Purinergic Signaling and the Postmenopausal Heart

PGC-1, Purines and the Postmenopausal Heart

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction; Diastolic Heart Failure
• Intervention / Treatment: Other: Gender

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Robina Matyal, MD; Phone Number: 6176401208; Email: rmatyal1@bidmc.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Robina Matyal, MD; Phone Number: 617-640-1208; Email: rmatyal1@bidmc.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients presenting for elective cardiac surgery. Patients will be enrolled and consented during hospital admission for surgery.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Men; Men who are undergoing cardiac surgery	Other: Gender; Differences between men and women will be observed
Women; Women who are undergoing cardiac surgery	Other: Gender; Differences between men and women will be observed

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Robina Matyal, MD, Beth Israel Deaconess Medical Center, Professor of Anesthesia; Principal Investigator: Simon Robson, MD, PhD, Beth Israel Deaconess Medical Center,Vice Chair Research

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: August 23, 2023
• First Submitted That Met QC Criteria: August 28, 2023
• First Posted (Actual): August 29, 2023

Study Record Updates

• Last Update Posted (Actual): August 29, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic
• Other Study ID Numbers: 2008P000151/13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No