Light-chain Cardiac Amyloidosis Research Articles

Prevalence and prognostic significance of restriction versus systolic dysfunction in patients with transthyretin and light chain cardiac amyloidosis

Abstract The tenet of cardiac amyloidosis (CA) as a paradigm of heart failure with restrictive ventricular physiology and preserved systolic function has come under scrutiny. Thus, we aimed to evaluate the prevalence and clinical significance of left ventricular (LV) systolic dysfunction versus restriction in a large real-world cohort with CA, assessed at the time of diagnosis. Methods This is a multicenter retrospective analysis including 540 transthyretin (ATTR)-CA and 280 light chain (AL)-CA. Patients were divided into 3 phenotypes: 1) preserved LV function: LV ejection fraction (EF) ≥50% associated with grade 0/I diastolic dysfunction; 2) restriction: LV-EF≥50% associated with grade II/III diastolic dysfunction; 3) systolic dysfunction: LV-EF<50% irrespective of diastolic function. We analysed progression from preserved LV function towards the other two phenotypes and their survival. Results In ATTR-CA, prevalence of preserved LV function was 27%, restriction was 44% and systolic dysfunction was 28%. Among patients with preserved LV function, annual conversion rate to restriction was 24% and to systolic dysfunction was 17%. At 3 years, survival free from all-cause mortality was 88%, 76% and 63% respectively (figure A). In AL-CA, prevalence of preserved LV function was 30%, restriction was 49% and systolic dysfunction was 20%. Among patients with preserved LV function, annual conversion rate to restriction was 28% and to systolic dysfunction was 8%. At 3 years, survival free from all-cause mortality was 56%, 39% and 29% respectively (figure B). Conclusions Restriction was the presenting phenotype in less than half of patients, while systolic dysfunction in approximately one quarter. The annual rate of progression form preserved LV function towards restriction or systolic dysfunction was high. In ATTR systolic dysfunction was associated with worse outcome, compared to restriction; in AL both restriction and systolic dysfunction were associated with equally ominous outcome.

Outcomes in patients with light chain cardiac amyloidosis undergoing heart transplantation: a single centre UK study

Abstract Background Light chain cardiac amyloidosis (AL-CA) results in restrictive cardiomyopathy associated with progressive heart failure and poor survival. Traditionally, outcomes following heart transplantation in patients with AL-CA have been worse than in other heart failure cohorts and consequently, many centres do not offer this population transplantation. Purpose and Methods This was a retrospective observational study of 18 patients with AL-CA (age 52.7years +/- 8.3, male 66%) referred to our centre in the UK for assessment for heart transplantation from 2008 to 2023. Seven patients (39%) were listed for transplant, and all received orthotopic heart transplantation (OHT). This study compared pre-transplantation characteristics in those offered cardiac transplantation with those not transplanted. We also examined post-transplantation outcomes in this group (n=7) compared with the overall heart transplantation population (n=95) at our centre. Results Patients with AL-CA who were not offered transplantation (n=11) were older (mean age 54.3 vs 50.3 years), were more likely male (72% vs 57%) but had similar baseline renal function to those transplanted (median eGFR 60.4 vs 54.2ml/min). Reasons against offering OHT included extensive multisystem or renal amyloid deposition (n=4), insufficient haematological response (n=2), heart failure not advanced enough for OHT (n=1) and malignancy (n=1). Pre-transplant right heart catheterisation of patients undergoing OHT demonstrated a mean transpulmonary gradient of 7.8mmHg (+/- 1.9) and cardiac output of 2.94/min (+/- 0.3). Five patients (71%) had a complete and two (29%) a partial haematological response to clonally directed chemotherapy. Three patients were bridged to transplant with biventricular assist devices for 9, 10 and 51 days, respectively. Five patients developed episodes of histologically confirmed rejection of grade 2R that resolved with medical management. One patient experienced first degree atrioventricular block and had a pulseless electrical activity arrest 19 days after transplantation before being fitted with a permanent pacemaker. Two patients went on to receive autologous stem cell transplantation. Patients with AL-CA undergoing OHT had a lower mortality rate compared with non-transplanted patients over a median follow up of 9 months (HR 0.3, 95%CI 0.07-1.3, p = 0.10). Two patients with AL-CA died at 42 days and 7.7 years after OHT. Five patients (71%) are alive under follow up at 4, 7.5, 9, 10 months and 7.7 years post OHT. There was no difference in survival between patients who underwent heart transplantation for AL-CA and patients who underwent heart transplantation for all other indications (HR 1.94, 95%CI 0.3 – 12, p=0.45). Conclusions In selected patients with AL-CA, OHT offers favourable outcomes. After clonally directed therapy to control the underlying plasma cell dyscrasia, heart transplantation should be considered in the absence of widespread systemic disease.

Incidence and clinical characteristics of cardiac amyloidosis in Tuscany and Umbria

Abstract Background Recent advances in imaging and increased disease awareness have led to a significant rise in newly diagnosed cases of cardiac amyloidosis (CA) over the past decade. However, there remains a lack of epidemiological data regarding the true incidence of the disease. Purpose To determine the incidence and clinical characteristics of newly diagnosed cases of CA in a large Italian population. Methods Subjects with suspected CA underwent diagnostic work-up in 20 Centers in Tuscany and Umbria regions within the Cardiac Amyloidosis RegistRY (CARRY), between January 1st 2022 and December 31st 2022. Results A total of 551 subjects were enrolled in the registry, with complete data on the final diagnosis available for 448 individuals. CA was diagnosed in 179 patients (40%), with 28 (16%) classified as light chain CA (AL-CA), 114 (64%) wild-type transthyretin CA (ATTR-CA), 12 (7%) variant ATTR-CA, and 25 (13%) undetermined CA. Considering a reference population in Tuscany and Umbria in 2022 (4,518,388, according to the Italian National Institute of Statistics), this yields an estimated cumulative incidence of 39.6 cases per million inhabitants per year. Alternative diagnoses in the remaining patients mostly included hypertensive heart disease (n=157, 58%), hypertrophic cardiomyopathy (n=25, 9%), moderate-to-severe valvular heart disease (n=11, 4%), or a mixed phenotype (n=72, 27%). The primary referral pathway for the suspicion of CA was cardiological (n=345, 77%), followed by incidental finding during screening visits (n=58, 13%), and haematology referral (n=33, 7%). Patients with confirmed CA were older (81 [75-85] vs. 77 [72-83] years, p<0.001), and more frequently reported musculoskeletal red flags of CA, such as carpal tunnel syndrome (85 [48%] vs. 53 [20%] years, p<0.001), and spontaneous tendon rupture (39 [22%] vs. 18 [7%] years, p<0.001). Median time to diagnosis from clinical suspicion was 73 (37-140) days for CA and 84 (36-156) days for alternative diagnoses (p=0.564). Conclusions The diagnosis of CA is on the rise globally, with an estimated incidence of 39.6 new cases per million inhabitants per year in two large regions of Italy. These findings should inform policymakers in redefining the status of CA as a rare disease, potentially influencing patient care and treatment costs.

Improving early mortality risk detection in light-chain cardiac amyloidosis patients with routine echocardiographic indicators and mayo staging

Abstract Background Light-chain cardiac amyloidosis (AL-CA) is a fatal cardiomyopathy caused by the deposition of monoclonal immunoglobulin light-chain in the cardiac fibers, conduction system, valves, and other parts of the heart. The Mayo 2004 staging system is widely used to assess the prognosis of AL-CA. Those in the highest-risk categories, Mayo 2004 stage IIIb, exhibit extremely poor responses to conventional treatment regimens, resulting in high early mortality rates. However, within the same stage, prognostic outcomes among patients can still vary significantly. Hence, a more detailed stratification of high-risk patients is crucial for pinpointing those at extreme risk. Objective To investigate whether conventional echocardiographic measurements can enhance the identification of high-risk patients with early mortality in AL-CA on the basis of existing risk stratification. Methods Continuous enrollment of patients diagnosed with AL-CA at our center from May 2020 to December 2022. Clinical data, echocardiography, and follow-up results of the patients were collected. Logistic regression analyses were used to identify risk factors for early mortality, with risk factor thresholds calculated using Receiver Operating Characteristic (ROC) curves. Kaplan-Meier survival analysis was employed to assess endpoint events. The diagnostic efficacy of the model was evaluated using the area under the ROC curve and the Integrated Discrimination Improvement (IDI). Results A total of 76 patients were included with an average age of 59±10 years. Among them, 51 were male (67.1%). The median follow-up duration was 10 months (ranging from 5 to 20 months). Early mortality, defined as death within 6 months, occurred in 20 patients (26.3%). Twenty-three patients were categorized under the Mayo 2004 stage IIIb (30.3%). The 6-month mortality rate for patients in the Mayo 2004 stage IIIb was 56.5%. The sensitivity of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity ratio divided left ventricular ejection fraction [(E/e’) /LVEF] in predicting early mortality in patients with AL-CA is 63%, and the specificity is 92%.When compared to the Mayo 2004 stage IIIb alone, (E/e')/LVEF≥0.5 combined with the Mayo 2004 stage IIIb had an area under the curve of 0.731 and 0.824, respectively, in the ROC curve. The IDI was 0.113 (95% CI: 0.013-0.213, P=0.026), representing an 11.3% enhancement in the predictive value of early mortality in AL-CA patients. Conclusion Routine echocardiography derived E/e' to LVEF ratio offered added prognostic value for early mortality beyond Mayo staging.Kaplan-Meier survival curve

Prevalence of amyloidosis among patients with mild to severe aortic stenosis. Validation of screening parameters

Abstract Background Cardiac amyloidosis (CA) is an increasingly recognized cause of human heart failure. Up to 16% of patients with severe aortic stenosis (AS) undergoing transcatheter valve replacement have been reported to suffer concomitant transthyretin CA (ATTR). Since the diagnosis of CA implies distinct therapies with prognostic relevance, early diagnosis of CA is crucial. Different parameters have been described to improve screening accuracy for detection of CA, but it is unknown whether these parameters are valid, and the prevalence of CA is stable throughout the spectrum of AS. Purpose To validate screening parameters for the detection of CA in mild, moderate and severe AS. Methods Patient 65 years and above undergoing echocardiography with mild to severe AS, defined as calculated valve orifice area <2 cm2 by velocity-time-integral, and an intraventricular septum thickness > 11mm, fulfilling at least one of two additional criteria (Sokolow-Lyon-Index to left ventricular mass index ratio < 1.5 or stroke volume index < 35 ml/m2) were prospectively included and screened for CA using bone scintigraphy and immunofixation in blood and urine. Results 57 patients were included and completed the diagnostic work-up. Mean age was 83 ± 0.7 years and 71% were male. Overall, 15 (26%) of patients were diagnosed with CA (12 with ATTR and 3 with light-chain CA, Figure1A). 17 patients had mild, 21 had moderate and 19 patients were diagnosed with severe AS. Among patients with mild AS 41% were diagnosed with CA, whereas only 24% of patients with moderate and 16% of patients with severe AS suffered CA (Figure 1B), these results did not show statistically significant differences (p= 0.2, by Chi-Square Quadrat test). Patients with CA were less likely to have NYHA classes I or II (20 vs. 57%, p= 0.03), had higher values of NT-proBNP (4572 [2323; 6044] vs. 817 [589; 2571], p< 0.001) and high-sensitive troponin (66 [47; 103.5] vs. 22.5 [17; 33.6], p< 0.001) and were more likely to have an atrioventricular block of any degree (60 vs. 26%, p=0.04). Conclusion Prevalence of CA among patients fulfilling the criteria of this screening algorithm seems to be high independent of AS severity. Clinicians should not only focus on patients with severe AS to detect CA early. Further research is needed to estimate the prevalence of CA among all patients with AS. Figure 1 A: Among patients with an age >65 years, IVS >11mm, AS and SLI/LVMMI >1.5 or SVI <35 ml/m2 26% (red area) of patients were diagnosed with CA (n= 57). B: In patients with mild AS 41% were diagnosed with CA, whereas in patients with moderate AS only 24% and in patients with severe AS 16% had CA. These differences did not show statistical significance (p= 0.2). IVS: intraventricular septum, AS: aortic stenosis, SLI: Skolow-Lyon-Index, LVMM= left ventricular myocardial mass index, SVI: stroke volume index, CA: cardiac-amyloidosis. (Statistics performed by chi-square test using GraphPad Prism 9.0).

Long-term outcomes in patients with dual pathology aortic stenosis and cardiac amyloidosis referred for valve intervention

Abstract Background The coexistence of aortic stenosis (AS) and cardiac amyloidosis (CA) is common. If treated with transcatheter aortic valve implantation (TAVI), patients with the combined phenotype (AS-CA) have a comparable short term survival to those with lone AS, whereas data on longer term outcomes is currently lacking. Purpose This study aimed to evaluate the clinical outcomes of AS-CA compared to lone AS over a 5-year follow-up. Methods Using a prospective, multicentre, observational, case-control design, we screened consecutive patients with severe AS referred for TAVI for co-existing CA. CA screening included blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) with additional SPECT/CT and light chain assessment prior to intervention. Transthyretin CA (ATTR) was diagnosed by bone scintigraphy and unremarkable light chain assessment, light-chain CA (AL) by endomyocardial biopsy. Mortality (all-cause and cardiovascular [CV]) and hospitalisation for heart failure (HHF) were captured as clinical endpoints. Results 376 patients (83±7 years, 52% female, EuroSCORE-II 4.9±2.9) were recruited, of which 43 (11.4%) had AS-CA (42 ATTR, 1 AL). Compared to lone AS, patients with AS-CA were older with higher cardiac biomarkers (NT-proBNP, high-sensitive Troponin-T) and a higher prevalence of atrial fibrillation. Heart team decision yielded valve replacement in 320 (85%) and conservative management in 56 (15%) patients, without differences between AS-CA and lone AS. Over a median follow-up of 5.4 (Q1: 4.9; Q3: 5.7) years, 230 (61.1%) patients died and 67 (17.8%) experienced HHF (with a total HHF number of 91). AS-CA was associated with higher all-cause mortality (crude HR 1.64, 95%CI 1.15-2.35; log-rank, p=0.006), which remained significant after multivariate adjustment for clinical confounders (EuroSCORE-II, valve replacement; adjusted HR 1.63, 95%CI 1.15-2.32; p=0.006). AS-CA was not associated with CV mortality (log-rank, p=0.18) or time to first HHF (log-rank, p=0.43), but the rate of HHF was significantly higher in AS-CA compared to lone AS (5.7 versus 3.5 per 1,000 patient years, p=0.022). Conclusions Among elderly patients referred for TAVI, long-term outcomes of AS-CA are characterized by higher mortality and a higher rate of heart failure hospitalisations compared to patients with lone AS. Studies evaluating the role of CA-specific treatments are warranted in this population.

Microvascular obstruction in cardiac amyloidosis.

Cardiac amyloidosis (CA) is characterized by deposition of amyloid fibrils within the extracellular space, causing disarray of the myocardial structure and capillary architecture. This study aims to characterize the prevalence of microvascular obstruction (MVO) in patients with CA and to assess the association between MVO and prognosis. The study population comprised 800 patients, of which 400 had light-chain CA (AL-CA) and 400 had transthyretin CA (ATTR-CA). MVO was present in 221 (27.6%) patients, and more common in ATTR-CA than AL-CA (124 [56.1%] vs. 97 [43.9%], p = 0.033). Patients with MVO had a more severe cardiac phenotype evidenced by higher N-terminal pro-brain natriuretic peptide (3516 ng/L [1944-6247] vs. 2508 ng/L [1203-5752], p < 0.001), worse global longitudinal strain (-10.5% [-12.6; -7.9] vs. -12.0% [-16.0; -8.9], p < 0.001), and higher extracellular volume (56% [51-61] vs. 50% [45-57], p < 0.001). Patients with AL-CA and MVO had a higher serum troponin (86 ng/L [47-148] vs. 59 ng/L [44-78], p < 0.001), and higher T2 (53 ms [50-56] vs. 50 ms [48-52], p < 0.001), but lower extracellular volume (55% [50-60] vs. 58% [53-61], p = 0.008) and lower indexed myocyte cell volume (48.6 g/m2 [41.1-59.8] vs. 55.7 g/m2 [47.5-68.4], p < 0.001) than patients with ATTR-CA and MVO. MVO was associated with an increased risk of mortality in the overall population (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.03-1.59, p = 0.025), and the subgroup with AL-CA (HR 1.59, 95% CI 1.17-2.17, p = 0.003) but not ATTR-CA (HR 1.04, 95% CI 0.77-1.40, p = 0.814). Microvascular obstruction is common in CA and is related to markers of amyloid infiltration. MVO is associated with an increased risk of mortality in AL-CA, but not in ATTR-CA. This reflects the intrinsic differences in disease biology between these two forms of CA, with MVO likely related to multiple myocardial processes, amyloid infiltration, oedema and myocyte death.

The Mayo ATTR-CM score versus other diagnostic scores and cardiac biomarkers in patients with suspected cardiac amyloidosis.

Several scores were developed to help the diagnosis of cardiac amyloidosis (CA). The most recent one, being the Mayo transthyretin amyloidosis cardiomyopathy (ATTR-CM) score, was not externally validated. We compared the diagnostic performance of the ATTR-CM score with previous tools (increased wall thickness [IWT] score, AMYLoidosis Index [AMYLI] score, and cardiac biomarkers) in a cohort of patients evaluated for a suspicion of CA. We analysed 362 consecutive patients referred to a third-level centre for suspected CA. Overall, 132 (36%) had transthyretin CA (ATTR-CA), and 91 (25%) immunoglobulin light chain CA (AL-CA); CA was excluded in 139 (38%). ATTR-CM score had a good diagnostic performance to distinguish ATTR-CA from AL-CA or no CA, with an area under the curve (AUC) of 0.795 (95% confidence interval [CI] 0.747-0.842, p < 0.001), and ATTR-CA from no CA (AUC 0.822, 95% CI 0.774-0.871, p < 0.001). Results were consistent in both patients with preserved (AUC 0.787, 95% CI 0.726-0.848, p < 0.001), and reduced or mildly reduced ejection fraction (AUC 0.790, 95% CI 0.709-0.871, p < 0.001). The ATTR-CM score showed a better discrimination compared to IWT and AMYLI score to distinguish ATTR-CA from AL-CA or no CA (p = 0.002), but not to distinguish ATTR-CA from no CA (p = 0.270). Diagnostic accuracy was significantly higher for the ATTR-CM score as compared to the rule-in cut-off of high-sensitivity troponin T. The Mayo ATTR-CM score has a good performance in identifying patients with ATTR-CA, with also better discrimination power when compared to other scores and biomarkers.

First report of the clinical characteristics and outcomes of cardiac amyloidosis in Saudi Arabia.

Cardiac amyloidosis (CA) is a potentially fatal multisystemic disease that remains significantly underdiagnosed, particularly in the Middle East. This study aims to evaluate the prevalence and clinical characteristics of CA in a high-risk population at a tertiary centre in Saudi Arabia. This cross-sectional, retrospective, single-centre study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. We reviewed the medical records of heart failure patients seen between August 2018 and July 2022 who exhibited red flags for CA and subsequently underwent CA screening. Red flags that prompted the workup included at least two of the following factors: the presence of unilateral or bilateral carpal tunnel syndrome, a family history of transthyretin amyloid (ATTR) amyloidosis and specific electrocardiographic features (relative/absolute low QRS voltage, pseudoinfarct pattern and atrioventricular/interventricular conduction abnormalities). Echocardiographic red flags included mainly increased wall thickness (≥12mm), significant diastolic dysfunction, reduced left ventricular (LV) longitudinal function, right ventricular (RV) dysfunction and elevated right atrial (RA)/pulmonary artery (PA) pressure. Cardiac magnetic resonance (CMR) red flags included aspects similar to those in an echocardiogram as well as a subendocardial or transmural late gadolinium enhancement (LGE) pattern. These patients were assessed for CA through technetium-99m pyrophosphate ([99mTc]Tc-PYP) bone scintigraphy, serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. A total of 177 patients were screened, of which 21.0 (11.9%) patients were diagnosed with transthyretin amyloid CA (ATTR-CA) and 13 (7.3%) patients were diagnosed with light chain CA (AL-CA). Compared with patients with negative/equivocal [99mTc]Tc-PYP scans (grades 0-1), patients with positive [99mTc]Tc-PYP scans (grades 2-3) were older (78.0 vs. 68.0years, P<0.001), had higher levels of troponin (P=0.003) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P<0.001), had a higher LV mass index (P<0.001), displayed a more depressed global longitudinal strain (GLS) (P<0.001) with a greater prevalence of a relative apical sparing pattern (P<0.001) and demonstrated a higher incidence of first-degree atrioventricular block (P=0.008) and low voltage patterns on electrocardiography (P<0.001). Patients with ATTR-CA and AL-CA were more likely to have a subendocardial or transmural LGE pattern on CMR (P<0.001) and had a significantly lower overall survival (P<0.001) when compared with other heart failure aetiologies. This is the first study to describe the clinical characteristics and outcomes of CA in the Middle East and Saudi Arabia. The prevalence of CA among screened heart failure patients here aligns with major international studies, suggesting significant underdiagnosis in the region. Therefore, larger multicentric studies and regional screening programmes are urgently needed to accurately characterize the epidemiology and outcomes of CA in the Middle East.

Epidemiology, diagnosis, and management of cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary subtypes: transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type and hereditary based on transthyretin gene mutation. Advances in diagnostics and therapeutics have transformed CA from a rare and untreatable condition to a more prevalent and manageable disease. Noninvasive diagnostic tools such as electrocardiography, echocardiography, and cardiac magnetic resonance can raise suspicion for CA; bone scintigraphy can non-invasively confirm ATTR, while AL necessitates histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging. Treatment approaches differ, ranging from silencing or stabilizing transthyretin and degrading amyloid fibrils in ATTR to employing anti-plasma cell therapies and autologous stem cell transplantation in AL.

Prognostic value of plasma big endothelin-1 in patients with light chain cardiac amyloidosis

BackgroundLight chain cardiac amyloidosis (AL-CA) is associated with a high incidence of mortality. Big endothelin-1 (ET-1), the precursor of endothelial-vasoconstrictive ET-1, is closely related to the concentration of bioactive ET-1....

Multimodality imaging approach in light chain (AL) cardiac amyloidosis: a case report.

Multimodality imaging approach in light chain (AL) cardiac amyloidosis: a case report.

Perivascular Amyloid Deposition in Immunoglobulin Light Chain Cardiac Amyloidosis and Its Implications on Echocardiographic Cardiac Remodeling

Perivascular Amyloid Deposition in Immunoglobulin Light Chain Cardiac Amyloidosis and Its Implications on Echocardiographic Cardiac Remodeling

Prognostic Value of Serum Galectin-3 for Survival in Patients with Cardiac Light-Chain Amyloidosis.

Amyloid light-chain (AL) amyloidosis is a multisystem disorder, with cardiac amyloid infiltration being a prevalent manifestation. This study aimed to explore the prognostic value of galectin-3 (Gal-3), a soluble marker associated with fibrosis, inflammation, heart failure, and kidney injury, in patients with cardiac AL amyloidosis. A total of 60 patients who were diagnosed with cardiac AL amyloidosis from January 2015 to May 2018 were enrolled. The prognostic value of Gal-3 was assessed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive accuracy of Gal-3. A Gal-3 cut-off value was identified to predict survival rates. The ROC curves demonstrated a moderate predictive accuracy of Gal-3 for 0.5- and 5-year survival, with area under the curve (AUC) values of 0.722 and 0.788, respectively. A Gal-3 cut-off value of 15.154 ng/mL was found to predict survival. Kaplan-Meier survival analysis revealed a significant difference in mean overall survival between patients with Gal-3 levels below and above the established cut-off (69.2 months versus 42.1 months, respectively; p = 0.036). Multivariate analysis confirmed that Gal-3 > 15.154 ng/mL remained an independent predictor of survival (HR 2.451, 95% CI 1.017-5.910, p = 0.046). This study suggests that Gal-3 holds independent prognostic value for survival in patients with cardiac AL amyloidosis. Gal-3 could potentially enhance the prognostic capabilities of the current soluble markers, thereby improving the management of cardiac AL amyloidosis. However, further validation in larger prospective studies is warranted.

Right Ventricular Strain Improves the Echocardiographic Diagnosis and Risk Stratification of Transthyretin Cardiac Amyloidosis Among Other Phenotypes of Left Ventricular Hypertrophy

Cardiac amyloidosis is a diffuse disease affecting all cardiac chambers. The value of right ventricular free-wall strain is uncertain as an echocardiographic red flag. We hypothesized that right ventricular free-wall strain is of added value for diagnostic and prognostic purposes in patients with transthyretin cardiac amyloidosis (ATTR-CA). A diagnosis of ATTR-CA required positive Tc-99m pyrophosphate scintigraphy and negative serum clonal dyscrasia. Patients with left ventricular (LV) hypertrophy (LVH; interventricular septal thickness ≥1.2cm) by echocardiography and negative pyrophosphate scintigraphy served as controls after exclusion of amyloid light-chain cardiac amyloidosis. Longitudinal strain was computed with speckle-tracking echocardiography. We studied 108 subjects with ATTR-CA and 106 controls with LVH, retrospectively. Right ventricular free-wall strain was independently associated with the diagnosis of ATTR-CA after adjusting for classical echocardiographic parameters, namely, relative apical sparing (RAS), e', and E/e'. Right ventricular free-wall strain≥-16% was incremental to LV RAS in the overall group and in the subgroup without extreme wall thickness (≤1.4cm; Harrell's C, net reclassification improvement=0.213, P<.001; and net reclassification improvement= 0.463, P=.015, respectively). Major adverse cardiovascular and cerebrovascular events (heart failure hospitalization, stroke, death) occurred in 47 ATTR-CA patients, during follow-up (median, 38; range, 6-60months). Right ventricular free-wall strain≥-16% was associated with 3-fold increased risk of MACCE in ATTR-CA patients independently of age, comorbidities, B-type natriuretic peptide, and tafamidis treatment. Right ventricular free-wall strain was additive to LV ejection fraction for risk stratification (chi square =10.2; P=.017). Right ventricular free-wall strain>-16% has incremental value to LV RAS for the differential diagnosis of ATTR-CA among LVH phenotypes and is associated with poor prognosis.

Oxidative damage in immunoglobulin light chain and transthyretin cardiac amyloidosis – a closer look

Heart failure is a progressive disease, representing a growing cause of morbidity, hospitalization, and mortality. An increasingly common type of heart failure with preserved ejection fraction (HFpEF) is an immunoglobulin light chain and transthyretin cardiac amyloidosis, in the pathophysiology of which oxidative damage appears to exert a strong impact. Reactive oxygen and nitrogen species have physiological signaling functions, but their overaccumulation, as in cardiac amyloidosis, leads to cardiomyocyte damage and apoptosis, and to cardiac hypertrophy and fibrosis. Moreover, such pathological processes worsen the redox damage with the perpetuation of an inflammatory state, in a vicious cycle. Here, the role of oxidative damage in the transthyretin and immunoglobulin light chain cardiac amyloidosis, the underlying pathogenic mechanisms, the therapeutic implications, and possible future strategies are reviewed.

Outcomes of Modified Mayo Stage IIIa and IIIb Cardiac Light-Chain Amyloidosis: Real-World Experience in Clinical Characteristics and Treatment-67 Patients Multicenter Analysis.

Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50-70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment.

A Novel Approach to Cardiac Magnetic Resonance Scar Characterization in Patients Affected by Cardiac Amyloidosis: A Pilot Study.

Background and Objectives: Cardiac magnetic resonance (CMR) imaging has become an essential instrument in the study of cardiomyopathies; it has recently been integrated into the diagnostic workflow for cardiac amyloidosis (CA) with remarkable results. An additional emerging role is the stratification of the arrhythmogenic risk by scar analysis and the possibility of merging these data with electro-anatomical maps. This is made possible by using a software (ADAS 3D, Galgo Medical, Barcelona, Spain) able to provide 3D heart models by detecting fibrosis along the whole thickness of the myocardial walls. Little is known regarding the applications of this software in the wide spectrum of cardiomyopathies and the potential benefits have yet to be discovered. In this study, we tried to apply the ADAS 3D in the context of CA. Materials and Methods: This study was a retrospectively analysis of consecutive CMR imaging of patients affected by CA that were treated in our center (Marche University Hospital). Wherever possible, the data were processed with the ADAS 3D software and analyzed for a correlation between the morphometric parameters and follow-up events. The outcome was a composite of all-cause mortality, unplanned cardiovascular hospitalizations, sustained ventricular arrhythmias (VAs), permanent reduction in left ventricular ejection fraction, and pacemaker implantation. The secondary outcomes were the need for a pacemaker implantation and sustained VAs. Results: A total of 14 patients were deemed eligible for the software analysis: 8 patients with wild type transthyretin CA, 5 with light chain CA, and 1 with transthyretin hereditary CA. The vast majority of imaging features was not related to the composite outcome, but atrial wall thickening displayed a significant association with both the primary (p = 0.003) and the secondary outcome of pacemaker implantation (p = 0.003). The software was able to differentiate between core zones and border zones of scars, with the latter being the most extensively represented in all patients. Interestingly, in a huge percentage of CMR images, the software identified the highest degree of core zone fibrosis among the epicardial layers and, in those patients, we found a higher incidence of the primary outcome, without reaching statistical significance (p = 0.18). Channels were found in the scar zones in a substantial percentage of patients without a clear correlation with follow-up events. Conclusions: CMR imaging plays a pivotal role in cardiovascular diagnostics. Our analysis shows the feasibility and applicability of such instrument for all types of CA. We could not only differentiate between different layers of scars, but we were also able to identify the presence of fibrosis channels among the different scar zones. None of the data derived from the ADAS 3D software seemed to be related to cardiac events in the follow-up, but this might be imputable to the restricted number of patients enrolled in the study.

Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis

Introduction and objetivesCardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. Material and methodsOne hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. ResultsDuring a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n = 109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n = 87, TI 249.2).AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p = 0.029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p = 0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p = 0.021). ConclusionsCA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Outpatient management of patients with cardiac light chain amyloidosis

Outpatient management of patients with cardiac light chain amyloidosis