Molecular Imaging of Primary Amyloid Cardiomyopathy

NCT ID: NCT02641145

Last Updated: 2025-11-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 171 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-01
• Study Completion Date: 2028-12-31

Brief Summary

Cardiac amyloidosis is a major cause of early treatment-related death and poor overall survival in individuals with systemic light chain amyloidosis. This project will develop a novel approach to visualize cardiac amyloid deposits using advanced imaging methods. The long-term goal of this work is to identify the mechanisms of cardiac dysfunction, in order to guide the development of novel life-saving treatments.

Detailed Description

Primary light chain amyloidosis (AL) is the most common systemic amyloidosis, resulting from a plasma cell dyscrasia, a hematological malignancy. It causes a restrictive cardiomyopathy (AL-CMP) in over 70% of individuals. AL-CMP is as lethal as stage 4 lung cancer and more lethal than any other form of restrictive heart disease; if untreated, the mortality rate is 50% within 18 months. Moreover, myocardial dysfunction, the hallmark of AL-CMP, significantly increases early treatment related mortality, predominantly cardiovascular death, and is a powerful predictor of poor long-term survival. Two potentially treatable mechanisms underlie myocardial dysfunction-mechanical effects of amyloid and toxic effects from circulating light chain/ amyloid interactions-and predispose to heart failure, arrhythmias, and sudden death in individuals with AL-CMP. Until now, efforts to determine the mechanisms of AL-CMP have been hampered by a lack of animal models and the limitations of noninvasive techniques to directly image myocardial amyloid. A recent breakthrough, 18F-florbetapir PET/CT, has provided for the first time specific and quantitative imaging of myocardial amyloid including toxic amyloid protofibrils. Furthermore, we propose to investigate three pre-clinically proven pathways of light chain toxicity in humans-myocardial oxidative metabolism, oxidative stress, and coronary microvascular function. Our central hypotheses are that myocardial 18F-florbetapir retention is a biomarker for aggressiveness of AL-CMP and that effective chemotherapy will, by reducing circulating light chains, decrease aggressiveness of AL-CMP and improve oxidative stress, myocardial oxidative metabolism, microvascular function and contractile function, prior to an improvement in myocardial amyloid content. In Aim 1, we will quantify myocardial 18F-florbetapir retention as a marker of aggressive myocardial disease in individuals with AL-CMP and active plasma cell dyscrasia compared to control individuals with AL-CMP and long-term hematological remission. In Aim 2, we propose, using advanced imaging, to assess the effects of light chain reduction due to chemotherapy on myocardial structure, function, and metabolism and define the time course of these changes. Serial ECV and strain imaging by CMR, serum F2-isoprostanes and peroxynitrite levels, myocardial oxidative metabolism (Kmono) and coronary flow reserve by 11C-acetate PET, and 18F-florbetapir imaging will not only intricately characterize the myocardial substrate in AL-CMP, but also identify changes in response to therapy. The proposed studies offer the potential to transform our current understanding of AL-CMP as a restrictive heart disease caused by passive amyloid-related architectural damage to that of a more complex disorder resulting from both passive and aggressive factors. The results of these studies may form the foundation for drug discovery programs to prevent and cure AL-CMP.

Interactions of environmental factors, immunity, and host-related factors likely trigger AL-amyloidosis, but have not yet been explored. Changes in metal ions and gut microbiota may be causal, representing the integrated effects of all these factors, or may be the downstream effect of systemic amyloid deposition in the organ systems. A plethora of recent literature strongly support the role of microbiota in the pathogenesis of several diseases, suggesting that gut microbiota changes with age, influences heart failure (HF) outcomes, and plays a role in the formation of β-amyloid deposits in Alzheimer's disease. Importantly, alterations in lifestyle, diet, prebiotics, probiotics, or phenols and gut microbiota may represent therapeutic and preventative strategies in amyloid disease, but it has not been explored in AL-amyloidosis. We propose to study the role of salivary and gut microbiome in AL amyloidosis.

Conditions

Amyloidosis, Primary; Cardiomyopathy

Keywords

amyloidosis; F-18 florbetapir; Positron emission tomography; cardiac magnetic resonance imaging

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Active AL cardiac amyloidosis

75 individuals with light chain systemic amyloidosis with active plasma cell dyscrasia and cardiac involvement will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of blood of the heart, as well as the heavy metal analysis of the blood at baseline, 6 months and 12 months after initiation of chemotherapy. 25 of these individuals will also undergo a N-13 ammonia PET scan of the heart following supine bicycle stress at baseline and at 6 months after initiation of chemotherapy.

Group Type: EXPERIMENTAL

F-18 florbetapir/C-11 acetate PET

Intervention Type: RADIATION

F-18 florbetapir PET scan, C-11 acetate PET scan

MRI

Intervention Type: DEVICE

Cardiac MRI with gadolinium contrast.

N-13 ammonia PET

Intervention Type: RADIATION

N-13 ammonia PET scan following supine bicycle stress.

Remission AL cardiac amyloidosis

25 individuals with light chain systemic amyloidosis with cardiac involvement and plasma cell dyscrasia in hematological remission (complete hematological remission or very good partial response-differential free light chain (dFLC)\<40 mg/dL for \> 1 year prior to enrollment) will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI scan of the heart as well as a heavy metal analysis of the blood at baseline.

Group Type: ACTIVE_COMPARATOR

F-18 florbetapir/C-11 acetate PET

Intervention Type: RADIATION

F-18 florbetapir PET scan, C-11 acetate PET scan

MRI

Intervention Type: DEVICE

Cardiac MRI with gadolinium contrast.

Active AL Pre-CMP

36 individuals with light chain systemic amyloidosis with active plasma cell dyscrasia and without cardiac involvement will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of the heart, as well as a heavy metal analysis of the blood at baseline. At 6 months they will undergo a research MRI of the heart and at 12 months they will have a clinical follow up. Subjects with contraindications to Cardiac MRI or gadolinium contrast may still be eligible for study participation.

Group Type: EXPERIMENTAL

F-18 florbetapir/C-11 acetate PET

Intervention Type: RADIATION

F-18 florbetapir PET scan, C-11 acetate PET scan

MRI

Intervention Type: DEVICE

Cardiac MRI with gadolinium contrast.

Multiple Myeloma Controls

25 individuals with diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria will undergo urine and blood testing only.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Heart Failure

10 individuals with diagnosis of heart failure without amyloidosis by standard criteria will undergo a research F-18 florbetapir PET, C-11 acetate PET, and MRI of the heart, as well as a heavy metal analysis of the blood at baseline..

Group Type: EXPERIMENTAL

F-18 florbetapir/C-11 acetate PET

Intervention Type: RADIATION

F-18 florbetapir PET scan, C-11 acetate PET scan

MRI

Intervention Type: DEVICE

Cardiac MRI with gadolinium contrast.

Interventions

F-18 florbetapir/C-11 acetate PET

F-18 florbetapir PET scan, C-11 acetate PET scan

Intervention Type: RADIATION

MRI

Cardiac MRI with gadolinium contrast.

Intervention Type: DEVICE

N-13 ammonia PET

N-13 ammonia PET scan following supine bicycle stress.

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• Age > 18 years
• Diagnosis of light chain amyloidosis by standard criteria (immunofixation of serum and urine, IgG free light chain (FLC) assay, a biopsy of fat pad/ bone marrow, or organ biopsy, followed by typing of the light chain using immunohistochemistry or immunogold assay with confirmation by Mass spectroscopy as needed)

• For subjects traveling from out of town referred for systemic AL therapy based on clinical evaluation and laboratory testing, but, pending biopsy results, study enrollment and procedures may begin before official confirmation of biopsy results. If biopsy is negative for AL amyloidosis, subject will be considered a screen failure. There will be no more than 10 subjects who fall under this screen failure for the duration of the study.
• Subjects with localized amyloid deposition and non-systemic AL disease will be eligible for enrollment in group D.
• Willing and able to provide consent

Exclusion Criteria

• Hemodynamic instability
• Decompensated heart failure (unable to lie flat for 1 hour)
• Concomitant non-ischemic non-amyloid heart disease (valvular heart disease or dilated cardiomyopathy)
• Known obstructive epicardial coronary artery disease with stenosis > 50% in any single territory
• Severe claustrophobia despite use of sedatives
• Presence of MRI contraindications such as metallic implants (pacemaker or ICD) at the time of study enrollment except for Control Heart Failure subjects. Control HF subjects with no devices, or, with strictly MR compatible devices will be eligible to undergo MRI.
• Significant renal dysfunction with estimated glomerular filtration rate < 30 ml/min/m2 within 14 days of each cardiac MRI study. Subjects who develop renal dysfunction over the course of the study, meeting criteria listed above, will be excluded from the cardiac MRI scan except for control HF subjects. These subjects with eGFR < 30 ml/min/1.73 m2 will undergo MRI without gadolinium contrast.
• Subjects on dialysis will be excluded
• Pregnant state. For women in child bearing age, a urine pregnancy test will be performed prior to the PET and the cardiac MRI studies
• Documented allergy to F-18 florbetapir, C-11 acetate or gadolinium.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

American Heart Association

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Sharmila Dorbala

Director, Nuclear Cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sharmila Dorbala, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital (AHA and NIH Studies)

Rodney Falk, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital (NIH Study)

Ronglih Liao, PhD

Role: PRINCIPAL_INVESTIGATOR

Stanford School of Medicine (AHA Study)

Locations

Brigham and Womens' Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Sharmila Dorbala, MD, MPH

Role: CONTACT

Phone: 617-732-6290

Email: sdorbala@partners.org

Facility Contacts

Sharmila Dorbala

Role: primary

References

Benz DC, Clerc OF, Cuddy SAM, Singh V, Kijewski MF, Bianchi G, Yee AJ, Ruberg FL, Jerosch-Herold M, Kwong RY, Di Carli MF, Liao R, Falk RH, Dorbala S. Changes in Myocardial Light Chain Amyloid Burden After Plasma Cell Therapy. JACC Cardiovasc Imaging. 2025 Sep 11:S1936-878X(25)00450-4. doi: 10.1016/j.jcmg.2025.07.017. Online ahead of print.

Reference Type: DERIVED

PMID: 40938234 (View on PubMed)

Clerc OF, Cuddy SAM, Jerosch-Herold M, Benz DC, Katznelson E, Canseco Neri J, Taylor A, Kijewski MF, Bianchi G, Ruberg FL, Di Carli MF, Liao R, Kwong RY, Falk RH, Dorbala S. Myocardial Characteristics, Cardiac Structure, and Cardiac Function in Systemic Light-Chain Amyloidosis. JACC Cardiovasc Imaging. 2024 Nov;17(11):1271-1286. doi: 10.1016/j.jcmg.2024.05.004. Epub 2024 Jul 10.

Reference Type: DERIVED

PMID: 39001736 (View on PubMed)

Katznelson E, Jerosch-Herold M, Cuddy SAM, Clerc OF, Benz DC, Taylor A, Rao S, Kijewski MF, Liao R, Landau H, Yee AJ, Ruberg FL, Di Carli MF, Falk RH, Kwong RY, Dorbala S. Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study. Front Cardiovasc Med. 2024 May 30;11:1371810. doi: 10.3389/fcvm.2024.1371810. eCollection 2024.

Reference Type: DERIVED

PMID: 38873265 (View on PubMed)

Cuddy SAM, Jerosch-Herold M, Falk RH, Kijewski MF, Singh V, Ruberg FL, Sanchorawala V, Landau H, Maurer MS, Yee AJ, Bianchi G, Di Carli MF, Liao R, Kwong RY, Dorbala S. Myocardial Composition in Light-Chain Cardiac Amyloidosis More Than 1 Year After Successful Therapy. JACC Cardiovasc Imaging. 2022 Apr;15(4):594-603. doi: 10.1016/j.jcmg.2021.09.032. Epub 2021 Dec 15.

Reference Type: DERIVED

PMID: 34922860 (View on PubMed)

Cuddy SAM, Bravo PE, Falk RH, El-Sady S, Kijewski MF, Park MA, Ruberg FL, Sanchorawala V, Landau H, Yee AJ, Bianchi G, Di Carli MF, Cheng SC, Jerosch-Herold M, Kwong RY, Liao R, Dorbala S. Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease? JACC Cardiovasc Imaging. 2020 Jun;13(6):1325-1336. doi: 10.1016/j.jcmg.2020.02.025. Epub 2020 May 13.

Reference Type: DERIVED

PMID: 32417333 (View on PubMed)

Other Identifiers

1R01HL130563-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2015P002477

Identifier Type: -

Identifier Source: org_study_id