The Microvascular Aging Effects - Women's Evaluation of Systemic aging Tenacity in Heart, Brain and Frailty (MAE-WEST HBF) ("You are never too old to become younger!") - PROJECT SUMMARY/ ABSTRACT- OVERALL The Microvascular Aging Effects – Women's Evaluation of Systemic aging Tenacity in Heart, Brain and Frailty (MAE-WEST HBF) (“You are never too old to become younger!”) Specialized Center of Research Excellence (SCORE) on Sex Differences, in response to NIH RFA-OD-22-014, PI C. Noel Bairey Merz will extend our recent findings that small vessel (microvascular) injury-related inflammation and inflammation-related mediators (iron deposition) contribute to the development of heart failure with preserved ejection fraction (HFpEF), cerebral small vessel disease (CSVD), impaired cognition, Alzheimer dementia and related dementias (ADRD), frailty and sarcopenia, conditions which predominate in aging women. Our application is also responsive to the recent NOT- OD-24-079: Notice of Special Interest: Women's Health Research focused on diseases that predominantly affect women such as cardiovascular disease and dementia. Over the life course, small vessel disease and systemic chronic inflammation are intrinsically augmented in females relative to males providing a rationale for our investigation in a single clinical cohort of predominantly women by extending our deep phenotyping analyses with rigorous measures to end-organ function including tissue biopsies. This direction is exciting, innovative, and has great potential impact on women's health. Our preliminary data support the hypothesis that small vessel injury-related iron deposition in the heart and brain is present in organ dysfunction. Prior work from our lab (Project 1) has identified myocardial iron deposition in the heart in the setting of persistent microvascular obstruction and microvascular hemorrhage as a potential mechanistic driver of chronic myocardial inflammation and adverse left ventricular remodeling. Given that women with coronary microvascular dysfunction (CMD) are more likely than men to suffer chronic ischemia for longer durations (due to underdiagnosis and undertreatment), chronic ischemia and subsequent myocardial iron deposition related to coronary microvascular dysfunction is a key knowledge gap regarding development of HFpEF in women. Notably, our most recent preliminary observation (Project 2) demonstrates cerebral small vessel disease (CSVD), in the brain is directly related to CMD in the heart. Further, brain iron deposition is associated with CMD. Finally, these preliminary results (Project 2) demonstrate relations between brain iron deposition and impaired cognition, potentially through altered brain functional connections. Cardiovascular and cerebrovascular disease increase the risk of frailty, and frail people with cardiovascular disease have worse outcomes than those without frailty but further research is needed to understand their mechanistic links to frailty and sarcopenia. Specifically, while studies in preclinical models suggest that CSVD cognitive impairment is preceded by subclinical alterations in gait speed and coordination, deeply phenotyped human evidence is needed (Project 3). Our overall goal is to identify “commonality” of mechanistic contributions to HFpEF, CSVD, impaired cognition, ADRD and frailty in order to provide insight to plan future multi-organ preventive aging treatment targets for women and men.
