Aims
An algorithm for non‐invasive diagnosis of amyloid transthyretin cardiac amyloidosis (ATTR‐CA) and novel disease‐modifying therapies have prompted an active search for CA. We examined the ...prevalence of CA in different settings based on literature data.
Methods and results
We performed a systematic search for screening studies on CA, focusing on the prevalence, sex and age distribution in different clinical settings. The prevalence of CA in different settings was as follows: bone scintigraphy for non‐cardiac reasons (n = 5 studies), 1% (95% confidence interval CI 0%–1%); heart failure with preserved ejection fraction (n = 6), 12% (95% CI 6%–20%); heart failure with reduced or mildly reduced ejection fraction (n = 2), 10% (95% CI 6%–15%); conduction disorders warranting pacemaker implantation (n = 1), 2% (95% CI 0%–4%); surgery for carpal tunnel syndrome (n = 3), 7% (95% CI 5%–10%); hypertrophic cardiomyopathy phenotype (n = 2), 7% (95% CI 5%–9%); severe aortic stenosis (n = 7), 8% (95% CI 5%–13%); autopsy series of ‘unselected’ elderly individuals (n = 4), 21% (95% CI 7%–39%). The average age of CA patients in the different settings ranged from 74 to 90 years, and the percentage of men from 50% to 100%. Many patients had ATTR‐CA, but the average percentage of patients with amyloid light‐chain (AL) CA was up to 18%.
Conclusions
Searching for CA in specific settings allows to identify a relatively high number of cases who may be eligible for treatment if the diagnosis is unequivocal. ATTR‐CA accounts for many cases of CA across the different settings, but AL‐CA is not infrequent. Median age at diagnosis falls in the eighth or ninth decades, and many patients diagnosed with CA are women.
Abstract
Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the ...heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.
•ACEi/ARB and MRA can be safely used in cardiac amyloidosis•Treatment must be started at a low dose and slowly up-titrated•Patients must be monitored quite closely•Beta-blockers are less tolerated in ...AL amyloidosis and/or worse haemodynamic function
Drugs for neurohormonal antagonism are usually denied to patients with cardiac amyloidosis (CA) because of safety concerns.
Patients diagnosed with CA at a tertiary referral centre from 2009 to 2019 were enrolled. In the absence of contraindications, beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB), and mineralocorticoid receptor antagonists (MRA) were started or up-titrated.
99 patients were evaluated (72% men, age 80 years 72,83, 33% light-chain and 67% transthyretin amyloidosis); 56% were started on or underwent up-titration of a beta-blocker, 25% of ACEi/ARB, and 39% of MRA; beta-blockers were then prescribed to 87% of patients, ACEi/ARB to 75%, and MRA to 63%, with median bisoprolol, ramipril, valsartan, and spironolactone daily equivalent doses of 2.5 mg, 5 mg, 80 mg, and 25 mg, respectively. Patients starting or starting/up-titrating a beta-blocker did not show a higher frequency of hypotension, fatigue, syncope, symptomatic bradycardia, need for pacemaker implantation, or HF hospitalization. Lower stroke volume and cardiac output (CO) predicted HF hospitalization regardless of amyloidosis type; lower left ventricular ejection fraction predicted hypotension, and lower CO and diastolic blood pressure predicted syncope. Patients who had an ACEi/ARB or MRA being started or up-titrated did not experience more adverse events than other patients.
ACEi/ARB and MRA can be safely used in CA, provided that no contraindications are present, treatment is started at a low dose and slowly up-titrated, and patients are monitored quite closely. Beta-blocker therapy is less tolerated in patients with AL amyloidosis and/or worse haemodynamic function.
Use of biomarkers to diagnose and manage cardiac amyloidosis Castiglione, Vincenzo; Franzini, Maria; Aimo, Alberto ...
European journal of heart failure,
February 2021, 2021-Feb, 2021-02-00, 20210201, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the deposition of immunoglobulin ...light chains (AL) and wild‐type or variant transthyretin (ATTRwt/ATTRv). Cardiac involvement is the main determinant of outcome in both AL and ATTR, and cardiac amyloidosis (CA) is increasingly recognized as a cause of heart failure. In CA, circulating biomarkers are important diagnostic tools, allow to refine risk stratification at baseline and during follow‐up, help to tailor the therapeutic strategy and monitor the response to treatment. Among amyloid precursors, free light chains are established biomarkers in AL amyloidosis, while the plasma transthyretin assay is currently being investigated as a tool for supporting the diagnosis of ATTRv amyloidosis, predicting outcome and monitor response to novel tetramer stabilizers or small interfering RNA drugs in ATTR CA. Natriuretic peptides (NPs) and troponins are consistently elevated in patients with AL and ATTR CA. Plasma NPs, troponins and free light chains hold prognostic significance in AL amyloidosis, and are evaluated for therapy decision‐making and follow‐up, while the value of NPs and troponins in ATTR is less well established. Biomarkers can be usefully integrated with clinical and imaging variables at all levels of the clinical algorithm of systemic amyloidosis, from screening to diagnosis and prognosis, and treatment tailoring.
The “inflammatory hypothesis” of atherosclerosis postulates that inflammatory cell signalling drives the formation, growth and ultimately the instability of atherosclerotic plaques, setting up the ...substrate for the thrombotic response that causes myocardial damage or infarction. The recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial has been hailed as the first demonstration, ex iuvantibus, of the inflammatory hypothesis. Indeed, interleukin (IL)-1β inhibition was found to reduce cardiovascular events in patients with previous myocardial infarction and raised high-sensitivity C-reactive protein, despite no effects on the lipid profile. These results prompt a dissection of inflammatory mechanisms of atherosclerosis in order to search for specific biomarkers with prognostic value and/or therapeutic targets.
Under this respect, the IL-33/suppression of tumorigenesis 2 (ST2) pathway deserves consideration. Indeed, its elements are particularly expressed in the endothelium of arterial vessels, and the interaction between IL-33 and the ST2 receptor blunts the immune response characteristic of atherosclerosis. By contrast, soluble ST2 (sST2) acts as a decoy receptor for IL-33, thus blocking its protective effects. Despite a solid theoretical framework, no definite demonstration of an involvement of the IL-33/ST2 pathway in atherosclerosis has been provided. Therefore, further studies are warranted to verify if elements of the IL-33/ST2 pathway may be proposed as markers of plaque burden and predictors of future cardiovascular events, and to explore the potential clinical benefit of enhanced IL-33/ST2 signalling in atherosclerosis.
•Knowledge on the IL-33/ST2 pathway in atherosclerosis is limited.•The elements of the IL-33/ST2 pathway are expressed in the endothelium of arterial vessels.•IL-33 blunts the immune response characteristic of atherosclerosis.•Soluble ST2 acts as a decoy receptor for IL-33, thus blocking its protective effects.
This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or ...those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.
Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.
We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.
A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e′ wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical–to–base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).
Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
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This study aimed to test the diagnostic value of 18F–florbetaben positron emission tomography (PET) in patients with suspicion of CA.
Diagnosis of cardiac involvement in immunoglobulin ...light-chain–derived amyloidosis (AL) and transthyretin-related amyloidosis (ATTR), which holds major importance in risk stratification and decision making, is frequently delayed. Furthermore, although diphosphonate radiotracers allow a noninvasive diagnosis of ATTR, demonstration of cardiac amyloidosis (CA) in AL may require endomyocardial biopsy.
Forty patients with biopsy-proven diagnoses of CA (20 ALs, 20 ATTRs) and 20 patients referred with the initial clinical suspicion and later diagnosed with non-CA pathology underwent a cardiac PET/computed tomography scan with a 60-min dynamic 18F-florbetaben PET acquisition, and 4 10-min static scans at 5, 30, 50, and 110 min after radiotracer injection.
Visual qualitative assessment showed intense early cardiac uptake in all subsets. Patients with AL displayed a high, persistent cardiac uptake in all the static scans, whereas patients with ATTR and those with non-CA showed an uptake decrease soon after the early scan. Semiquantitative assessment demonstrated higher mean standardized uptake value (SUVmean) in patients with AL, sustained over the whole acquisition period (early SUVmean: 5.55; interquartile range IQR: 4.00 to 7.43; vs. delayed SUVmean: 3.50; IQR: 2.32 to 6.10; p = NS) compared with in patients with ATTR (early SUVmean: 2.55; IQR: 1.80 to 2.97; vs. delayed SUVmean: 1.25; IQR: 0.90 to 1.60; p < 0.001) and in patients with non-CA (early SUVmean: 3.50; IQR: 1.60 to 3.37; vs. delayed SUVmean: 1.40; IQR: 1.20 to 1.60; p < 0.001). Similar results were found comparing heart-to-background ratio and molecular volume.
Delayed 18F-florbetaben cardiac uptake may discriminate CA due to AL from either ATTR or other mimicking conditions. 18F-florbetaben PET/computed tomography may represent a promising noninvasive tool for the diagnosis of AL amyloidosis, which is still often challenging and delayed. (A Prospective Triple-Arm, Monocentric, Phase-II Explorative Study on Evaluation of Diagnostic Efficacy of the PET Tracer 18F-Florbetaben Neuraceq in Patients With Cardiac Amyloidosis FLORAMICAR2; EudraCT number: 2017-001660-38)
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Cardiovascular magnetic resonance (CMR) is part of the diagnostic work-up for cardiac amyloidosis (CA). Deep learning (DL) is an application of artificial intelligence that may allow to automatically ...analyze CMR findings and establish the likelihood of CA.
1.5 T CMR was performed in 206 subjects with suspected CA (n = 100, 49% with unexplained left ventricular (LV) hypertrophy; n = 106, 51% with blood dyscrasia and suspected light-chain amyloidosis). Patients were randomly assigned to the training (n = 134, 65%), validation (n = 30, 15%), and testing subgroups (n = 42, 20%). Short axis, 2-chamber, 4-chamber late gadolinium enhancement (LGE) images were evaluated by 3 networks (DL algorithms). The tags "amyloidosis present" or "absent" were attributed when the average probability of CA from the 3 networks was ≥ 50% or < 50%, respectively. The DL strategy was compared to a machine learning (ML) algorithm considering all manually extracted features (LV volumes, mass and function, LGE pattern, early blood-pool darkening, pericardial and pleural effusion, etc.), to reproduce exam reading by an experienced operator.
The DL strategy displayed good diagnostic accuracy (88%), with an area under the curve (AUC) of 0.982. The precision (positive predictive value), recall score (sensitivity), and F1 score (a measure of test accuracy) were 83%, 95%, and 89% respectively. A ML algorithm considering all CMR features had a similar diagnostic yield to DL strategy (AUC 0.952 vs. 0.982; p = 0.39).
A DL approach evaluating LGE acquisitions displayed a similar diagnostic performance for CA to a ML-based approach, which simulates CMR reading by experienced operators.
Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular ...fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin MCP), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (-20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (-61% and -69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.
The objective of the present work was to evaluate the potential of deep learning tools for characterizing the presence of cardiac amyloidosis from early acquired PET images, i.e. 15 min after ...18F-Florbetaben tracer injection. 47 subjects were included in the study: 13 patients with transthyretin-related amyloidosis cardiac amyloidosis (ATTR-CA), 15 patients with immunoglobulin light-chain amyloidosis (AL-CA), and 19 control-patients (CTRL). 18F-Florbetaben PET/CT images were acquired in list mode and data was sorted into a sinogram, covering a time interval of 5 min starting 15 min after the injection. The resulting sinogram was reconstructed using OSEM iterative algorithm. A deep convolutional neural network (CAclassNet) was designed and implemented, consisting of five 2D convolutional layers, three fully connected layers and a final classifier returning AL, ATTR and CTRL scores. A total of 1107 2D images (375 from AL-subtype patients, 312 from ATTR-subtype, and 420 from Controls) have been considered in the study and used to train, validate and test the proposed network. CAclassNet cross-validation resulted with train error mean ± sd of 2.001% ± 0.96%, validation error of 4.5% ± 2.26%, and net accuracy of 95.49% ± 2.26%. Network test error resulted in a mean ± sd values of 10.73% ± 0.76%. Sensitivity, specificity, and accuracy evaluated on the test dataset were respectively for AL-CA sub-type: 1, 0.912, 0.936; for ATTR-CA: 0.935, 0.897, 0.972; for control subjects: 0.809, 0.971, 0.909. In conclusion, the proposed CAclassNet model seems very promising as an aid for the clinician in the diagnosis of CA from cardiac 18F-Florbetaben PET images acquired a few minutes after the injection.
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