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Recognizing
ATTR‑CM

Transthyretin amyloid cardiomyopathy (ATTR‑CM)* is a progressive, unrelenting disease that can diminish quality of life, cause recurrent hospitalization, and lead to premature death.^1–3

*Also known as ATTR cardiomyopathy, or ATTR cardiac amyloidosis (ATTR‑CA).

Diagnosing ATTR‑CM

Delayed diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) prevents timely intervention and contributes to premature death^1,4,5

3–5 years median survival¹

in untreated patients following diagnosis

>4 years median diagnostic delay¹

Although cardiac amyloidosis has become an increasingly recognized cause of heart failure and arrythmia, misdiagnosis is common.^5,7

A noninvasive diagnostic algorithm is available to facilitate timely identification of patients with ATTR‑CM.⁸ Early diagnosis enables early interventions that may help slow disease progression.^4,6,7

Patient Populations Considered At-Risk for ATTR‑CM⁶

Although cardiac amyloidosis has become an increasingly recognized cause of heart failure and arrythmia, misdiagnosis is common.^5,7

ATTR‑CM Red Flags

Transthyretin (TTR) amyloid fibrils can accumulate both within and outside of the heart, leading to diverse signs and symptoms.⁴ People with ATTR‑CM commonly present with nonspecific symptoms that correlate with heart failure (eg, dyspnea, fatigue, and edema) — the key to diagnosis is a high index of suspicion.⁴ Certain clinical signals may be indicative of ATTR‑CM, particularly if occurring in combination.⁶

Potential Signs of Amyloid Fibril Accumulation Within the Heart

Echocardiogram and ECG

Reduction in longitudinal strain with apical sparing⁶
Discrepancy between left ventricular (LV) thickness and QRS voltage⁶
Atrioventricular block in the presence of increased LV wall thickness⁶
Hypertrophic phenotype with associated inﬁltrative features⁶

Cardiac magnetic resonance imaging (CMR)

Marked extracellular volume (ECV) expansion, abnormal nulling time for the myocardium, or diffuse late gadolinium enhancement⁶

Therapeutic response

Intolerance to standard heart failure therapies (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers)⁴

Biomarkers

Mild increase in troponin levels on repeated occasions⁶

Potential Signs of Amyloid Fibril Accumulation Outside of the Heart

Neuropathic

Symptoms of polyneuropathy and/or dysautonomia⁶

Orthopedic

History of bilateral carpal tunnel syndrome⁶
Lumbar spinal stenosis⁴
Spontaneous rupture of the distal biceps tendon⁴

Ocular

Vitreous involvement, such as abnormal blood vessel formation, dark ﬂoaters, pupillary abnormalities, and/or dry eye⁹

Renal

Renal impairment and proteinuria¹⁰

Gastrointestinal

Chronic diarrhea or diarrhea alternating with constipation, often with an absence of abdominal pain¹⁰

Recognizing the Unique Features of ATTR‑CM Subtypes

There are two subtypes of ATTR‑CM: wild-type ATTR‑CM (wtATTR‑CM) and hereditary ATTR‑CM (hATTR‑CM).*^,4 These subtypes are designated by the mechanism of TTR tetramer destabilization, which occurs either through age-related changes to the protein or due to variants in the TTR gene.⁴

*Also known as variant ATTR‑CM (vATTR‑CM).

80% of patients

20%^†

Wild-type ATTR-CM^4,10,12

Sporadic disease
TTR gene has normal sequence; TTR protein becomes unstable with age
Reduced symptom severity at diagnosis
Typically manifests later in life (>60 years of age)

Variant ATTR-CM^1,12,13

Autosomal dominant pattern of inheritance
TTR gene has variant sequence that destabilizes the TTR protein
Worse disease at diagnosis (poorer ejection fraction, renal function, and performance status)
Symptom onset at 30–80 years of age

^†In a study of 879 people with ATTR-CM.¹¹

A prevalent pathogenic TTR gene variant is V122I, which affects 3–4% of all Black Americans and has been found in 10% of those aged 65 years or older with severe congestive heart failure¹⁴

Sex Differences in ATTR‑CM

Although predominantly diagnosed in men, ATTR‑CM is becoming increasingly recognized in women¹⁵

*In a study of 1732 consecutive patients, comprising 1095 with wild-type ATTR‑CM and 637 with hereditary ATTR‑CM.¹⁵

Although predominantly diagnosed in men, ATTR‑CM is becoming increasingly recognized in women¹⁵

On average, women are 3.3 years older than men at diagnosis.¹⁵

Both sexes have similar mortality rates, 1-year disease progression rates, and overall structure and function when accounting for body size.¹⁵

References:

Lane T, et al. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation. 2019;140(1):16-26. 2. Rintell D, et al. Patient and Family Experience with Transthyretin Amyloid Cardiomyopathy (ATTR-CM) and Polyneuropathy (ATTR-PN) Amyloidosis: Results of Two Focus Groups. Orphanet J Rare Dis. 2021;16(1):70. 3. Nativi-Nicolau J, et al. Natural History and Progression of Transthyretin Amyloid Cardiomyopathy: Insights from ATTR-ACT. ESC Heart Fail. 2021;8(5):3875-3884. 4. Rozenbaum MH, et al. Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review. Cardiol Ther. 2021;10(1):141-159. 5. Gillmore JD, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133(24):2404-12. 6. Kittleson MM, et al. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020;142(1):e7-e22. 7. Griffin JM, et al. ATTR Amyloidosis: Current and Emerging Management Strategies: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2021;3(4):488-505. 8. Witteles RM, et al. Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC Heart Fail. 2019;7(8):709-716. 9. Gertz M, et al. Avoiding Misdiagnosis: Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Amyloidosis for the General Practitioner. BMC Fam Pract. 2020;21(1):198. 10. Reynolds MM, et al. Ocular Manifestations of Familial Transthyretin Amyloidosis. Am J Ophthalmol. 2017;183:156-162. 11. Law S, et al. Characteristics and Natural History of Early-Stage Cardiac Transthyretin Amyloidosis. Eur Heart J. 2022;43(27):2622-2632. 12. Ruberg FL, et al. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-2891. 13. Michels da Silva D, et al. Inflammatory and Molecular Pathways in Heart Failure-Ischemia, HFpEF and Transthyretin Cardiac Amyloidosis. Int J Mol Sci. 2019;20(9):2322. 14. Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* Cardiac Amyloidosis: An Age-Dependent Autosomal Dominant Cardiomyopathy Too Common to Be Overlooked as a Cause of Significant Heart Disease in Elderly African Americans. Genet Med. 2017;19(7):733-742. 15. Patel RK, et al. Sex Differences Among Patients With Transthyretin Amyloid Cardiomyopathy – From Diagnosis to Prognosis. Eur J Heart Fail. 2022;24(12):2355-2363.

Recognizing ATTR‑CM