Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive heart condition caused by the buildup of misfolded transthyretin (TTR) proteins. These proteins deposit as amyloid fibrils within the heart muscle, leading to stiffness and eventual heart failure. Understanding the prevalence of ATTR-CM has become increasingly important as new treatments become available. Current data indicate it is far more common than previously believed.
Distinguishing Wild-Type and Hereditary Forms
ATTR-CM is generally discussed within the context of its two primary forms. Wild-Type ATTR-CM (ATTRwt-CM) is not inherited and is associated with the normal aging process, typically manifesting in older individuals, especially men. The TTR protein, which is structurally normal in this form, spontaneously misfolds and aggregates over time.
Hereditary ATTR-CM (ATTRv-CM) is caused by a genetic mutation in the TTR gene, which results in the production of an unstable TTR protein prone to misfolding. Over 130 different mutations have been identified, with the clinical presentation varying widely based on the specific variant.
Reported Global and Regional Incidence Data
ATTR-CM is now increasingly recognized, especially in certain high-risk populations. Across the general population, the prevalence of wild-type ATTR-CM is estimated to be around 1 in 5,800 worldwide. Reported incidence rates for both forms combined have been noted to be around 4 to 17 cases per 100,000 individuals.
When focusing on specific patient groups, the prevalence estimates rise significantly, underscoring the importance of targeted screening. For instance, in cohorts of older patients with heart failure who have thickened heart walls, the prevalence of ATTR-CM can be as high as 20%. Autopsy studies have found TTR amyloid deposits in the heart of up to 25% of unselected individuals aged 85 or older. The prevalence of ATTR-CM also shows regional variation, with some studies in Europe reporting a prevalence of 24% among high-risk heart failure patients, compared to 9% in Asia and 5% in North America.
Demographic Patterns and Specific Risk Factors
Demographic factors significantly influence the likelihood of developing ATTR-CM, with age and sex being major determinants for the wild-type form. ATTRwt-CM predominantly affects older men, with the average age at diagnosis often being over 70 years. The male predominance is notable, as more than 88% of ATTRwt-CM patients in some studies are men.
Ancestry is a strong risk factor for the hereditary form due to specific TTR gene mutations. The V122I variant, the most common hereditary mutation in the United States, has a prevalence of about 3.4% in the general African American population. This translates to an estimated 1.5 million carriers in the U.S. The clinical penetrance, or the likelihood of developing symptoms, for the V122I variant is estimated to be significant, with one study finding it to be 39% among elderly African American heart failure patients.
The Impact of Underdiagnosis on True Prevalence
The reported prevalence of ATTR-CM is widely considered to be an underestimate of the true number of cases due to significant underdiagnosis. The symptoms of ATTR-CM often mimic those of more common heart conditions, such as hypertrophic cardiomyopathy, leading to frequent misdiagnosis. This diagnostic confusion results in a substantial delay in diagnosis.
A lack of awareness among clinicians outside of specialized centers has historically contributed to the low reported numbers. However, the advent of non-invasive diagnostic tools, particularly nuclear scintigraphy, has been transformative. These imaging techniques allow for diagnosis without the need for a heart biopsy, revealing a previously hidden burden of the disease. The increasing use of these tools is now uncovering a much higher true prevalence, suggesting that ATTR-CM is a far more common cause of heart failure in the elderly population than was recorded just a few years ago.