Purinergic Signaling and the Postmenopausal Heart

Study Overview
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Brief Summary
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There is an increased risk of diastolic heart failure in post menopausal women. Estrogen plays a positive role in regulating molecular pathways in heart remodeling. Such pathways may work through purinergic signaling and its downstream effects on the heart's mitochondrial metabolism and angiogenic response to stress. Loss of estrogen functionality in post menopausal women may account for the increased risk of diastolic heart failure. The investigators will explore said pathways using cardiac tissue obtained from patients undergoing cardiac surgery.

Detailed Description
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Cardiovascular disease (CVD) is the leading cause of death of women in the United States, accounting for around 1 of every 3 deaths. Estrogen deficiency, as seen in aging women or after oophorectomy, has been linked to loss of cardiovascular protection, typically seen during reproductive life. Up to half of women evaluated for myocardial ischemia have normal appearing coronary arteries. These women can develop heart failure with a preserved ejection fraction (termed HFpEF) for which the etiology is unclear. Hormonal replacement therapy (HRT) after menopause remains controversial but current evidence cannot support this for either primary or secondary prevention of CVD. There are clearly modulatory influences on estrogenic signaling, that could well influence cardiovascular health in later life. Previous studies have demonstrated that estrogen improves energy production within the heart by increasing 5' adenosine monophosphate-activated protein (AMPK) and mitochondrial biogenesis via upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α); a master switch of mitochondrial function, linked to vascular integrity and angiogenesis. Estrogen has been also found to modulate purinergic signaling by boosting expression of adenosine receptors and of CD39, the dominant endothelial ecto-ADPase that generates adenosine. There are also close relationships between purinergic signaling and dipeptidyl peptidase-4 (DPP-4; otherwise known as adenosine deaminase complexing protein 2 or CD26), possibly mediated by adenosine deaminase bioactivity. Decreased PGC-1α and aberrant purinergic signaling in metabolic syndrome may lead to impaired mitochondrial function, provoking diastolic dysfunction, and also result in impaired angiogenesis. The investigators hypothesize there are central roles of PGC-1α, purines and DPP-4 linked neuropeptide pathways in the control of angiogenesis and mitochondrial activity. These become increasingly disordered in setting of estrogen loss provoking development of metabolic syndrome, thereby exacerbating HFpEF and microvascular disease. Specific Aim 1: To determine how ischemia and cardiometabolic dysfunction in women's heart disease are exacerbated by the loss of puringeric pathways from estrogen deficiency. The investigators expect to determine that diastolic dysfunction is a functional consequence of this microvascular loss and cardiometabolic dessynchrony. Specific Aim 2: To evaluate the role of adenosingergic receptor activation and DPPIV inhibition on angiogenesis in a ovariectomized swine model of chronic myocardial ischemia and metabolic syndrome. Here, the investigators will explore relationships between the regulated and linkages in the exocytosis of nucleotides and neuropeptides, formation of nucleosides (adenosine) and alterations in angiogenic activity secondary to these. Summary: The investigators will study fundamental mechanisms in heart disease underpinning biological differences in women. The investigators will also offer new therapeutic strategies that target cardiac metabolism.

Official Title
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PGC-1, Purines and the Postmenopausal Heart

Conditions
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Diastolic Heart Failure, Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Other: Gender


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing cardiac surgery under cardiopulmonary bypass. Exclusion Criteria: Refusal to participate Emergency surgery Pre-existing heart block Preexisting atrial fibrillation Redo surgery Estrogen or hormone replacement therapy History of chronic heart failure History of major kidney disease

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 88 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Men<br>Men who are undergoing cardiac surgery | Other: Gender<br>* Differences between men and women will be observed<br>|
| Women<br>Women who are undergoing cardiac surgery | Other: Gender<br>* Differences between men and women will be observed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparative quantification of expression of CD39 and adenosinergic receptors | Expression of CD39, ADORA2A and ADORA2B in cardiac tissue measured using Western blotting | 6 months | 
| Comparative quantification of expression of PGC-1 alpha, mitochondrial markers | Expression of PGC-1 alpha, AMPK and mitochondrial markers using Western blot | 6 months | 
| Comparative quantification of expression of angiogenic markers | Expression of angiogenic markers (PDGF, VEGF, Angiostatin) | 6 months |