Molecular Imaging of Primary Amyloid Cardiomyopathy

Last updated: December 1, 2023
Sponsor: Brigham and Women's Hospital
Overall Status: Active - Recruiting

Phase

N/A

Condition

Amyloidosis

Cardiomyopathy

Circulation Disorders

Treatment

N-13 ammonia PET

MRI

F-18 florbetapir/C-11 acetate PET

Clinical Study ID

NCT02641145
2015P002477
1R01HL130563-01A1
  • Ages 18-99
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

Inclusion criteria:

  • Age > 18 years
  • Diagnosis of light chain amyloidosis by standard criteria (immunofixation of serum andurine, IgG free light chain (FLC) assay, a biopsy of fat pad/ bone marrow, or organbiopsy, followed by typing of the light chain using immunohistochemistry or immunogoldassay with confirmation by Mass spectroscopy as needed)
  • For subjects traveling from out of town referred for systemic AL therapy based onclinical evaluation and laboratory testing, but, pending biopsy results, studyenrollment and procedures may begin before official confirmation of biopsyresults. If biopsy is negative for AL amyloidosis, subject will be considered ascreen failure. There will be no more than 10 subjects who fall under this screenfailure for the duration of the study.
  • Subjects with localized amyloid deposition and non-systemic AL disease will beeligible for enrollment in group D.
  • Willing and able to provide consent
  • Additional inclusion criteria for the Remission AL-CMP: Hematological response definedas complete hematological remission or very good partial response-differential freelight chain (dFLC)<40 mg/dL for > 1 year prior to enrollment
  • Additional inclusion criteria for the Active AL-CMP - exercise: Ability to performsupine bicycle exercise. Enrollment to this arm will stop after 36 subjects completebaseline and 6 months studies.
  • Additional inclusion criteria for the Active AL Pre-CMP - Normal left ventricular wallthickness (≤ 12 mm) and normal LVEF (≥55%) on echocardiography within 3 months orincreased wall thickness with normal cardiac biomarker levels: not meeting abovedefinition.
  • Additional inclusion criteria for Control Multiple Myeloma subjects: diagnosis ofmultiple myeloma without concomitant amyloidosis by standard criteria
  • Additional inclusion criteria for Control Heart Failure subjects: diagnosis of heartfailure without amyloidosis by standard criteria
  • Additional inclusion criteria for the active AL-CMP: Abnormal TnT 5th generationlevels (>9 ng/L: Female, >14 ng/L: Male) or abnormal age appropriate N terminalpro-brain natriuretic peptide, NT-proBNP (abnormal values: <50 years: >450 pg/ml; 50-75 years:>900 pg/ml; >75 years: >1800 pg/ml)

Exclusion

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 dilatedcardiomyopathy)
  • Known obstructive epicardial coronary artery disease with stenosis > 50% in any singleterritory
  • Severe claustrophobia despite use of sedatives
  • Presence of MRI contraindications such as metallic implants (pacemaker or ICD) at thetime of study enrollment except for Control Heart Failure subjects. Control HFsubjects with no devices, or, with strictly MR compatible devices will be eligible toundergo MRI.
  • Significant renal dysfunction with estimated glomerular filtration rate < 30 ml/min/m2within 14 days of each cardiac MRI study. Subjects who develop renal dysfunction overthe course of the study, meeting criteria listed above, will be excluded from thecardiac MRI scan except for control HF subjects. These subjects with eGFR < 30ml/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 beperformed prior to the PET and the cardiac MRI studies
  • Documented allergy to F-18 florbetapir, C-11 acetate or gadolinium.
  • Additional exclusion criteria for the active AL-CMP subjects: Subjects unable toreturn to BWH for 6 and 12 month clinical evaluation
  • Additional exclusion criteria for active AL-CMP-exercise subjects: Inability toexercise or return to BWH for C-11 acetate PET/CT at baseline and 6 month clinicalevaluations.
  • Additional exclusion criteria for active AL Pre-CMP- Inability to return to BWH 12month clinical evaluation. Additional exclusion criteria for microbiota study: Documented hypertrophic cardiomyopathy,HIV or chronic viral hepatitis, documented inflammatory bowel disease, systemicantibiotics, antivirals, antifungals or antiparasitic agents within 6 months, unable tomail the stool sample in a timely manner, bowel surgery, colon cancer, receivedchemotherapy, and pregnancy.

Study Design

Total Participants: 171
Treatment Group(s): 3
Primary Treatment: N-13 ammonia PET
Phase:
Study Start date:
April 01, 2016
Estimated Completion Date:
January 08, 2025

Study 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.

Connect with a study center

  • Brigham and Womens' Hospital

    Boston, Massachusetts 02421
    United States

    Active - Recruiting

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