mm Hg rather than 140/90 mm Hg is considered elevated arterial blood pressure (2). Approximately half of the United States adult population meets the updated criteria for hypertension. Most patients with elevated blood pressure are diagnosed with primary hypertension, where the etiology is unable to be identified. Chronic hypertension is associated with heart disease and stroke, the leading causes of death in the US. Despite advances in pre-clinical disease models of hypertension and pharmacologic agents, the underlying mechanisms of hypertension are yet to be fully determined.

The use of pre-clinical animal models has helped reveal the pathogenesis of hypertension and the testing of potential therapeutic agents. However, mechanistic questions in animal models can often be answered only through invasive procedures, such as nephrectomy, renal artery occlusion, or extreme exposures as is the case of unilateral nephrectomy with saline via oral gavage in addition to mineralocorticoid and angiotensin-II infusion to elicit hypertension in C57BL/6N mice (3, 4). The translational capability of animal models of hypertension depends on the ability to recapitulate findings in human patients with hypertension. This can pose a challenge, as animal models are considered hypertensive at systolic blood pressure levels higher than human hypertensive patients. For instance, in renovascular hypertension model of rats the animal is considered hypertensive if systolic blood pressure is > 160 mm Hg, mean arterial pressure in genetic hypertension of rats is 190-200 mm Hg, while neurogenic hypertension models in mongrel dogs and pigs, as well as rabbit models 160-190 mmHg is considered elevated blood pressure (5-9). These levels of systolic blood pressure are considered stage II hypertension or even hypertensive crisis in humans, and increase the risk for stroke, angina and aortic dissection among others.

In the American Heart Association Scientific Statement on Animal Models of Hypertension, Lerman et al. present a comprehensive summary on small and large animal models taking into consideration anatomical, physiological and hemodynamic properties of each model. Lerman and colleagues highlight the sex differences in blood pressure and drug response of these models as recent studies demonstrate inconsistent phenotypes in preclinical studies and sex differences in the prevalence and mechanisms of hypertension in human patients.

One of the challenges with animal models of hypertension, and limitations of using small animal models, is the lack of disease progression and chronicity as is seen in human hypertension. Rat models are limited by their lifespan of two years, and rarely studies follow-up these animals for more than a year. Animals models of complex disease, as in hypertension, should show high commonality to human disease. In many cases the models used to study mechanisms of hypertension do not lead to the histopathology seen in humans. Contrary to human hypertension, rat and mice models of hypertension do not develop classic atherosclerotic lesions (6). The sequelae of clinical hypertension, end-organ damage of the heart, brain, kidney and systemic vasculature, as in the case of atherosclerosis, is only present in a fraction of animal models of hypertension (6). Renal damage leading to hypertension is not easily induced in mice; however, nephrectomy in certain rat strains causes hypertension, glomerular damage and even death of the animal (11).

Due to the varied phenotypes within hypertension, and the influence of this disease by comorbidities, reproducibility of data, including physiological outcomes, may be affected by biological variables. To attain rigor and reproducibility in preclinical research animals models should be carefully selected and monitored, considering that certain animal models of hypertension have undergone changes in genotype, phenotype and/or response to pharmacologic agents as is the case of Dahl salt-sensitive rats and the recombination-activating gene-1 (Rag1) knockout mouse (12-14). Lack of rigor and reproducibility due to improper animal model selection or misinterpretation of results can lead to translational failure (15). Larger preclinical studies with increased sample size or inclusion of more than one strain may improve the ability to distinguish mechanisms of disease etiology from disease progression. Although translational failures may occur, successful translation through the rigorous use of animal models provides targets for human hypertension diagnosis and management.

Most importantly outcome measures from preclinical studies should focus on parameters with clinical relevance, such as end-organ damage prevention. Collaboration between clinicians and translational researchers, through a team approach as exemplified by Dr. Thomas Addis, with continuous reevaluation of animal models and comparison with clinical condition will enhance applicability and inform future research (3). Ultimately, a combination of models, genetic and phenotypic, may offer a more comprehensive understanding of the underlying mechanisms and determinants of differences in response to treatment for hypertension, leading to the identification of new disease markers (16).

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