Medically reviewed by Dr. Jyoti Rao, Consultant, Medical Affairs | Last reviewed August 2026
Key Takeaways
- ATTRv is hereditary and inherited in an autosomal dominant pattern; ATTRwt occurs without an inherited TTR variant and is not an inherited disorder.
- ATTRwt is typically a disease of older adults, strongly male-predominant, and almost exclusively cardiac.
- ATTRv phenotype depends on the variant—some are cardiac-predominant, some neuropathy-predominant, and some mixed.
- Both subtypes involve transthyretin amyloid deposition in the myocardium, but the distinction matters for genetic counseling, family risk, phenotype interpretation, and treatment planning.
ATTRv and ATTRwt Differ in Origin, Not in the Final Myocardial Pathway
The distinction between ATTRv and ATTRwt is etiologic. In ATTRv, an inherited pathogenic variant in the TTR gene destabilizes the transthyretin protein; in ATTRwt, the normal-sequence protein becomes amyloidogenic over time without an inherited variant. The downstream process is shared as misfolded transthyretin forms amyloid deposits in the myocardium, leading to ventricular stiffening and progressive cardiac dysfunction. Because both forms ultimately follow this shared cardiac pathway, the broader picture of progressive amyloid heart failure described in the [ATTR-CM overview] remains applicable to both. The key distinction lies in etiology, including variant interpretation, penetrance, and family-risk implications.
Wild-Type ATTR-CM Is Largely a Cardiac Disease of Older Age
ATTRwt is increasingly recognized as an important cause of heart failure in older adults and is strongly male-predominant. Its presentation is dominated by the heart, often with characteristic features including preserved ejection fraction with increased wall thickness, conduction disease, and a history of bilateral carpal tunnel syndrome. Because ATTRwt is not caused by an inherited TTR variant, it doesn’t carry the same inherited family risk or need for cascade genetic testing as ATTRv.
Hereditary ATTR-CM Varies by Variant and Can Involve the Nerves
ATTRv is more heterogeneous because the phenotype tracks with the specific pathogenic variant. Some variants are cardiac-predominant, some are neuropathy-predominant, and some produce a mixed cardiac and neurologic syndrome. The V122I variant (also written p.V142I) is the most common pathogenic TTR variant associated with ATTR-CM in the United States and occurs predominantly in people of African ancestry, where it tends to present as a later-onset, cardiac-predominant disease. Other variants, such as V30M (p.V50M), are classically associated with a neuropathy-predominant phenotype. This variability is why genotype helps explain the clinical picture but doesn't by itself define how advanced the cardiac disease is.
The clinical distinctions between the two subtypes are summarized below.
| Feature | ATTRv (hereditary) | ATTRwt (wild-type) |
|---|---|---|
| Origin | Inherited pathogenic TTR variant | Normal-sequence TTR, no inherited variant |
| Inheritance | Autosomal dominant, variable penetrance | Not inherited |
| Typical age | Varies by variant | Older adults |
| Sex | Varies by variant | Strongly male-predominant |
| Phenotype | Cardiac, neuropathic, or mixed | Predominantly cardiac |
| Family risk | Yes—genetic counseling and cascade screening | None |
Why the Distinction Changes Family Screening More Than the Cardiac Approach
The practical consequence of separating ATTRv from ATTRwt is mostly familial. A hereditary diagnosis opens a conversation about at-risk relatives and predictive testing, while a wild-type diagnosis doesn't. For the patient in front of you, both subtypes still require the same disciplined cardiac diagnosis, staging, and follow-up, and both enter the same treatment landscape once transthyretin amyloidosis is confirmed. Establishing which subtype is present requires a structured diagnostic evaluation including TTR genetic testing when hereditary disease is suspected.
Frequently Asked Questions
What’s the difference between ATTRv and ATTRwt?
ATTRv (hereditary, variant) ATTR-CM is caused by an inherited pathogenic TTR variant and can present with cardiac, neurologic, or mixed features. ATTRwt (wild-type) ATTR-CM occurs without an inherited variant, usually in older men, and is almost entirely cardiac. Both forms involve transthyretin amyloid deposition in the heart.
Does ATTRwt run in families?
No. Wild-type ATTR-CM isn't inherited and doesn't carry risk to relatives. Only hereditary ATTRv, which is caused by a pathogenic TTR variant inherited in an autosomal dominant pattern, has family implications.
Does the subtype change cardiac treatment?
The core principles of cardiac diagnosis, staging, and supportive management are similar, but genotype and phenotype can influence individualized treatment planning. ATTRv also requires genetic counseling and consideration of testing for at-risk relatives.
Can hereditary ATTR-CM cause neuropathy as well as heart disease?
Yes. Depending on the variant, hereditary ATTR can be cardiac-predominant, neuropathy-predominant, or mixed. Wild-type ATTR is predominantly cardiac, although it’s associated with musculoskeletal manifestations such as carpal tunnel syndrome.
Part of the Spotlight On ATTR-CM resource center.
References:
- World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM). Global Heart
- Transthyretin Amyloid Cardiomyopathy—2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options. Journal of Clinical Medicine
This content is intended for healthcare professionals for educational purposes and isn't a substitute for individual clinical judgment. It was developed with AI assistance and reviewed by a qualified healthcare professional for clinical accuracy prior to publication.