Table 3.

Comparison of global guidelines with panel recommendations.^16,29

Key Points	AHA	ESC	Indian panel recommendations
Aim of position papers	To help practicing cardiologists focus on diagnosis and management of ATTR-CM	To help cardiologists and other physicians in suspecting, diagnosing, and treating patients with CA •Suspicion: LV wall thickness>12 mm along with presence of at least one red signal •Diagnosis: non-invasive (for ATTR-CM) and invasive (all types) •Treatment: managing cardiac complications and disease modifying agent	To develop India specific diagnostic approach protocol to help cardiologists in India to raise the suspicion and diagnosis of ATTR-CM
When to suspect	Presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) triggers consideration of ATTR-CM especially if there is discordance between wall thickness on ECG and QRS voltage on ECG	Presence of LV wall thickness >12 mm along with either heart failure, aortic stenosis, or red flag signs/symptoms, particularly if older than 65 years	Considering propensity of Indians to develop heart conditions at an earlier age, age limit should be kept lower (≥40 years) for suspecting ATTR-CM Thick-walled non-dilated hypokinetic ventricle should be considered as an important red flag HFpEF, LV thickness ≥11 mm), GLS, aortic stenosis, arrythmias, cardiac conduction abnormalities are some of the other common red flags
Non-invasive diagnostic tests
ECG	Recommends ECG in the diagnostic protocol Also important in patients with advanced diseases as <40% of such patients show low voltage on ECG Absence of low voltage does not rule out ATTR-CM	Recommends ECG at the time of first suspicion and every 6 months	Recommends ECG, chest x-ray and ECHO as the primary and mandatory screening test The tests should also be used for follow up periodically
ECHO	Does not recommend it for diagnosis of ATTR-CM since, it cannot distinguish between ATTRv and ATTRwt. However, can identify nonamyloid causes of LV Thickening (HCM, aortic stenosis, and Fabry disease)	Recommends ECHO under following conditions: Unexplained LV thickness (≥12 mm) plus 1 or 2: 1 Characteristic echocardiography findings (≥2 of a, b, and c have to be present) a) Grade 2 or worse diastolic dysfunction b) reduced tissue Doppler s’, e’, and a’ waves velocities (<5 cm/s) c) decreased global longitudinal LV strain (absolute value < −15%). 2 Multiparametric echocardiographic score ≥8 points: d) relative LV wall thickness (IVS + PWT)/LVEDD >0.6: 3 points e) doppler E wave/e0 wave velocities >11: 1 point f) TAPSE ≤19 mm: 2 points g) LV global longitudinal strain absolute value ≤ −13%: 1 point h) systolic longitudinal strain apex to base ratio >2.9: 3 points	Recommends ECHO for raising suspicion of ATTR-CM It is recommended as the cornerstone for early diagnosis of all types of cardiac amyloidosis; to identify increased LV thickness, granular sparkling of myocardium, and pericardial effusion. Left ventricular wall thickness (>11 mm), right ventricular wall thickness, free valves of the right atrium, LV longitudinal strain are some of important features seen on ECHO
Nuclear scintigraphy	Scans may be positive even in AL amyloidosis, and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL-CM Assessment of ATTR-CM with bone scintigraphy is accomplished by quantitative approaches comparing heart to rib uptake Grade 0 is no cardiac and normal rib uptake Grade 1 is cardiac less than rib uptake Grade 2 is cardiac equal to rib uptake Grade 3 is cardiac greater than rib uptake with mild/absent rib uptake In the absence of a light chain abnormality, the 99mTc-PYP scintigraphy is diagnostic of ATTR-CM if there is Grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5	While recommending scintigraphy, SPIE, UPIE and serum FLC, four scenarios should be considered a) Scintigraphy does not show cardiac uptake and assessments for monoclonal proteins are negative – Amyloidosis unlikely b)Scintigraphy shows cardiac uptake and monoclonal proteins are negative – if Grade 2/3 uptake – ATTR-CM; Grade 1 – confirmation by biopsy c)Scintigraphy does not show cardiac uptake and at least one of the monoclonal protein tests is abnormal – CMR to see cardiac involvement followed by biopsy if CMR inconclusive d)Scintigraphy shows cardiac uptake and at least one of the monoclonal protein tests is abnormal. TTR amyloidosis with concomitant MGUS, AL amyloidosis, or coexistence of both AL and ATTR amyloidosis are possible	It is considered as a gold standard for confirming the diagnosis of ATTR-CM as it is accurate, cheap, interpretation is simple and has high sensitivity and specificity. Pyrophosphate scans are recommended
CMR Imaging	Consider CMR as the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies	Characteristic CMR findings (a and b have to be present): •diffuse subendocardial or transmural LGE •abnormal gadolinium kinetics •ECV ≥0.40% (strongly supportive, but not essential/diagnostic	CMR is useful if ECHO findings are inconclusive or ambiguous, recommended as optional (depending on the cost availability and need)
Hematologic consideration	Based on history, ECHO and ECG findings suggestive of amyloidosis Scintigraphy along with serum FLC and serum and urine IFE (Measurement of serum IFE, urine IFE, and serum FLC is >99% sensitive for AL amyloidosis)	Based on clinical, laboratory and ECG suspicion Scintigraphy coupled to assessment for monoclonal proteins by SPIE, UPIE, and quantification of serum FLC is recommended	Based on clinical findings: Combination of SPIE, UPIE and serum FLC to rule out AL amyloidosis, has 99% sensitivity for abnormal pro-amyloidotic precursor in AL amyloidosis
Genetic testing	Recommends genetic testing to distinguish ATTRv and ATTRwt after confirmation of ATTR-CM from bone scintigraphy or EMB	Strongly recommends genetic testing once ATTR-CM is confirmed in order to differentiate between ATTRwt and ATTRv Genetic testing should be performed even in elderly patients, as a significant number of patients can have TTR mutations	Once diagnosis of ATTR-CM is confirmed the first-degree relatives should be offered genetic testing It should not be a rate limiting step in the initiation of treatment Not recommended as a mandatory test
Invasive diagnostic tests
EMB	It is mandatory in other 3 scenarios: 1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light Chain analysis to exclude AL-CM 2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm ATTR-CM 3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM	It is recommended to confirm ATTR-CM in case of any discrepancy Demonstrates amyloid deposits after Congo red staining irrespective of the degree of LV wall thickness Diagnosis of CA in case of MGUS (or any hematological disorder that produces FLC), AL amyloidosis, or coexistence of both AL and ATTR amyloidosis require histology with amyloid typing, usually via EMB	Biopsy may not be needed to confirm diagnosis of amyloidosis Fat aspiration biopsy may be positive in 80% of cases of AL and 40% cases of ATTR

AHA, American Heart Association; AL-CM, amyloid light-chain amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; CMR, cardiac magnetic resonance; ECV, extracellular volume fraction; ECG, echocardiogram; ECHO, echocardiography; EMB, endomyocardial biopsy; ESC, European Society of Cardiology; HCM, hypertrophic cardiomyopathy; FLC, free light chain; GLS, global longitudinal strain; HFpEF, heart failure with preserved ejection fraction; IVS, interventricular septum; IFE, immunofixation electrophoresis; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; LGE, late gadolinium enhancement; PWT, posterior wall thickness; 99mTc-PYP, technetium pyrophosphate; TAPSE, tricuspid annular plane systolic excursion; MGUS, monoclonal gammopathy of undetermined significance; SPIE, serum protein electrophoresis with immunofixation; UPIE, urine protein electrophoresis with immunofixation.