Proteomics Analysis for Heart Valve Disease

(HALT Trial)

Recruiting at 2 trial locations

Overseen By Roukoz Abou Karam

Age: 65+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: Anticoagulants

Disqualifiers: Chronic kidney disease, Hypercoagulable state, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

300 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the HALT Biomarkers study are to identify a panel of circulating proteins that discriminates between patients with and without Hypo-Attenuated Leaflet Thickening (HALT) and can be used to supplement the diagnosis of HALT; to characterize changes in circulating proteins after treatment of HALT with systemic anticoagulation; and to identify circulating proteins that predict the occurrence of HALT. The study population will be adult patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) or bioprosthetic valve degeneration. Enrollment will continue until 30 patients with HALT are identified for completion of phase 1. Based on a HALT incidence rate of 10%, we anticipate enrolling 300 patients. Patients are enrolled prior to undergoing transfemoral TAVR. Blood samples, clinical data and echocardiograms will be collected at the following timepoints: baseline (pre-TAVR, T0), post-TAVR (pre-discharge, T1), 30-day follow-up (window 3-9 weeks, T2), and 6-month follow-up (T3). Cardiac 4D CT will be performed at the 30-day follow-up visit to screen for the occurrence of HALT. Patients with HALT will be treated with systemic anticoagulation for 5-6 months, at which point a follow-up CT scan and blood sample will be obtained. Control subjects will also undergo a 6-month study visit with blood sample collection. The study will be conducted within two phases. Phase 1 will serve as a derivation / discovery study in which candidate protein biomarkers of HALT will be identified. Once this is successfully completed, a second cohort will be enrolled within phase 2. Phase 2 will be performed under the auspices a future contract or amendment and will seek to cross-validate the initial study findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic anticoagulation therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Proteomics Analysis for Heart Valve Disease?

Proteomics analysis helps identify proteins involved in heart valve diseases, which can lead to early diagnosis and treatment. It has been used to uncover disease-specific and sex-specific protein differences, providing insights into cardiac remodeling and potential individualized treatment strategies. ^{1 2 3 4 5}

Is proteomics analysis safe for humans?

The research articles do not provide specific safety data for proteomics analysis in humans, but they focus on its use in studying proteins related to heart diseases, which suggests it is primarily a research tool rather than a treatment with direct safety concerns. ^{3 4 6 7 8}

How does the proteomics analysis treatment for heart valve disease differ from other treatments?

This treatment is unique because it uses proteomics (the study of proteins) to understand heart valve disease at a molecular level, which can help identify specific proteins involved in the disease. This approach is different from traditional treatments that focus on managing symptoms or risk factors, as it aims to uncover the underlying biological mechanisms and potentially lead to more targeted therapies. ^{1 3 5 9 10}

Eligibility Criteria

Adults over 65 with severe aortic stenosis or valve degeneration, who are getting a specific heart valve replacement (Medtronic Evolut series). Not for those with bleeding disorders, on chronic anticoagulation therapy, severe kidney disease, short life expectancy due to other conditions, currently in another study, or pregnant.

Inclusion Criteria

I have severe aortic stenosis or my heart valve replacement is severely degenerated.

I am having a heart valve replacement through my leg using a specific Medtronic device.

I am older than 65 years.

Exclusion Criteria

I cannot take blood thinners in pill form due to health reasons.

Pregnant, lactating, or planning pregnancy within next 12 months

I have a bleeding disorder or a condition affecting blood clotting.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Blood samples, clinical data, and echocardiograms are collected pre-TAVR

1 week

1 visit (in-person)

Post-TAVR Assessment

Blood samples and clinical data are collected post-TAVR, pre-discharge

1 week

1 visit (in-person)

30-day Follow-up

Cardiac 4D CT performed to screen for HALT; blood samples collected

3-9 weeks

1 visit (in-person)

Treatment for HALT

Patients with HALT are treated with systemic anticoagulation

5-6 months

6-month Follow-up

Follow-up CT scan and blood sample collection for all participants

6 months

1 visit (in-person)

Treatment Details

Interventions

• Proteomics Analysis

Trial Overview The HALT Biomarker Study aims to find protein markers in the blood that can help diagnose and track treatment response of Hypo-Attenuated Leaflet Thickening (HALT) after patients receive transcatheter aortic valve replacements. It involves two phases: discovery and validation.

Participant Groups

Group I: HALT Cohort Experimental Treatment 1 Intervention

Patients who develop HALT

Group II: Control Group Experimental Treatment 1 Intervention

Patients who do not develop HALT

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Medtronic

Industry Sponsor

Trials

627

Recruited

767,000+

Geoff Martha

Medtronic

Chief Executive Officer since 2020

Finance degree from Penn State University

Dr. Richard Kuntz

Medtronic

Chief Medical Officer since 2023

MD, MSc

Catholic Medical Center

Collaborator

Trials

6

Recruited

2,700+

Minneapolis Heart Institute

Collaborator

Trials

6

Recruited

4,500+

Findings from Research

A new optimized protocol for homogenizing aortic valve tissue and extracting proteins was developed, significantly improving protein yield and reducing variability between laboratories.

Using this protocol, researchers identified and quantified proteins in the aortic valve of patients with aortic stenosis, revealing potential sex-based differences in protein dysregulation, which could inform future therapeutic targets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of a Protocol for Protein Extraction from Calcified Aortic Valves for Proteomics Applications: Development of a Standard Operating Procedure. Trindade, F., Ferreira, AF., Saraiva, F., et al.[2022]

Recent advancements in mass spectrometry and bioinformatics have significantly enhanced the ability to conduct quantitative proteomics in cardiovascular research, allowing for detailed analysis of human samples.

The study highlights the use of both gel-based and gel-free proteomic strategies to identify biomarkers related to aortic aneurysms and other cardiovascular conditions, improving our understanding of disease processes and protein interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomic analysis in cardiovascular research. Oda, T., Matsumoto, K.[2023]

Degenerative aortic stenosis (AS) is a leading cause of valve replacement globally, and unlike coronary artery disease, it is not improved by traditional risk factor reduction therapies, highlighting the need for a deeper understanding of its underlying mechanisms.

The study developed a novel method for analyzing protein expression in normal versus stenotic aortic valves, aiming to identify biomarkers that could aid in the early diagnosis and treatment of aortic stenosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential protein expression analysis of degenerative aortic stenosis by iTRAQ labeling. Alonso-Orgaz, S., Martin-Rojas, T., Calvo, E., et al.[2015]

Proteomics enables the large-scale analysis of proteins in biological systems, significantly advancing cardiovascular biomedicine by identifying circulating protein biomarkers for heart diseases from plasma samples.

This field also helps uncover disease mechanisms and potential therapeutic targets in cardiovascular tissues, allowing for a better understanding of health and disease through the examination of tens of thousands of proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomics Research in Cardiovascular Medicine and Biomarker Discovery. Lam, MP., Ping, P., Murphy, E.[2021]

A study analyzing 75 human left ventricular myocardial biopsies revealed that patients with aortic stenosis and mitral regurgitation exhibit distinct proteomic profiles, with increased proteins related to extracellular matrix and cytoskeleton, but decreased proteins associated with energy metabolism and proteostasis compared to healthy controls.

Notably, male patients with aortic stenosis had higher levels of fibrosis-related proteins, while female patients showed a significant reduction in proteostasis-related proteins, indicating that both disease type and sex influence cardiac remodeling and may guide personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease- and sex-specific differences in patients with heart valve disease: a proteome study. Nordmeyer, S., Kraus, M., Ziehm, M., et al.[2023]

Proteomics is a powerful tool for understanding cardiovascular dysfunctions by identifying protein alterations that can serve as drug targets, disease biomarkers, and therapeutic proteins, which is crucial for developing effective treatments.

Functional proteomic studies can reveal how changes in the proteome relate to cardiovascular diseases, enhancing our understanding of the underlying mechanisms and guiding the design of gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomics: state of the art and its application in cardiovascular research. Scobioala, S., Klocke, R., Michel, G., et al.[2019]

Proteomics is evolving towards absolute quantitative strategies, allowing researchers to measure protein concentrations in terms of copies per cell or ng per mg of tissue, which is essential for drug target selection and biomarker evaluation in cardiac research.

The study outlines a method for creating a quantitative map of the human left ventricular proteome using mass spectrometry, which can help identify disease-altered proteins and improve our understanding of cardiac function at the molecular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determining protein concentrations of the human ventricular proteome. Scholten, A., Heck, AJ.[2015]

A study analyzing serum samples from five patients with calcific aortic stenosis (CAS) before and after aortic valve replacement surgery identified 51 proteins with differential expression, highlighting significant biological responses to the surgical intervention.

Two proteins, antithrombin-III and zinc-α-2-glycoprotein, were confirmed to have increased levels post-surgery and may serve as unique biomarkers for monitoring the biochemical changes associated with CAS treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of Serial Presurgical and Postsurgical Changes in the Serum Proteome in a Series of Patients with Calcific Aortic Stenosis. Satoh, K., Yamada, K., Maniwa, T., et al.[2020]

This study successfully quantified nearly 2000 proteins in heart tissue samples from patients with aortic valve stenosis (AVS), revealing significant upregulation of 239 proteins in the atrial myocardium and 54 in the ventricular myocardium, indicating biological changes associated with the disease.

The identified proteins are linked to key pathological processes in AVS, such as cardiac hypertrophy, fibrosis, mitochondrial impairment, and reduced blood supply, providing valuable insights into the underlying mechanisms of AVS at the proteomic level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomic mapping of atrial and ventricular heart tissue in patients with aortic valve stenosis. Barbarics, B., Eildermann, K., Kaderali, L., et al.[2022]

A study on myxomatous valve disease (MVD) in dogs identified over 300 proteins in mitral valves, with 117 showing significant changes in expression, indicating that early-stage degeneration has distinct proteomic characteristics that persist into late stages.

The research utilized shotgun proteomic analysis to reveal that the protein changes associated with MVD occur early and remain throughout the disease progression, providing insights that could help understand the disease's mechanisms in both dogs and humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential protein expression between normal, early-stage, and late-stage myxomatous mitral valves from dogs. Lacerda, CM., Disatian, S., Orton, EC.[2010]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Optimization of a Protocol for Protein Extraction from Calcified Aortic Valves for Proteomics Applications: Development of a Standard Operating Procedure. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

Proteomic analysis in cardiovascular research. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Differential protein expression analysis of degenerative aortic stenosis by iTRAQ labeling. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Proteomics Research in Cardiovascular Medicine and Biomarker Discovery. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Disease- and sex-specific differences in patients with heart valve disease: a proteome study. [2023]

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Proteomics: state of the art and its application in cardiovascular research. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Determining protein concentrations of the human ventricular proteome. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Monitoring of Serial Presurgical and Postsurgical Changes in the Serum Proteome in a Series of Patients with Calcific Aortic Stenosis. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Proteomic mapping of atrial and ventricular heart tissue in patients with aortic valve stenosis. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Differential protein expression between normal, early-stage, and late-stage myxomatous mitral valves from dogs. [2010]