Heart failure is a major and escalating global public health problem with a prevalence of more than 5.8 million cases in the USA alone, and an additional 550,000 new diagnoses are made every year. Scientists have made enormous progress in revealing the mechanistic factors that lead to heart failure, and there have been significant advances in interventions that can slow the progression of the condition. Yet, for patients diagnosed with heart failure, mortality and morbidity remain high, and quality of life is poor.
The development of preventative and reparative therapies of the future will depend critically on surgical animal models. However, creating these models is extremely challenging and requires extensive expertise and training to maintain consistency across cohorts. Furthermore, traditional methods to measure hemodynamic endpoints can introduce additional unwanted variability into research data. Below, we describe the role Inotiv has played in the development of the surgical procedures needed to create reliable heart failure models. We also introduce the advances in telemetry that can ensure consistency across and between research programs.
The sophisticated surgery required to create a myocardial infarction (MI) model
A common cause of heart failure is ischemic heart disease, characterized by a reduced blood supply to the heart due to narrowed or blocked coronary arteries, also known as myocardial infarction (MI). In humans who have survived an MI, there is a progressive loss of function in the left ventricle, leading eventually to heart failure. MI models, which recapitulate this process, are useful tools to investigate the pathophysiological processes that underpin left ventricle dysfunction and test potential pharmaceutical interventions.
Our procedures to generate the MI model were developed via rigorous on-site training sessions with our research partners. By outsourcing their surgical procedures to Inotiv, researchers can reclaim the substantial time and resources necessary to perform survival heart surgery. As an example, to create the MI model, surgeons must manipulate arteries the width of a human hair under a 20-40x microscope, in a heart that beats 350 times a minute: Even a fraction of error will generate unwanted variability.
With extensive practice and refinement using an ex vivo model, Inotiv’s surgeons achieve precise and consistent suture placement in every animal that’s delivered to a research program. As a result, MI models created by our surgeons can run on a treadmill after recovery, lack adhesions or lung damage, and have minimal standard deviations in ejection fraction (EF) — a measurement of the percentage of pumped blood leaving the heart — across cohorts.
The transverse aortic constriction model (TAC)
Similarly, Inotiv’s TAC model has been validated by both Inotiv scientists and the researchers who use them. The procedure to create a TAC model involves constriction of a precisely targeted region of the aortic arch in young animals. At only eight weeks post-surgery, there is evidence of left ventricle hypertrophy and signs of overt heart failure by 18 weeks. The rapid emergence of this pathology is a key benefit of the TAC model for researchers developing interventions to limit cardiac hypertrophy. Inotiv’s procedures additionally ensure a low rate of post-surgery complications and minimal standard deviations in EF across cohorts.
Telemetry to enhance hemodynamic measurements
To further embed consistency in a research program, all our models can be implanted with telemeters. These devices reduce the need for technicians to handle the animals, thereby minimizing stress and its associated impact on outcomes. Both the MI and TAC models can be implanted with a PhysioTel® — an implantable telemetry device from Data Sciences International (DSI). The device can monitor an unparalleled number of physiologic endpoints for 24 hours per day, seven days per week, for up to eight weeks.
Combined with rigorous pre and post-operative care, generating MI and TAC models with these approaches means our customers are assured of consistency. Of course, each research program has different priorities, and our team at Inotiv is available to discuss your needs.
Please contact us to learn how we can support your study with our surgical services.
PhysioTel® is a registered trademark of Data Sciences International (DSI).