Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations

Heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older
Black and Hispanic Americans. ATTR cardiac amyloidosis (ATTR CA) is caused by myocardial
deposition of misfolded transthyretin protein (TTR or prealbumin) and is classified by the
genetics of TTR into wild-type (ATTRwt) or hereditary (hATTR or ATTRm). ATTR CA, irrespective
of genotype, is an age-dependent, often unrecognized, mechanism underlying HFpEF. While hATTR
CA results from point mutations that promote TTR misfolding and amyloid aggregation, factors
that contribute to ATTRwt CA are not well defined. While previously thought to be
untreatable, promising therapies that have been recently reported are most effective if
administered early in disease course. Only a small proportion of individuals with wild-type
TTR will develop ATTRwt CA, overwhelmingly reported in Caucasian males beyond age 60 years.
However, as an autosomal protein, allele distribution is not sex specific. For hATTR, a
substitution of isoleucine for valine (Val122Ile) is the most frequent TTR mutation in the
US, observed exclusively in Black Americans with an allele frequency of 3.4%. But there are
no data regarding the prevalence of ATTRwt CA in African Americans and no data for ATTR CA
prevalence, irrespective of genotype, in the Hispanic population. One of the reasons for the
knowledge deficit is the challenge of diagnosis. Endomyocardial biopsy, while nearly 100%
sensitive and specific, is impractical as a screening test and genotyping alone of patients
is insufficient to identify ATTR CA because wild-type patients develop disease. In this
study, the investigators will use a highly accurate technique for ATTR CA identification
using Tc99m-pyrophosphate (PYP) imaging that avoids the need for biopsy. Tc99m-PYP myocardial
uptake can occur before echocardiographic or clinical changes, suggesting enhanced
sensitivity. While studies using the technique have suggested that 10-15% of elderly
hospitalized patients with HF may have ATTR CA, Tc99m-PYP has not been applied broadly in HF
patients as a means to facilitate early diagnosis. In addition, the investigators will test
the diagnostic accuracy of a point-of-care diagnostic tool that utilizes a novel biomarker,
retinol binding protein 4 (RBP4), and an assay to measure TTR stability. The overall
hypothesis is that a significant proportion of HF in elderly Blacks and Hispanics is caused
ATTR CA. Using these non-invasive tests, the investigators will establish the prevalence of
ATTR CA and explore the relationship between RBP4 concentration and TTR stability in a
prospective cohort study of elderly Black and Hispanic Americans with HF.

Inclusion Criteria:

1. Black or Hispanic of Caribbean origin.

2. Age ≥ 60 years.

3. Diagnosis of heart failure, confirmed by one of two methods:

1. Modified criteria utilized by Rich et al. which include a history of acute
pulmonary edema or the occurrence of at least two of the following that improved
with diuretic therapy without another identifiable cause: dyspnea on exertion,
paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema or
exertional fatigue, and

2. National Health and Nutrition Examination Survey (NHANES) congestive heart
failure (CHF) criteria with a score ≥3.

4. Able to understand and sign the informed consent document after the nature of the
study has been fully explained.

Exclusion Criteria:

1. Primary amyloidosis (AL) or secondary amyloidosis (AA).

2. Prior liver or heart transplantation.

3. Active malignancy or non-amyloid disease with expected survival of less than 1 year.

4. Heart failure, in the opinion of the investigator, primarily caused by either valve
disease or ischemic heart disease.