Novel Characterization of Sex Specific Biologic Signatures in Valvular Heart Disease

This project aims to validate sex-specific biologic signatures associated with aortic valve disease developed in a large multicenter CMR registry, using unsupervised phenomapping.

The aim to use standard and advanced CMR techniques (MRF, DTI, chemical exchange transfer, and radiomics analysis) is to determine advanced CMR predictors of reverse remodeling following aortic valve surgery and develop sex-specific thresholds for risk. Infrastructure developed by this study will enable development of an innovative, scalable, sex-specific precision medicine cardiovascular imaging pipeline to determine overall risk and treatment response.

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis; Mitral Regurgitation; Aortic Regurgitation
• Intervention / Treatment: Diagnostic test: CMR; Other: Quality of Life Questionnaire

Detailed Description

Chronic valvular heart disease leads to significant left ventricular (LV) remodeling. Current national guidelines for surgical/procedural referral for valvular heart disease do not consider sex differences in presence of symptoms, LV remodeling and dysfunction. However, our prior research in patients with chronic aortic regurgitation, validated by our recent multicenter study, demonstrated that despite higher left ventricular function, and less ventricular dilation, females experienced more heart failure symptoms, fewer referrals for surgical intervention, and higher prevalence of adverse outcomes compared to males. Similarly, published HVTI data have demonstrated increased adverse outcomes in women referred for surgical mitral valve intervention.

Cardiac magnetic resonance (CMR) provides an exciting opportunity to characterize sex differences in LV remodeling.In combination with conventional CMR measures, novel CMR techniques such as Magnetic Resonance Fingerprinting (MRF), Diffusion Tensor imaging (DTI) and radiomics analysis provide tissue level specificity with potential to enhance phenomapping.

Limitations in understanding sex-specific remodeling patterns stem from heterogeneity of presentation, which confound traditional analytic methods. Phenomapping, a method of machine learning, clusters imaging features and patients into distinct phenotypic groups. Unsupervised phenomapping enables unbiased grouping of patients by both clinical characteristics as well as complex imaging features. In recent studies, this unbiased phenomapping approach demonstrates superior risk stratification of cardiac disease compared to traditional approaches that can be used to guide individualized treatment

The aim to use advanced CMR techniques (MRF, DTI, chemical exchange transfer, and radiomics analysis) is to determine advanced CMR predictors of reverse remodeling following procedural valve intervention and develop sex-specific thresholds for risk. Results from this study would enable the development of sex-specific precision medicine pathway, augmented by advanced imaging features, to better predict overall risk and treatment response, and thus enable novel patient selection criteria.

Study hypothesis: Radiomics, MRF, chemical exchange transfer, and DTI will elucidate distinct sex-specific biologic signatures, in addition to standard CMR imaging features, and are associated with adverse outcomes, and reverse remodeling following surgical/procedural valve intervention.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Deborah Kwon, MD; Phone Number: 216-444-8526; Email: kwond@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Sub-Investigator: Xiaofeng Wang, PhD
      • Sub-Investigator: Christopher Nguyen, PhD
      • Contact: Degorah Kwon, MD; Phone Number: 216-444-8526
      • Contact: Lydia DeAngelo; Phone Number: 401-225-1929; Email: deangel2@ccf.org
      • Sub-Investigator: Eric Roselli, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients with at least moderate Aortic Stenosis or Aortic Regurgitation who are scheduled for a surgical repair or replacement of their aortic valve.

Description

Inclusion Criteria:

• Age 18-90 years of age
• Suspected moderate or severe (2-3+ or more) aortic regurgitation, or moderate or more aortic stenosis on the basis of prior known clinical history, echocardiogram or cardiac MRI.

Exclusion Criteria:

• Acute traumatic cardiac injury
• Aortic dissection or aortic root rupture
• Congenital heart diseases such as patent ductus arteriosus, coarctation of aorta, ASD and VSD
• Presence of A-V fistula or intracardiac shunts

• Any contraindications to cardiac MRI including:

  • Patients with any MR-incompatible implant, including cardiac pacemakers or defibrillators, or older types of cerebral aneurysm clips.
  • Patients who weigh more than 440 lbs. or have a very wide waist circumference.
  • Patients with claustrophobia may have difficulty tolerating the exam.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Intervention; Cardiac MRI (CMR) with Magnetic Resonance Fingerprinting (MRF), fSENC (a new CMR technology which may detect subclinical signs of myocardial damage by measuring myocardial strain), Diffusion Tensor imaging (DTI), and chemical exchange transfer imaging with contrast at baseline and without contrast at follow up. Rapid Assessment of Physical Activity questionnaire Kansas City Cardiomyopathy Questionnaire

Diagnostic test: CMR; CMR (with contrast at baseline and non-contrast at follow-up); Other: Quality of Life Questionnaire; Rapid Assessment of Physical Activity questionnaire and the Kansas City Cardiomyopathy Questionnaire

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in LV Dilation and/or change in LVEF	Significant change in LV remodeling will be defined as a change in EF by 10 units (reverse remodeling is defined at least 10 unit decrease) or change in LV end-diastolic/systolic volume by 10% (Reverse remodeling is defined as at least decrease in LV end-diastolic/systolic volume by 10%	6-12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Aortic Regurgiation	Change in Aortic Regurgitant Fraction will be modeled as a continuous variable, as well as a threshold change of 5 points or more, as measured by cardiac MRI	6-12 months
Change in BNP	NT-proBNP will be modeled as a continuous variable as well as a threshold change of 30% or decrease to level < 1000	6-12 months
6 minute walk test	6 minute walk test will be modeled as a continuous variable as well as a threshold change of 30meters or more	6-12 months
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score	KCCQ will be modeled as a continuous variable, as well as a threshold change of 5 points or more. KCCQ scoring transforms Likert-scale answers into 0-100 scores (higher is better) for domains like Physical Limitation, Symptom Frequency, Quality of Life, and Social Limitations, with a summary score reflecting overall health, where 0-24 is very poor, 25-49 poor/fair, 50-74 fair/good, and 75-100 good/excellent health.	6-12 months

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Deborah Kwon, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2024
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: January 13, 2025
• First Submitted That Met QC Criteria: January 13, 2025
• First Posted (Actual): January 17, 2025

Study Record Updates

• Last Update Posted (Estimated): January 2, 2026
• Last Update Submitted That Met QC Criteria: December 28, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Mitral Valve Insufficiency; Aortic Valve Insufficiency
• Other Study ID Numbers: 24-861

Drug and device information, study documents

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