Assess ATTR-CM

// Diagnosis of ATTR-CM

The number of patients diagnosed with transthyretin amyloid cardiomyopathy
(ATTR-CM), particularly wild-type ATTR-CM, has dramatically increased during the past 20 years. This is mainly due to remarkable advances in noninvasive diagnostic cardiac imaging techniques, especially concerning cardiac magnetic resonance (CMR) imaging, cardiac scintigraphy (Tc-PYP scan) and repurposed bone scintigraphy and an increasing awareness of ATTR-CM.

When to suspect cardiac amyloidosis

ATTR-CM causes a form of cardiomyopathy that manifests with heart failure (HF) symptoms, including dyspnoea, fatigue and peripheral oedema. While these symptoms are nonspecific and commonly observed in other types of heart failure, certain clinical features may specifically suggest wild-type ATTR-CM (ATTRwt) or hereditary variant
ATTR-CM (ATTRv) when cardiac involvement is present. Cardiac amyloidosis should be considered in men >65 years or women >70 years with increased left ventricular wall thickness ≥12 mm with either HF or ≥1 ‘red flag’. Cardiac ‘red flags’ include, but are not limited to, cardiac conduction abnormalities, a decreased QRS voltage-to-mass-ratio and atrioventricular block. Atrioventricular block may be seen in up to 22% of people with cardiac amyloidosis.

Additionally, there are extracardiac ‘red flags’ which can heighten suspicion for the disease: 

Bilateral carpal tunnel syndrome – often one of the earliest indicators of ATTR-CM – is the most common noncardiac manifestation and can precede clinical heart failure by several years.

Impact of earlier diagnosis on treatment goals in ATTR-CM

Due to diagnosis at earlier stages of the disease, the goals of patient treatment have expanded beyond prolonging survival, and now also include:

• Maintaining quality of life
• Preserving independence
• Reducing hospitalisations
   

The stabilisation or improvement of prognostic biomarkers can serve as a practical clinical assessment tool, and the measurement of these parameters can easily be performed in clinical practice every 6–12 months as part of multiparametric patient monitoring. State-of-the-art diagnostics, including biomarkers at the time of diagnosis of ATTR-CM, allow for patient stratification and prognosis – both are critical for the best possible patient care. In addition, regularly measuring all biomarkers – NT-proBNP, troponin, estimated glomerular filtration rate (eGFR) and serum TTR levels – provides a good overall assessment of the effectiveness of treatment and the progression of the patient.

Contemporary measures of ATTR-CM disease progression include the holistic assessment of functional capacity, cardiac morbidity, quality of life and multiple biomarkers.

Cardiac morbidity 

The number of hospitalisations due to heart failure decompensation requiring intravenous diuretic treatment is a significant indicator of disease progression. The recommended threshold for this parameter is one or more hospital admissions within a 6-month period, while the absence of any hospitalisations during this time is considered stabilisation of ATTR-CM.

Functional capacity

Physical assessments such as the number of metres walked in 6 min (6MWD) are an objective way to detect disease severity, progression and treatment effects. Decrease of 30–40 metres every 6 months (in the absence of obvious non-cardiovascular cause) is the threshold indicating disease progression.

Quality of life

Quality of life assessment, using tools such as EuroQol five dimensions (EQ-5D) tool and Kansas City Cardiomyopathy Questionnaire (KCCQ), is an established chronic disease measure that is considered an essential indicator of response in HF treatment. It is recommended to perform quality of life measurements in a relatively short timeframe (6–12 months). Threshold indicating disease progression: A five-point decrease in KCCQ represents deterioration, a 10-point decrease in KCCQ represents moderate deterioration. A 10% decline in EQ-5D score represents deterioration.

Biomarkers and laboratory markers

Biomarkers play an important role at all levels of the algorithm, from screening to diagnosis, prognosis, risk stratification and monitoring of response to therapy:

• Troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are the strongest predictors of survival in patients with ATTR. Threshold indicating disease progression for NT-proBNP is 30% increase with 300 pg/mL cut-off (to be measured during a 30-day period of clinical stability and under same atrial rhythm) and a 30% increase for Troponin with measurements recommended every 6 months
• A universally applicable staging system combining NT-proBNP and eGFR has been developed by Gillmore JD et al. in 2018 for risk stratification of patients with wild-type ATTR-CM or hereditary ATTR-CM known as the NAC staging score. It allows the stratification of patients in three subgroups with significantly different survival and risk for all-cause mortality. Advance in NAC staging score indicates disease progression
• In a series of biopsy-proven wild-type ATTR-CM amyloidosis, lower baseline serum transthyretin (TTR) levels were associated with shorter survival as independent predictor of outcome. These data suggest TTR may be a useful prognostic marker and predictor of outcome in wild-type ATTR amyloidosis

Serum TTR is emerging as an important prognostic biomarker for mortality and cardiac morbidity in people with ATTR-CM.