Once diagnosed, the untreated patients with ATTR-CM have a median survival of ∼2 to 3.5 years.³

It is important to clinically differentiate between ATTR-CM and AL, as they have different clinical courses. In particular, AL cardiomyopathy seems to be associated with only slightly increased wall thickness, but it appears to show the highest frequencies of hemodynamic derangement (mainly because of diastolic dysfunction) and low QRS voltages on ECG, and its clinical course may be rather aggressive.⁴
 

Patient considerations

• Predominantly affects older Caucasian men⁷
• Symptom onset typically over the age of 60 years⁸
• Common characteristics that may present in patients with wtATTR-CM
  - Heart failure⁷
  - Atrial arrhythmias, atrial fibrillation⁶
  - The most common initial symptom was CTS⁹
  - ATTR amyloid deposits were frequently found in the ligamentum flavum of the lumbar spine⁹

• [Inherited mutations in TTR are common in patients of African (V122I), Irish (T60A), Italian (I68L) and Danish (L111M) descent]^3,8,10,11

• Men and women¹⁰
• Symptom onset may occur as early as 50-60 years of age¹⁰
• Common characteristics that may present in patients with hATTR-CM
  - Heart failure⁷
  - Peripheral dysfunction (e.g. peripheral neuropathy)⁷
  - Autonomic dysfunction (e.g. autonomic neuropathy, gastrointestinal complaints, unexplained weight loss, orthostatic hypotension)⁷
  - History of carpal tunnel syndrome⁷

Once diagnosed, the untreated patients have a median survival of ∼2 to 3 years³

HFpEF in patients typically over the age of 60²

• As diastolic function is impaired in HFpEF, diastolic reserve is also reduced— patients display blunted increases in preload volume with exertion, despite marked elevations in filling pressure³
• Prevalence among older patients with HFpEF
  ○ ∼ 10% of patients with HFpEF referred to a dedicated centre had ATTR-CM confirmed by EMB^4†
  ○ Considering a positive DPD scan as highly suggestive of cardiac TTR amyloidosis, this study shows that ATTRwt accounts for 13% of the HFpEF cases^2‡
• In patients undergoing transcatheter aortic valve replacement (TAVR) for severe calcific AS, prevalence of ATTR-CM was 16% overall and 22% among men⁵

Intolerance to standard heart failure therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta blockers⁷

• Intolerance to standard heart failure medications is common in patients with cardiac amyloidosis, such agents exacerbate symptomatic hypotension in the setting of concomitant autonomic dysfunction or by lowering the heart rate and reducing the cardiac output⁷

Discordance between QRS voltage on ECG and LV wall thickness⁸

• The classic ECG feature of ATTR-CM is a discordance between QRS voltage and LV mass ratio⁹
• The amplitude of the QRS voltage is not reflective of the increased LV wall thickness because the increase is due to extracellular amyloid protein deposition rather than myocyte hypertrophy⁶
  - Absence of a low QRS voltage does not, however, rule out amyloidosis, as low voltage can vary among cardiac amyloidosis etiologies¹⁰

Echocardiography showing increased LV wall thickness¹²

• Unexplained increased LV wall thickness (e.g. hypertension) should raise suspicion for cardiac amyloidosis¹³

Diagnosis of orthopaedic conditions, including carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture and/or hip and knee arthroplasty¹⁶

• Carpal tunnel syndrome and lumbar spinal stenosis 
  -Carpal tunnel syndrome is the most common initial symptom of systemic wtATTR-CM amyloidosis;¹⁷ lumbar spinal stenosis quite frequently may be a consequence of SSA¹⁸
  -Carpal tunnel syndrome and lumbar spinal stenosis are known clinical predictors of ATTR-CM and may precede heart failure symptoms by several years¹⁹
  -Among patients undergoing carpal tunnel release surgery, 10.2% had amyloid deposits²⁰
• Biceps tendon rupture
  -Among patients with wtATTR-CM (n=111), biceps tendon rupture has been observed in 33.3% of patients, occurring in the dominant arm in 95% and bilaterally in 24.3% of patients²¹
• Hip and knee arthroplasty
  -In a study of 313 patients (172 with ATTR-CM), hip and knee arthroplasty surgeries were more frequent than in the general population, and on average, arthroplasty occurred 7.2 years before ATTR-CM diagnosis¹⁶

Nervous system dysfunction, including polyneuropathy and autonomic dysfunction, including gastrointestinal complaints and/or unexplained weight loss²²

• Gastrointestinal complaints due to autonomic dysfunction include chronic diarrhoea, constipation or both²²
• Orthostatic hypotension due to autonomic dysfunction is another symptom that may occur with ATTR-CM²²

*Notably those with a low-flow, low-gradient AS pattern.^5
†A prospective analysis in 108 patients (61% women, age range: 57-74 years) seen at the Johns Hopkins' HFpEF Clinic who underwent endomyocardial biopsy to evaluate myocardial tissue histopathology.^4
‡A prospective, cross-sectional, single-centre study at a tertiary university hospital in Madrid, Spain, to determine the prevalence of wtATTR-CM among elderly patients admitted due to HFpEF. The study included 120 patients ≥60 years of age (59% women, mean age: 82±8 years) admitted for HFpEF, with LV ejection fraction ≥50% and LV hypertrophy ≥12 mm. ^99mTc-DPD (^99mtechnetium-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid) scintigraphy used to confirm ATTR-CM.²

AS: aortic stenosis; ATTR: transthyretin amyloidosis; ATTR-CM: transthyretin amyloid cardiomyopathy; ECG: electrocardiogram; EMB: endomyocardial biopsy; hATTR-CM: hereditary transthyretin amyloid cardiomyopathy; HFpEF: heart failure with preserved ejection fraction; LV: left ventricular; MOA: mechanism of action; MOD: mechanism of disease; SSA, Senile systemic amyloidosis; wtATTR-CM: wild-type transthyretin amyloid cardiomyopathy.

When ATTR-CM is suspected, diagnosis can be made non-invasively with nuclear scintigraphy and testing to rule out AL amyloidosis⁵

• Nuclear scintigraphy with [^99mTc-PYP*/^99mTc-DPD/^99mTc-HMDP] provides a unique myocardial uptake pattern in amyloid⁶
  - Studies comparing [99mTc-PYP/99mTc-DPD/99mTc-HMDP] scintigraphy with EMB found that bone radiotracers have avidity for ATTR deposits, whereas avidity for AL cardiac amyloid deposits is minimal or absent³
  - Nuclear scintigraphy may identify ATTR deposits early in the course of disease⁶
  - The mechanism for the differential uptake in ATTR versus AL cardiac amyloidosis is unknown, but it has been suggested that the preferential uptake by ATTR may be a result of higher calcium content⁶

• A multi-centre international study of scintigraphy at amyloid centres of excellence demonstrated 100% specificity for ATTR-CM using visual grade 2 or 3 with concurrent testing to rule out AL⁷

Diagnosing ATTR-CM with [^99mTc-PYP/^99mTc-DPD/^99mTc-HMDP] imaging

The role of [^99mTc-PYP/^99mTc-DPD/^99mTc-HMDP] imaging for the diagnosis of ATTR-CM

• A variety of bone radiotracers have avidity for cardiac amyloid deposits: [^99mTc-PYP/^99mTc-DPD/^99mTc-HMDP]⁶
• Images can be scanned early (1 hour) or late (3 hours)⁶
  - Interval between injection and scan⁸
• Both planar and single-photon emission computed tomography (SPECT) imaging should be reviewed and interpreted using visual and quantitative approaches irrespective of the timing of acquisition⁶

Two-step interpretation of [^99mTc-PYP/^99mTc-DPD/^99mTc-HMDP] images to diagnose ATTR-CM⁶

• Visual interpretation should include an evaluation of planar and SPECT images to confirm diffuse radiotracer uptake in the myocardium⁶
• SPECT imaging can be used to differentiate myocardial radiotracer uptake from residual blood pool activity, focal myocardial infarct and  overlapping bone (e.g. from rib hot spots from fractures). Recommend repeating SPECT at 3 hours if excess blood pooling is noted at 1 hour⁶
• If myocardial tracer uptake is visually present on SPECT, proceed to step 2, semi-quantitative grading⁶

There are 2 approaches to performing semi-quantitative grading⁶

See how nuclear scintigraphy, endomyocardial biopsy (EMB) and genetic testing can support early ATTR-CM diagnosis²

HISTOLOGY

EMB—an invasive approach to diagnose ATTR-CM⁴

Congo red staining of myocardial tissue on light microscopy and apple-green birefringence on polarized light microscopy images⁴

• To determine the amyloid type, immunohistochemistry (IHC) tests and/or mass spectrometry should be performed⁶
• Risk of complications and the need for specialised centres and expertise may contribute to a diagnostic delay⁶

TESTING

GENETIC TESTING - used in the ATTR-CM diagnostic process

• To confirm TTR mutation in patients with ATTR amyloidosis³

^99mTc-DPD: ^99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid; ^99mTc-HMDP: ^99m-technetium-hydroxymethylene diphosphonate; ^99mTc-PYP: ^99mtechnetium-pyrophosphate; AApoAI, Apolipoprotein AI amyloidosis; AL: immunoglobulin light chain amyloid fibril protein; ATTR: transthyretin amyloidosis; ATTR-CM: transthyretin amyloid cardiomyopathy; CMR, cardiac magnetic resonance imaging; MOA: mechanism of action; MOD: mechanism of disease; TTR: transthyretin.