Leveraging large cohorts to identify factors associated with microvascular dysfunction

Cognitive Impairment Post-Oophorectomy: Assessment of Novel Markers of Vascular-Health

Principal Investigator:
Dr. Edward O’Brien, Libin Cardiovascular Institute of Alberta

Dr. Todd Anderson, Libin Cardiovascular Institute of Alberta

Gillian Einstein
, University of Toronto
Preben  Kjølhede, Universitetssjukhuset, Sweden
Ninnie Borendal Wodlin, Universitetssjukhuset, Sweden
Liane Belland, University of Calgary
William Gerthoffer, University of South Alabama
Khokan Sikdar, University of Calgary

Women with a family history of certain cancers are often screened for gene mutations, and if found may elect to undergo surgical removal of their ovaries and fallopian tubes (i.e., a prophylactic salpingo-oophorectomy, PSO). Although PSO prevents cancer, the impact of this surgery on young women is not trivial as premature menopause will impact a woman’s cardiovascular health and potentially cognitive / mental health. Our ultimate goal aligns with Research Theme 2 and seeks to better understand if menopause results in vascular cognitive impairment.  To do this we will pursue two smaller projects in this seed grant that will allow us generate important data for a subsequent larger grant that encompasses our ultimate goal.  Specific Aim #1: In conjunction with Dr. Gillian Einstein (Laboratory of Cognitive Neuro-Sciences and Women’s Health, Dept. Psychology, Univ. Toronto) we will investigate the role of estrogen deprival post-PSO on cognitive function (qualitative and imaging studies) and relate this to a circulating biomarker of vascular disease, Heat Shock Protein 27 (HSP27). Dr. O’Brien’s laboratory studies ovarian hormone-related vascular protection, and discovered HSP27 as a potential down-stream “foot soldier” of estrogens, that is “vascular protective” and now recognized as a novel biomarker of cardiovascular events (MI, stroke, death).

Specific Aim #2: In conjunction with Dr. Todd Anderson, an expert in the study of microvascular dysfunction, we will validate the connection between vascular physiologic parameters (such as “VTI”) and levels of HSP27 in his “FATE” CAD cohort. Hence, with completion of these two specific aims we will be able to explore in future studies the correlation of vascular markers such as HSP27 and VTI with vascular cognitive impairment.

Associations of Arterial Stiffness and Load with Microvascular Coronary Artery Flow in Heart Failure with Preserved Ejection Fraction

Principal Investigator:
Dr. Thais Coutinho, University of Ottawa Heart Institute

Dr. Rob Beanlands
, University of Ottawa Heart Institute

Dr. Lisa Mielniczuk, 
University of Ottawa Heart Institute

Heart failure with preserved ejection fraction (HFpEF) is a disease of increasing prevalence, characterized by marked abnormalities in arterial compliance and endothelial function, in addition to left ventricular stiffening. Such arterial abnormalities not only majorly contribute to the pathophysiology of HFpEF, but are also thought to underlie the female predominance of this disease. Recently, experts have highlighted coronary artery microvascular inflammation and dysfunction as an additional potential pathophysiologic mechanism in HFpEF, further corroborating the importance of the arterial system in the genesis of this condition. However, there is a significant knowledge gap about the status of the coronary microvasculature in HFpEF, and about the influences of greater aortic stiffness on coronary microvascular function in men and women with HFpEF. The present proposal will address this knowledge gap.

At the completion of our study we will have determined the role of arterial stiffness and load as determinants of coronary microvascular function in HFpEF patients, known to be at high risk for mortality, hospitalizations and adverse cardiovascular events. We will also establish the value of arterial stiffness as a biomarker for detection of coronary artery microvascular dysfunction, and thus, as a potential biomarker for early detection of coronary artery disease.

Blood pRessure and vAscular hEalth around menopause (BRAVE)

Principal Investigator:
Dr. Louise Pilote, McGill University Health Center

Dr. Nadia Khan, University of British Colombia
Dr. Thais Coutinho, University of Ottawa Heart Institute
Dr. Stella Daskalopoulou, McGill University Health Center

Blood pRessure And Vascular hEalth around menopause (BRAVE) is one of the key projects of Research Priority Area Theme 2 of the Canadian Vascular Network and has now been amplified to include measures of cognitive impairment, novel methods of microvascular dysfunction detection and assessment of hemodynamic load with new VN collaborations. BRAVE is a multi-center study including pre- and postmenopausal women, and each site is responsible for measuring specific aspects. The McGill University Health centre (Montreal) is responsible for the measurement of microvascular dysfunction and arterial stiffness, the University of Ottawa Heart Institute investigates abnormal arterial hemodynamics, and the St Paul’s Hospital in Vancouver covers cognitive decline measures. All sites assess the role of biological and contextual factors on blood pressure (BP) variability in women around menopause. Our study will also serve to identify novel measures of microvascular dysfunction and other sub-clinical conditions associated with BP variability.

Still 1 in 5 women sustain a stroke in her life. The risk of vascular events in women increases around menopause. BP variability would be as important, as hypertension, if not more, in the prediction of vascular events, especially stroke. There is an urgent need to implement “primordial prevention” and slow down the progression of risk factors such as BP variability in menopausal women. There exists a knowledge gap about the determinants of BP variability, the so-called primordial causes. The risk factor profile of women around menopause is likely determined by biological and non-biological factors. Our project will identify these contexts into which BP profiles worsen around menopause. Another knowledge gap regards the biomarkers associated with BP variability. The identification of novel vascular biomarkers of BP variability will help target preventive strategies for a broader category of sub-clinical diseases and related conditions such as cognitive impairment.