SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). OBJECTIVES: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. METHODS: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. RESULTS: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). CONCLUSIONS: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.

Atrial electrofunctional predictors of incident atrial fibrillation in cardiac amyloidosis.

BACKGROUND: Atrial fibrillation (AF) is common in patients with cardiac amyloidosis (CA) and is a significant risk factor for heart failure hospitalization and thromboembolic events. OBJECTIVE: This study was designed to investigate the atrial electrofunctional predictors of incident AF in CA. METHODS: A multicenter, observational study was conducted in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiography and cardiac magnetic resonance imaging. The primary end point was new-onset AF occurrence. RESULTS: Overall, 96 patients (AL-CA, n = 40; ATTR-CA, n = 56) were enrolled. During an 18-month median follow-up (Q1-Q3, 7-29 months), 30 patients (29%) had incident AF. Compared with those without AF, patients with AF were older (79 vs 73 years; P = .001). They more frequently had ATTR (87% vs 45%; P < .001); electrocardiographic interatrial block (IAB), either partial (47% vs 21%; P = .011) or advanced (17% vs 3%; P = .017); and lower left atrial ejection fraction (LAEF; 29% vs 41%; P = .004). Age (hazard ratio [HR], 1.059; 95% CI, 1.002-1.118; P = .042), any type of IAB (HR, 2.211; 95% CI, 1.03-4.75; P = .041), and LAEF (HR, 0.967; 95% CI, 0.936-0.998; P = .044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF <40%, and age >78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by 1 (8.5%) or none (7.6%) of these 3 risk factors. CONCLUSION: In patients with CA, older age, IAB on 12-lead electrocardiography, and reduced LAEF on cardiac magnetic resonance imaging are significant and independent predictors of incident AF. A closer screening for AF is advisable in CA patients carrying these features.

Hospitalization-based epidemiology of systemic and cardiac amyloidosis in the Veneto Region, Italy.

AIM: Defining the epidemiology of systemic and cardiac amyloidosis (CA) is a contemporary challenge. The present study aimed to estimate incidence and time trends in amyloidosis-related hospitalizations (AH) in Veneto Region (5 million inhabitants, Northeastern Italy). METHODS: International Classification of Diseases (ICD-9) codes were used to identify AH in Veneto from 2010 to 2020. AH were defined as any hospitalization with a discharge summary reporting an ICD-9 code for systemic amyloidosis. Hospitalization for CA was defined as records with ICD-9 code for systemic amyloidosis and ICD-9 code for heart failure,cardiomyopathy or arrhythmia. Hospital/outpatient encounters for carpal tunnel syndrome (CTS) surgeries also were extracted. AH incidence was estimated using a buffer of 5 years. RESULTS: In the time range 2015-2020, the incidence rate of AH was 23.5 cases per 106 (95% confidence interval, CI, 21.8; 25.3), mainly affecting patients>65 years (76.2%) and males (63.5%), with a progressively increasing trend (percent annual increase 17%, 95% CI 12; 22%). The 10 year prevalence of AH in 2020 was 124.5 per 106 (95% CI 114.9; 134.8). In 2020, annual hospitalized prevalent cases of CA were about 70% of all cases (159/228), mainly patients >65 years and males. Among patients with multiple CTS surgeries, a subsequent code for cardiac disease was found in 913 after a median of 3.9 years, more frequently in men than in women (463/6.526 7.1% versus 450/11.406 3.9%). CONCLUSIONS: In Veneto, we recorded a significantly increasing trend in the incidence of AH, with concordant increasing prevalence estimates.

Thromboembolic and Bleeding Events in Transthyretin Amyloidosis and Coagulation System Abnormalities: A Review.

Transthyretin amyloidosis (ATTR) is a group of diseases caused by the deposition of insoluble fibrils derived from misfolded transthyretin, which compromises the structure and function of various organs, including the heart. Thromboembolic events and increased bleeding risk are among the most important complications of ATTR, though the underlying mechanisms are not yet fully understood. Transthyretin plays a complex role in the coagulation cascade, contributing to the activation and regulation of the coagulation and fibrinolytic systems. The prevalence of atrial fibrillation, cardiac mechanical dysfunction, and atrial myopathy in patients with ATTR may contribute to thrombosis, though such events may also occur in patients with a normal sinus rhythm and rarely in properly anticoagulated patients. Haemorrhagic events are modest and mainly linked to perivascular amyloid deposits with consequent capillary fragility and coagulation anomalies, such as labile international-normalised ratio during anticoagulant therapy. Therefore, it is paramount to carefully stratify the thrombotic and haemorrhagic risks, especially when initiating anticoagulant therapy. Our review aims to ascertain the prevalence of thromboembolic and haemorrhagic events in ATTR and identify potential risk factors and predictors and their impact on antithrombotic therapy.

Incidence and determinants of atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening. METHODS: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. RESULTS: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008). CONCLUSIONS: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Cardiac Magnetic Resonance-Detected Acute Myocardial Edema as Predictor of Favourable Prognosis: A Comprehensive Review.

Acute myocardial edema (AME) is increased water content in the myocardium and represents the first and transient pathophysiological response to an acute myocardial injury. In-vivo and non-invasive evaluation is feasible with cardiac magnetic resonance (CMR), which is a powerful imaging technique capable of tissue characterization. In the clinical setting, early demonstration of AME has a recognized diagnostic value for acute coronary syndromes and acute myocarditis, although its prognostic value is not well established. This article provides a comprehensive narrative review on the clinical meaning of AME in heart diseases. In particular, the available evidence of a possible favourable prognostic value in several clinical scenarios is addressed.

Chest pain in cardiac amyloidosis: occurrence, causes and prognostic significance.

BACKGROUND: Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is lacking. METHODS: Clinical, echocardiographic, laboratory characteristics, available coronary arteries imaging and endomyocardial biopsy (EMB) findings of 174 patients with CA (n = 104 with transthyretin, ATTR; n = 70 with light chains, AL) were analyzed. RESULTS: Chest pain was reported in 66 (38%) CA patients. Compared to those without, patients with chest pain had more frequently a history of coronary artery disease (CAD) (27% vs 15%, p = 0.048) and heart failure (HF) symptoms (62% vs 43%, p = 0.015), higher high sensitivity troponin I (hs-cTnI, 101 vs 65 ng/L, p = 0.032) and higher brain natriuretic peptide (597 vs 407 ng/L, p = 0.024). Among CA patients with chest pain undergoing coronary arteries imaging (n = 37), obstructive CAD was detected in 14 (38%), 13 of whom with ATTR-CA. Of these 37 patients, EMB was available in 10 and vascular/perivascular amyloid deposition was detected in 4/5 (80%) of AL-CA patients and 1/5 ATTR-CA. Among patients with suspected acute coronary syndrome (n = 22), obstructive CAD was detected in 9/17 (53%) ATTR-CA and 0/5 AL-CA; hs-cTnI levels were similar between those with and without obstructive CAD. During a follow-up of 17 (8-34) months, chest pain was a significant predictor of HF hospitalization (HR1.86, 95% CI 1.02-3.39, p = 0.042), even after adjustment for CA subtype and CAD. CONCLUSION: Chest pain is a common symptom in patients with CA, reflects a more advanced cardiac impairment and predicts future HF hospitalization. The etiology of chest pain seems to differ, with obstructive CAD more frequent in ATTR-CA whilst amyloid vascular/perivascular involvement more common in AL-CA.

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], P<0.001). All AApoAIV-CA patients had classical CA features on echocardiography/cardiac magnetic resonance, including an apical-sparing strain pattern, which was less common in AApoAI-CA (15 [100%] versus 7 [54%], P=0.003), whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA (all grade 1) (14% versus 82%, P<0.001). Patients with AApoAI and AApoAIV had a good prognosis (median survival >172 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.

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.

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 electrocardiogram (ECG) remains 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.

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.

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

AIMS: 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. METHODS AND RESULTS: Consecutive patients with AL and ATTR-CA diagnosed at participating centres (2017-2020) were included. Clinical data recorded within ±1 month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically-indicated PM implantation. Patients with PM (n = 41) and/or permanent defibrillator in situ (n = 13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were male, median age 76 years. During a median follow-up of 33 months (interquartile range 21-46), 36 (8.9%) patients experienced the primary outcome: 10 AL-CA, 2 variant ATTR-CA and 24 wild-type ATTR-CA (p = 0.08 at time-to-event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p = 0.002), PR interval (HR 1.013, p = 0.002) and QRS >120 ms (HR 4.7, p = 0.001) on baseline electrocardiogram were independently associated with PM implantation. The absence of these three factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6 months. CONCLUSION: In a large cohort of AL and ATTR-CA patients, 8.9% received a PM within 3 years after diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation.

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 = 210) compared with 2019 (N = 207). Baseline characteristics of patients were also similar. In 2020, a significantly higher number of patients presented more than 6 h after symptoms onset (57 versus 38%, P < 0.001) and with signs of heart failure (33 versus 20%, P = 0.018), required urgent surgery (13 versus 5%, P = 0.004) and ventilatory support (26 versus 13%, P < 0.001). Hospitalization duration was longer in 2020 (median 10 versus 8 days, P = 0.03). The primary end point was met by 19 (9.0%) patients in 2020 versus 10 (4.8%) in 2019 (P = 0.09). 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.