Clinical Trial: Molecular Imaging of Primary Amyloid Cardiomyopathy

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Molecular Imaging of Primary Amyloid Cardiomyopathy

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 Summary: 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
Sponsor: Brigham and Women's Hospital

Current Primary Outcome:

• Change in F-18 florbetapir myocardial retention index from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
  quantitative measure of F-18 florbetapir uptake by the heart muscle
• Change in Serum oxidative stress markers from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
  serum F-2 isoprostane and peroxynitrite levels
• Change in Myocardial oxidative metabolism markers from baseline to 6 months [ Time Frame: Baseline and 6 months ]
  K mono and coronary flow reserve obtained by C-11 acetate PET/CT at rest and stress
• Change in Magnetic resonance imaging markers from baseline to 6 months and 12 months [ Time Frame: Baseline, 6 and 12 months ]
  Extracellular volume index, T-1 mapping, late gadolinium enhancement, global strain, left ventricular mass

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Change in Myocardial energy efficiency from baseline to 6 months [ Time Frame: Baseline and 6 months ]
  Myocardial energy efficiency, Kmono reserve, will be determined by C-11 acetate PET
• Light Chain Toxicity [ Time Frame: Baseline ]
  Study subject urine light chain's will be extracted and infused into zebrafish and isolated cardiomyocytes to study light chain toxicity

Original Secondary Outcome: Change in Myocardial energy efficiency from baseline to 6 months [ Time Frame: Baseline and 6 months ]

Information By: Brigham and Women's Hospital

Dates:
Date Received: December 22, 2015
Date Started: April 2016
Date Completion: April 2020
Last Updated: May 16, 2017
Last Verified: May 2017