Cardiac reserve is a widely used health indicator and prognostic tool. While it is well established how to assess cardiac reserve clinically, in preclinical models it is more challenging lacking standardization. Further, although cardiac reserve incorporates both systolic (i.e., contractile reserve) and diastolic (i.e., relaxation reserve) components of the cardiac cycle, less focus has been placed on diastolic reserve. The aim of our study was to determine which technique (i.e., echocardiography, invasive hemodynamic, Langendorff) and corresponding parameters can be used to assess the systolic and diastolic reserves in preclinical models. Healthy adult male and female CD-1 mice were administered dobutamine and evaluated by echocardiography and invasive hemodynamic, or Langendorff to establish systolic and diastolic reserves. Here we show that systolic reserve can be assessed using all techniques in vivo and in vitro. Yet, the current indices available are ineffective at capturing diastolic reserve of healthy mice in vivo. When assessing systolic reserve, sex affects the dose-response of several commonly used echocardiography parameters (i.e., FS, EF). Taken together, this study improves our understanding of how sex impacts the interpretation assessment of cardiac reserve and establishes for the first time that in healthy adult mice the diastolic reserve cannot be assessed by currently established methods in vivo.

Background Heart failure (HF) is a global health concern that affects nearly 26 million people each year. The Spontaneously Hypertensive Rat (SHR) was established in 1963 and is the most commonly used rodent model for studying human HF. Unlike humans, the SHRs develop hypertension around their reproductive age (i.e., when animals are selected for breeding), providing the opportunity for natural selection towards adaptive traits for hypertension‐induced heart failure. Therefore, the primary objective of this review was to evaluate whether SHRs have evolved over time to the cardiac sequelae of hypertension. We hypothesized that, while the severity of hypertension will remain stable within the SHR colony, the HF phenotype will become less pronounced with time as a result of compensatory changes to manage high blood pressure. Methods We performed a retrospective review evaluating several indices of cardiovascular health in the SHR over the past 60 years. For statistical analyses, studies that met the inclusion criteria were separated into 2 cohorts: Initial (mid‐late 1900’s) and Current (early 2000’s ‐present) Colony SHRs. Wistar‐Kyoto rats (i.e., normotensive rats used to establish the SHR line via selective breeding) were used as controls to normalize changes in technique and methods that have occurred over these decades. Results Systolic blood pressure did not differ between Initial and Current Colony SHRs, indicating that the severity of hypertension had remained stable within the SHR Colony over time. Current Colony SHRs presented with increased cardiac concentric hypertrophy (i.e., elevated heart weight and posterior wall thickness). Since these changes were not observed in the Wistar‐Kyoto control rats, cardiac‐derived changes in Current Colony SHRs were unlikely due to differences in techniques, equipment, anesthesia or environmental conditions. Conclusion These findings establish that the SHR colony has evolved over time, with greater concentric hypertrophy. Using natural selection to find positive adaptive traits may be advantageous in identifying new therapeutic treatment strategies.

Background The Spontaneously Hypertensive Rat (SHR) Colony was established in 1963 and is the most commonly used rodent model for studying heart failure. Ideally, animal models should recapitulate the clinical disease as closely as possible. Any drift in a genetic model may create a new model that no longer adequately represents the human pathology. Further, instability overtime may lead to conflicting data between laboratories and/or irreproducible results. While systolic blood pressure is closely monitored during inbreeding, the sequelae of heart failure (e.g., cardiac hypertrophy) are not. Thus, the object of this review was to investigate whether the hypertension-induced sequelae of heart failure in the SHR have remained stable after decades of inbreeding. Methods A systematic review was performed to evaluate indices of cardiovascular health in the SHR over the past 60 years. For post hoc statistical analyses, studies were separated into 2 cohorts: Initial (mid - late 1900’s) and Current (early 2000’s - present) Colony SHRs. Wistar-Kyoto rats (WKY) were used as controls. Results Systolic blood pressure was consistent between Initial and Current Colony SHRs. However, Current Colony SHRs presented with increased concentric hypertrophy (i.e., elevated heart weight and posterior wall thickness) while cardiac output remained consistent. Since these changes were not observed in the WKY controls, cardiac-derived changes in Current Colony SHRs were unlikely due to differences in environmental conditions. Conclusions Together, these data firmly establish a cardiac-based phenotypic shift in the SHR model and provide important insights into the beneficial function of concentric hypertrophy in hypertension-induced heart failure.