Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS: We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS: Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). CONCLUSIONS: Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis

Electrocardiographic Features and Rhythm Disorders in Cardiac Amyloidosis

: Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of amyloid fibrils, mainly derived from transthyretin, either wild-type or hereditary variants, or immunoglobulin light chains misfolding. It is characterized by an increased left ventricular (LV) mass and diastolic dysfunction, which can lead to heart failure with preserved ejection fraction and/or conduction disturbances. The diagnosis is based on invasive pathology demonstration of amyloid deposits, or non-invasive criteria using advanced cardiovascular imaging techniques. Nevertheless, 12-lead electrocardiograms (ECG) remain of crucial importance in the assessment of patients with CA, since they can manifest peculiar features such as low QRS voltages, in discordance with the LV hypertrophy, but also pseudo-infarction patterns, sinus node dysfunction, atrioventricular blocks, premature supraventricular and ventricular beats, which support the presence of a myocardial disease. Great awareness of these common ECG characteristics of CA is needed to increase diagnostic performance and improve patient's outcome. In the present review, we discuss the current role of the ECG in the diagnosis and management of CA, focusing on the most common ECG abnormalities and rhythm disorders

Light-chain cardiac amyloidosis for the non-expert: pearls and pitfalls

: Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA). AL-CA is a medical urgency for which a diagnostic delay can be catastrophic for patients' outcome. In this manuscript, we focus on the pearls and pitfalls that are relevant to achieve a correct diagnosis and to avoid diagnostic and therapeutical delays. Through the aid of three unfortunate clinical cases, some fundamental diagnostic aspects are addressed, including the following: first, a negative bone scintigraphy does not exclude CA, with patients with AL-CA frequently showing no or mild cardiac uptake, and its execution should not delay hematological tests; second, fat pad biopsy does not have a 100% sensitivity for AL amyloidosis and, if negative, further investigations should be performed, particularly if the pre-test probability is high. Third, Congo Red staining is not sufficient to reach a definitive diagnosis and amyloid fibrils typing with mass spectrometry, immunohistochemistry, or immunoelectron microscopy is crucial. To achieve a timely and correct diagnosis, all the necessary investigations must be performed, always considering the yield and diagnostic accuracy of each examination

Relative apical sparing in cardiac amyloidosis is not always explained by an amyloid gradient

Aims: Myocardial longitudinal strain (LS) by two-dimensional (2D) speckle-tracking echocardiography has a diagnostic and prognostic role in cardiac amyloidosis (CA). Typically, the apical segments of the left ventricle (LV) are less affected by LS abnormalities, a finding called relative apical sparing (RELAPS). Whether a variable burden of CA might explain the RELAPS remains unknown.We aimed to evaluate the extent, distribution, and deposition pattern of amyloid in autopsy hearts of CA patients and to correlate the histopathology findings with 2D echocardiography. Methods and results: This is a retrospective study of whole heart specimens of CA patients who died and underwent autopsy and 2D echocardiography. Amyloid burden quantification was assessed by histomorphometry in each segment at different LV levels. The LS analysis results were compared with the amyloid burden and the base-to-apex distribution.Histopathology investigation of 27 hearts with CA [immunoglobulin light chains (AL) 17 cases and transthyretin (ATTR) 10 cases] demonstrated an amyloid base-to-apex gradient. In 11 CA patients with 2D echocardiography, analysis of LS and histological amyloid burden allowed to identify different patterns: RELAPS (8 cases, 73%), with (2) or without (6) amyloid gradient, normal or mildly reduced LS with diffuse low amyloid (2, 18%), and severely reduced LS with diffuse high amyloid (1, 9%). Conclusion: The typical RELAPS pattern at echocardiography is not always explained by a base-to-apex gradient of amyloid burden at histopathology, suggesting that RELAPS might be an epiphenomenon of complex interactions among amyloid infiltration, myocardial structure, and adaptation

Characteristics and hospital course of patients admitted for acute cardiovascular diseases during the coronavirus disease-19 outbreak

INTRODUCTION: During the coronavirus disease-19 (COVID-19) outbreak in spring 2020, people may have been reluctant to seek medical care fearing infection. We aimed to assess the number, characteristics and in-hospital course of patients admitted for acute cardiovascular diseases during the COVID-19 outbreak.METHODS: We enrolled all consecutive patients admitted urgently for acute myocardial infarction, heart failure or arrhythmias from 1 March to 31 May 2020 (outbreak period) and 2019 (control period). We evaluated the time from symptoms onset to presentation, clinical conditions at admission, length of hospitalization, in-hospital medical procedures and outcome. The combined primary end point included in-hospital death for cardiovascular causes, urgent heart transplant or discharge with a ventricular assist device.RESULTS: A similar number of admissions were observed in 2020 (N\u200a=\u200a210) compared with 2019 (N\u200a=\u200a207). Baseline characteristics of patients were also similar. In 2020, a significantly higher number of patients presented more than 6\u200ah after symptoms onset (57 versus 38%, P\u200a<\u200a0.001) and with signs of heart failure (33 versus 20%, P\u200a=\u200a0.018), required urgent surgery (13 versus 5%, P\u200a=\u200a0.004) and ventilatory support (26 versus 13%, P\u200a<\u200a0.001). Hospitalization duration was longer in 2020 (median 10 versus 8 days, P\u200a=\u200a0.03). The primary end point was met by 19 (9.0%) patients in 2020 versus 10 (4.8%) in 2019 (P\u200a=\u200a0.09).CONCLUSION: Despite the similar number and types of unplanned admissions for acute cardiac conditions during the 2020 COVID-19 outbreak compared with the same period in 2019, we observed a higher number of patients presenting late after symptoms onset as well as longer and more complicated clinical courses

Incidence and risk factors for pacemaker implantation in light-chain and transthyretin cardiac amyloidosis

The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light-chain (AL) and transthyretin (ATTR) CA

Low QRS Voltages in Cardiac Amyloidosis: Clinical Correlates and Prognostic Value

BACKGROUND: Low QRS voltages (LQRSVs) are a common electrocardiographic feature in patients with light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) cardiac amyloidosis (CA). OBJECTIVES: The aim of this study was to identify clinical and echocardiographic correlates of LQRSV and to investigate their prognostic significance in patients with CA. METHODS: This was a multicenter, retrospective study performed in 6 CA referral centers including consecutive patients with AL and ATTR CA. LQRSVs were defined as a QRS amplitude ≤5 mm (0.5 mV) in all peripheral leads. The study outcome was cardiovascular (CV) mortality. RESULTS: Overall, 411 (AL CA: n = 120, ATTR CA: n = 291) patients were included. LQRSVs were present in 66 (55%) patients with AL CA and 103 (35%) with ATTR CA (P < 0.001). In AL CA, LQRSVs were independently associated with younger age (P = 0.015), higher New York Heart Association functional class (P = 0.016), and natriuretic peptides (P = 0.041); in ATTR CA, LQRSVs were independently associated with pericardial effusion (P = 0.008) and lower tricuspid annulus peak systolic excursion (P = 0.038). During a median follow-up of 33 months (Q1-Q3: 21-46), LQRSVs independently predicted CV death in both AL CA (HR: 1.76; 95% CI: 2.41-10.18; P = 0.031) and ATTR CA (HR: 2.64; 95% CI: 1.82-20.17; P = 0.005). Together with the National Amyloidosis Centre (NAC) staging, LQRSVs provided incremental prognostic value in ATTR CA (AUC for NAC model: 0.83 [95% CI: 0.77-0.89]; AUC for NAC + LQRSV model: 0.87 [95% CI: 0.81-0.93]; P = 0.040). CONCLUSIONS: LQRSVs are common but not ubiquitous in CA; they are more frequent in AL CA than in ATTR CA. LQRSVs reflect an advanced disease stage and independently predict CV death. In ATTR CA, LQRSVs can provide incremental prognostic accuracy over the NAC staging system in patients with intermediate risk