Evaluating the natural evolution of myocardial stiffness in aging, sex differences, and through menopause transition in women, using a free-breathing magnetic resonance elastography approach

PROJECT SUMMARY/ABSTRACT While cardiovascular disease (CVD) is the leading cause of death in men and women, substantial sex differences exist in disease prevalence and prognosis. A key impact of menopause is risk of future CVD. Post-menopausal women are twice as likely to have heart failure with preserved ejection fraction (HFpEF) and heart failure hospitalization rates disproportionately increase in women as they age. We hypothesize that a key contributor to this trend are hormonal changes during menopausal transition which accelerate myocardial stiffening. The impact of menopausal transition on myocardial stiffness is unknown. If understood, new disease prevention and therapy monitory strategies with significant potential for long-term benefits could be investigated. Elevated myocardial stiffness, a precursor of several CVDs, can go undetected prior to heart failure symptoms from diastolic dysfunction because left ventricular (LV) ejection fraction is preserved, and absolute LV chamber stiffness is not routinely measured. Current quantitative stiffness measurements require ex vivo mechanical testing or invasive pressure-volume measurements, hampering their adoption as practical clinical biomarkers. This proposal’s objective are to 1) establish a baseline for normal stiffness values during natural aging through menopausal transition and 2) identify sex as a biological variable. To accomplish these goals, we will develop a free breathing 3D non-invasive cardiac magnetic resonance elastography (cMRE) technique to measure myocardial stiffness. The technological advances in this study will make myocardial stiffness imaging in heart failure patients with dyspnea more reliably, regional, and enable quantitative cross-sectional and longitudinal monitoring of myocardial stiffness. Our preliminary data shows that LV myocardial stiffness increases significantly in healthy women, but not men, after the age of 50, which corresponds to the average age of menopausal transition. If cMRE can be used to detect elevated myocardial stiffening during menopausal transition and prior to the development of diastolic disfunction, the monitoring of current and new preventive interventions prior to heart failure symptoms will be made possible. To accomplish these objectives, we will: • Develop a 3D, free-breathing cMRE application. • Retrospectively bin cMRE data for multiple 3D MRE volumes that vary during the cardiac cycle. • Validate cMRE in static and pulsatile realistic cardiac phantoms. • Identify a clinical and technically feasible acquisition durations in a normal volunteer pilot study. • Evaluate the influence of natural aging, sex, and menopausal transition on myocardial stiffness. The natural evolution of myocardial stiffness in natural aging, in relation to sex-biases, and throughout menopausal transition will be evaluated using a newly developed and implemented free breathing non-invasive quantitative cMRE approach, which may have significant implications for the prevention of heart failure.