Study aims to achieve earlier diagnosis of ATTR cardiac amyloidosis in minority populations

Reviewed by James Ives, M.Psych. (Editor)Sep 4 2019

Researchers at Boston Medical Center (BMC) and Boston University School of Medicine (BUSM), in collaboration with Columbia University Irving Medical Center (CUIMC), are leading a national, multi-site study aimed to achieve earlier diagnosis of transthyretin cardiac amyloidosis (ATTR-CM). The National Institutes of Health has awarded a five-year, $7.2M grant to fund the Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) trial.

Led by co-principal investigators Frederick L. Ruberg, MD at BMC/BUSM's Amyloidosis Center of Excellence and Mathew S. Maurer, MD from CUIMC's Cardiac Amyloidosis Program, the grant will enable the establishment of an important, community-based cohort of older minority patients with congestive heart failure. A total of 800 participants will be recruited from BMC/BUSM in Boston and the CUIMC, NYP-Allen and Harlem Hospitals in New York City. Since ATTR cardiac amyloidosis is underdiagnosed, the investigators will test the hypothesis that utilization of highly sensitive heart imaging and blood tests can potentially help to diagnose this disease earlier, which means patients could be treated earlier in the disease progression, potentially leading to better patient outcomes.

Previous research has shown that heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older Black and Hispanic Americans. HFpEF is a form of heart failure in which the heart muscle pumps normally, but is too stiff to fill the volume of blood needed for consistent heart function with normal heart pressures. Symptoms include shortness of breath, swelling, and fatigue. An important but under-recognized cause of this form of heart failure is ATTR-CM. The disease is under-recognized because previously it was difficult to diagnose and it was perceived to be very rare. SCAN-MP is particularly designed to identify unrecognized ATTR-CM in older Black and Caribbean Hispanic patients who are served by BMC/BUSM, CUIMC, NYP-Allen and Harlem Hospital.

Amyloidosis results from an abnormal buildup of misfolded protein called amyloid, which results in protein deposits in the heart, nerves and other body systems. There are two types of ATTR amyloidosis, classified by the DNA coding sequence of the Transthyretin (TTR) gene. Wild-type (ATTRwt) occurs in the context of a normal DNA sequence and hereditary (hATTR or ATTRv) results from inherited mutations in the TTR gene sequence. Both types generally affect only older adults, over the age of 60 years. SCAN-MP will not only identify ATTR-CM, but also determine whether there is a genetic or non-genetic cause. This is important because certain currently available treatments are restricted to the hereditary type of ATTR-CM only.

Identification of a mutation in the TTR gene means that family members of the affected patient are also at risk for ATTR-CM. Importantly, there are no data regarding the prevalence of ATTR-CM in Hispanic people, typically due to the challenge of diagnosis. The investigators hypothesize that a significant proportion of heart failure in elderly people who are Black and Hispanic is caused by ATTR-CM.

SCAN-MP will help us better understand the prevalence of ATTR cardiac amyloidosis among Black and Hispanic Americans, which could then help us to target better screening for this disease and lead to earlier diagnosis and treatment. Now that we have treatments available, it is essential we identify afflicted patients early, when treatments are most effective. Thus, we think that the findings of SCAN-MP should directly impact the health outcomes of minority patients with ATTR amyloidosis."

Frederick L. Ruberg, director of advanced cardiovascular imaging at Boston Medical Center

The SCAN-MP trial, which will enroll patients in Boston and New York, will use a highly accurate nuclear medicine imaging technique for ATTR-CM identification, avoiding the need for a heart biopsy in most cases. Imaging changes can occur before echocardiographic or clinical changes, which suggests enhanced sensitivity for facilitating early diagnosis. Data from SCAN-MP will also calibrate a new point-of-care diagnostic tool to permit an office-based diagnosis of ATTR-CM. The trial will continue to follow participants longitudinally, looking at their quality of life, mobility, frailty, perceptions of the health care system, social determinants of health, and other issues that may impact cardiac amyloidosis diagnosis and treatment.

In addition to supporting an earlier diagnosis, this grant will also assist in answering important questions regarding genetics and sex-based differences previously reported in ATTR-CM. It will explore whether hATTR or ATTRwt have different rates of progression, whether men or women are more affected, clarify the role of genetics in ATTR-CM development, and evaluate biochemical mechanisms that underlie misfolding of the TTR protein that causes ATTR-CM. Insights into the mechanism of TTR misfolding that precede amyloid fibril formation and deposition will be gained through collaboration with Dr. Jeffery Kelly at The Scripps Research Institute.

The funding is provided through the National Heart, Lung and Blood Institute (NHBLI) of the National Institutes of Health (NIH) and is being conducted under the auspices of an Investigational New Drug (IND) for re-labeling of the PYP imaging reagent issued by the Food and Drug Administration, Division of Medical Imaging Products (DMIP).

This grant comes at an exciting time for amyloidosis discovery, as the first specific FDA-approved treatments for ATTR-CM became available in May this year, with other agents in currently in testing. The results of SCAN-MP will represent an important advancement in the approach to minority patients with heart failure.