Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease affecting the heart muscle. It is caused by the transthyretin (TTR) protein, which is produced by the liver to transport vitamin A and a thyroid hormone. In ATTR-CM, this protein misfolds and accumulates as amyloid deposits in the heart, causing the walls to stiffen and thicken. This impairs the heart’s ability to pump blood effectively and can lead to heart failure.
Understanding ATTR-CM
There are two forms of ATTR-CM. The first is wild-type ATTR-CM (ATTRwt), a form not caused by a genetic mutation but associated with the natural aging process. In ATTRwt, the TTR protein becomes unstable over time, leading to misfolding and deposition, and it most often affects men over the age of 60.
The second form is hereditary ATTR-CM (ATTRv), which results from an inherited mutation in the TTR gene. This genetic alteration produces an unstable TTR protein from birth, predisposing it to misfold. While symptoms can appear as early as one’s 30s, they often manifest later in life and can affect the nerves and kidneys in addition to the heart.
Estimated Prevalence in the General Population
Determining the exact prevalence of ATTR-CM in the general population is challenging, and current figures are widely considered underestimates. Recent data suggests that what was once thought to be a rare disease is more common than previously believed, especially among older adults.
Reported prevalence numbers vary significantly between countries. In the United States, older data suggested a prevalence of approximately 6.1 cases per million people, while studies in European countries have reported higher figures, such as 50 per million in Sweden. Some estimates suggest the true prevalence of the age-related wild-type form could be as high as 16.6 per 100,000 when accounting for undiagnosed individuals.
The wild-type form of ATTR-CM is believed to be much more common than the hereditary form, with a majority of diagnosed cases being ATTRwt. Its prevalence increases sharply with age, while hereditary ATTR-CM’s prevalence can be concentrated in specific geographic and ethnic populations due to founder effects.
Prevalence in At-Risk Populations
The prevalence of ATTR-CM is substantially higher in specific at-risk groups. Identifying these groups is a focus of clinical practice, as it allows for earlier detection. These subpopulations share common clinical histories that should prompt consideration of an ATTR-CM diagnosis.
Older Adults with Heart Failure
Among older adults, particularly those with heart failure with preserved ejection fraction (HFpEF), ATTR-CM is increasingly recognized. HFpEF is a condition where the heart pumps normally but is too stiff to fill properly. Studies suggest that ATTR-CM may be the underlying cause in a significant portion of these cases, with some reports indicating a prevalence of up to 15% in HFpEF patients over the age of 83.
Patients with Aortic Stenosis
Aortic stenosis, a narrowing of the aortic valve opening, is another condition where ATTR-CM is frequently found. This is particularly true for older patients undergoing valve replacement surgery. In systematic reviews of screening studies, the prevalence of ATTR-CM in patients with aortic stenosis was found to be around 11%.
Individuals with Carpal Tunnel Syndrome
A history of bilateral carpal tunnel syndrome (CTS) is a known indicator for ATTR-CM, often preceding cardiac symptoms by several years. Amyloid deposits can accumulate in the ligaments of the carpal tunnel, leading to nerve compression. In older adults presenting with CTS and heart failure, the rate of undiagnosed ATTR-CM can be as high as 28%.
Specific Ethnic Groups
Hereditary ATTR-CM has a notably higher prevalence in certain ethnic populations due to specific gene mutations. The most common mutation in the United States is V122I, which is found almost exclusively in individuals of West African or Afro-Caribbean descent. Approximately 3% to 4% of Black Americans carry this genetic variant. In studies of older Black patients with heart failure, the prevalence of the V122I mutation has been reported to be as high as 6.8%.
Factors Influencing Prevalence Data
The reported prevalence of ATTR-CM has been influenced by historical diagnostic challenges. For many years, the condition was frequently missed because its symptoms, such as shortness of breath and fatigue, overlap with more common causes of heart failure. This clinical mimicry often led to misdiagnosis, with patients being incorrectly labeled as having hypertensive heart disease or other forms of cardiomyopathy.
A definitive diagnosis historically required an invasive endomyocardial biopsy, where a small piece of heart tissue is examined for amyloid deposits. The risks and complexities of this procedure meant it was not performed routinely, contributing to underdiagnosis. Consequently, prevalence figures were based on limited and often late-stage diagnoses.
The landscape of ATTR-CM diagnosis has been transformed by non-invasive imaging techniques. Nuclear scintigraphy, using tracers like technetium pyrophosphate (PYP), has become a reliable method for identifying TTR amyloid in the heart without a biopsy. This advancement has made it easier to screen for and confirm ATTR-CM, and as awareness has grown, the number of identified cases has risen, reflecting better detection rather than a true increase in the disease’s occurrence.