Molecular Imaging of Primary Amyloid Cardiomyopathy

Cardiomyopathy Clinical Trial

— MICA  

Official title:

Molecular Imaging of Primary Amyloid Cardiomyopathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02641145
• Other study ID #: 2015P002477
• Secondary ID: 1R01HL130563-01A
• Status: Recruiting
• Phase: N/A
• Start date: April 1, 2016
• Est. completion date: January 8, 2025

Study information

• Verified date: December 2023
• Source: Brigham and Women's Hospital
• Contact: Sharmila Dorbala, MD, MPH
• Phone: 617-732-6290
• Email: sdorbala[@]partners.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 171
• Est. completion date: January 8, 2025
• Est. primary completion date: January 8, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

• Additional inclusion criteria for the Remission AL-CMP: Hematological response defined as complete hematological remission or very good partial response-differential free light chain (dFLC)<40 mg/dL for > 1 year prior to enrollment

• Additional inclusion criteria for the Active AL-CMP - exercise: Ability to perform supine bicycle exercise. Enrollment to this arm will stop after 36 subjects complete baseline and 6 months studies.

• Additional inclusion criteria for the Active AL Pre-CMP - Normal left ventricular wall thickness (= 12 mm) and normal LVEF (=55%) on echocardiography within 3 months or increased wall thickness with normal cardiac biomarker levels: not meeting above definition.

• Additional inclusion criteria for Control Multiple Myeloma subjects: diagnosis of multiple myeloma without concomitant amyloidosis by standard criteria

• Additional inclusion criteria for Control Heart Failure subjects: diagnosis of heart failure without amyloidosis by standard criteria

• Additional inclusion criteria for the active AL-CMP: Abnormal TnT 5th generation levels (>9 ng/L: Female, >14 ng/L: Male) or abnormal age appropriate N terminal pro-brain natriuretic peptide, NT-proBNP (abnormal values: <50 years: >450 pg/ml; 50-75 years:>900 pg/ml; >75 years: >1800 pg/ml)

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.

• Additional exclusion criteria for the active AL-CMP subjects: Subjects unable to return to BWH for 6 and 12 month clinical evaluation

• Additional exclusion criteria for active AL-CMP-exercise subjects: Inability to exercise or return to BWH for C-11 acetate PET/CT at baseline and 6 month clinical evaluations.

• Additional exclusion criteria for active AL Pre-CMP- Inability to return to BWH 12 month clinical evaluation.

Additional exclusion criteria for microbiota study: Documented hypertrophic cardiomyopathy, HIV or chronic viral hepatitis, documented inflammatory bowel disease, systemic antibiotics, antivirals, antifungals or antiparasitic agents within 6 months, unable to mail the stool sample in a timely manner, bowel surgery, colon cancer, received chemotherapy, and pregnancy.

Related Conditions & MeSH terms

• Amyloidosis
• Amyloidosis, Primary
• Cardiomyopathies
• Cardiomyopathy
• Immunoglobulin Light-chain Amyloidosis

Intervention

Radiation:
• F-18 florbetapir/C-11 acetate PET
F-18 florbetapir PET scan, C-11 acetate PET scan

Device:
• MRI
Cardiac MRI with gadolinium contrast.

Radiation:
• N-13 ammonia PET
N-13 ammonia PET scan following supine bicycle stress.

Locations

Country	Name	City	State
United States	Brigham and Womens' Hospital	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	American Heart Association, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in F-18 florbetapir myocardial retention index from baseline to 6 months and 12 months	quantitative measure of F-18 florbetapir uptake by the heart muscle	Baseline, 6 and 12 months
Primary	Change in Serum oxidative stress markers from baseline to 6 months and 12 months	serum F-2 isoprostane and peroxynitrite levels	Baseline, 6 and 12 months
Primary	Change in Myocardial oxidative metabolism markers from baseline to 6 months	K mono and coronary flow reserve obtained by C-11 acetate PET/CT at rest and stress	Baseline and 6 months
Primary	Change in Magnetic resonance imaging markers from baseline to 6 months and 12 months	Extracellular volume index, T-1 mapping, late gadolinium enhancement, global strain, left ventricular mass	Baseline, 6 and 12 months
Secondary	Change in Myocardial energy efficiency from baseline to 6 months	Myocardial energy efficiency, Kmono reserve, will be determined by C-11 acetate PET	Baseline and 6 months
Secondary	Light Chain Toxicity	Study subject urine light chain's will be extracted and infused into zebrafish and isolated cardiomyocytes to study light chain toxicity	Baseline
Secondary	Understand the role of gut microbiota and heavy metals in the pathogenesis of AL Amyloidosis	This will be tested using machine learning methods with 16S rRNA sequencing of salivary and stool samples in a 40-patient cohort with AL-amyloidosis compared to healthy controls from the NIH funded human microbiome project (HMP).This will also be used to test if the gut microbiome affects amyloid formation using a transgenic mouse model of AL amyloidosis that expresses the human LC in the gut and develops amyloid in the stomach.	Baseline