Proteomics Analysis for Heart Valve Disease

(HALT Trial)

Recruiting at 2 trial locations

Overseen By Fahad S Gilani

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to identify specific protein markers in the blood that assist in diagnosing and tracking Hypo-Attenuated Leaflet Thickening (HALT), a heart valve condition. It will also examine how these proteins change after treatment with blood thinners. Participants are patients requiring a specific heart valve procedure (TAVR) due to severe valve issues. The study includes regular check-ups and blood tests to monitor changes in the heart valve condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to groundbreaking medical research.

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 prior data suggests that this proteomics analysis is safe for patients undergoing TAVR?

Research shows that scientists are studying proteomics analysis to help doctors better understand heart valve disease. In a previous study, this analysis examined changes in proteins in patients with heart problems, such as aortic valve disease. The aim was to determine if these proteins could aid in predicting or managing the disease.

Regarding safety, no direct evidence from these studies indicates harmful side effects from the proteomics analysis itself. It primarily gathers information about proteins in the blood. The trial is in an early stage, assessing safety and effectiveness. However, since it focuses on analyzing blood proteins, it is generally expected to be safe. Major safety concerns would prevent the trial from being conducted with human participants at this stage. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about proteomics analysis for heart valve disease because it offers a fresh approach by examining the proteins involved in the condition. Unlike traditional methods that might focus on imaging or symptomatic treatments, proteomics digs deep into the molecular level to potentially uncover early indicators of heart valve issues. This could lead to more personalized treatment plans and possibly even prevent the progression of the disease by addressing it at its root. By understanding the protein interactions, scientists aim to unlock insights that current options may overlook, paving the way for innovative therapies.

What evidence suggests that this proteomics analysis is effective for identifying biomarkers of HALT?

Research has shown that studying proteins can help identify key proteins related to heart valve problems. This trial will compare two groups: the HALT Cohort, consisting of patients who develop HALT, and a Control Group of patients who do not. Studies have found that changes in protein levels can signal conditions like calcific aortic valve disease, which is similar to HALT. For example, one study linked three specific proteins to this disease. Additionally, research has discovered that many proteins are involved in inflammation and damage to heart valves. These findings suggest that examining protein patterns could help detect and understand heart valve issues like HALT. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9606238/

Integrated proteomic and metabolomic profile analyses ... This study aimed to define changes in the metabolic and protein profiles of patients with calcific aortic valve disease (CAVD).

2. withpower.com withpower.com/trial/phase-1-aortic-valve-stenosis-5-2020-8e507

Proteomics Analysis for Heart Valve Disease (HALT Trial) What data supports the effectiveness of the treatment Proteomics Analysis for Heart Valve Disease? Proteomics analysis helps identify proteins involved in ...

3. nature.com nature.com/articles/s44161-024-00567-0

Integrative proteomic analyses across common cardiac ... Among proteins with one or more significant associations, 261 (59.2%) were shared across multiple outcomes and 15 (3.4%) were shared across all ...

4. ahajournals.org ahajournals.org/doi/10.1161/JAHA.124.036336

Plasma Proteomic Assessment of Calcific Aortic Valve ... This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease.

5. clinicalproteomicsjournal.biomedcentral.com clinicalproteomicsjournal.biomedcentral.com/articles/10.1186/s12014-022-09345-1

Data-independent acquisition mass spectrometry in severe ... Taken together, our results strongly suggest an ongoing inflammatory process involving damage to the cardiac valves among these cases of severe ...

6. jacc.org jacc.org/doi/10.1016/j.jacc.2025.03.004

5-Year Outcomes After Transcatheter or Surgical Aortic ... Clinical endpoints reported in this analysis include 5-year rates of all-cause mortality or disabling stroke as well as valve performance as ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04552275?term=AREA%5BConditionSearch%5D(hypo-)&rank=3

Study Details | NCT04552275 | The HALT Biomarker Study The purpose of the HALT Biomarkers study are to identify a panel of circulating proteins that discriminates between patients with and without Hypo-Attenuated ...