Christian Gagliardi

Left Ventricular Structure and Function in Transthyretin-Related Versus Light-Chain Cardiac Amyloidosis

Background— Immunoglobulin amyloid light-chain (AL)-related cardiac amyloidosis (CA) has a worse prognosis than either wild-type (ATTRwt) or mutant (ATTRm) transthyretin (TTR) CA. Detailed echocardiographic studies have been performed in AL amyloidosis but not in TTR amyloidosis and might give insight into this difference. We assessed cardiac structure and function and outcome in a large population of patients with CA and compared findings in TTR and AL-related disease. Methods and Results— We analyzed 172 patients with CA (AL amyloidosis, n=80; ATTRm, n=36; ATTRwt, n=56) by standard echocardiography and 2-dimensional speckle-tracking imaging-derived left ventricular (LV) longitudinal (LS), radial, and circumferential strains. Despite a preserved LV ejection fraction (55±12%), LS was severely impaired in CA. Standard measures of LV function and speckle-tracking imaging worsened as wall thickness increased, whereas apical LS was preserved regardless of the pathogenesis of CA and the degree of wall thickening. Compared with ATTRm and AL amyloidosis, ATTRwt was characterized by greater LV wall thickness and lower ejection fraction. LS was more depressed in both ATTRwt and AL amyloidosis (−11±3% and −12±4%, respectively, P=0.54) than in ATTRm (−15±4%, P<0.01 versus AL amyloidosis and ATTRwt). TTR-related causes were favorable predictors of survival, whereas LS and advanced New York Heart Association class were negative predictors. Conclusions— In patients with CA, worsening LV function correlated with increasing wall thickness regardless of pathogenesis. Patients with ATTRwt had a statistically greater wall thickness but lesser mortality than those with AL amyloidosis, despite very similar degrees of LS impairment. This paradox suggests an additional mechanism for LV dysfunction in AL amyloidosis, such as previously demonstrated light-chain toxicity.

Cardiac amyloidosis: the great pretender

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic “red flags” (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition.

Identification of TTR-Related Subclinical Amyloidosis With 99mTc-DPD Scintigraphy

We have previously documented that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light-chain cardiac amyloidosis [(1)][1] and other non-amyloidotic cardiomyopathies with a

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths

Aims Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. Methods and results Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. Conclusion The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.

Cardiac involvement in hereditary-transthyretin related amyloidosis

Hereditary transthyretin-related amyloidosis remains a widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non-endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular “hypertrophy”. Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis.

Does the etiology of cardiac amyloidosis determine the myocardial uptake of [18F]-NaF PET/CT?

Cardiac amyloidosis (CA) leads to variable degrees of myocardial infiltration with a final echocardiographic phenotype of “hypertrophy.” Although many non-invasive imaging techniques (MRI, CT, scintigraphy, PET) are useful, the definitive diagnosis is still based on myocardial histology. We explored the possible role of [18F]-NaF PET/CT in the diagnosis of this disease in two cases with wild-type (ATTRwt) or mutant (ATTRm) Ile68Leu transthyretin (TTR)-related CA.

Etiology of amyloidosis determines myocardial 99mTc-DPD uptake in amyloidotic cardiomyopathy.

Tc-DPD (Tc-3,3-diphosphono-1,2-propanodicarboxylic acid) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light chain cardiac amyloidosis and other nonamyloidotic cardiomyopathies with a hypertrophic phenotype, in which myocardial tracer uptake is low or absent. Myocardial bone tracer uptake in the rarer forms of amyloidosis (eg, apolipoprotein-related) has been rarely studied. We present 4 cases of cardiac amyloidosis that underwent Tc-DPD scintigraphy; myocardial DPD uptake was present in patients with ATTR, wtTTR and apolipoprotein AI and negative in cases with AL and apolipoprotein AII-related disease.

A SIMPLE VOLTAGE/MASS INDEX IMPROVES DIAGNOSIS OF CARDIAC AMYLOIDOSIS: AN ELECTROCARDIOGRAPHIC AND ECHOCARDIOGRAPHIC STUDY OF 570 PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

Amyloidotic cardiomyopathy (AC) can mimic other diseases with left ventricular (LV) hypertrophy, including hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD). Low QRS voltage on ECG provides valuable clues for the non-invasive suspicion of AC. However its sensitivity is limited

Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure: Ile68Leu transthyretin amyloidosis

Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin‐related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild‐type transthyretin amyloidosis (ATTRwt).

Prevalence, risk factors and correlation with cardiac involvement of carpal tunnel syndrome in amyloidosis

Background Carpal tunnel syndrome (CTS) is one of the most common clinical manifestations of TTR-related amyloidosis, both hereditary (ATTR), and wild type (senile systemic amyloidosis, SSA) and often precedes cardiac symptoms. The exact prevalence of CTS in light-chain amyloidosis (AL), ATTR and SSA is not known. We therefore aimed to establish prevalence, risk factors and possible association with cardiac involvement in patients with TTRrelated and AL amyloidosis.