The role of repeated assessments of late gadolinium enhancement or spin-lattice relaxation times on CMR or of strain assessments utilizing echocardiography is unclear.
For AL amyloidosis, it is unclear that such monitoring meaningfully adds to disease response assessments utilizing changes in serum free light chains and cardiac biomarkers. Prognosis in amyloidosis is dependent primarily on the degree of cardiac involvement and, in AL amyloidosis, on circulating light-chain levels.
Because chemotherapy options have greatly expanded in recent years, prognosis for AL amyloidosis has markedly improved as well, with the life expectancy of most patients, including many of those with significant cardiac involvement, measured in years rather than months. Various staging systems have been proposed for AL amyloidosis, with the majority focusing primarily on the degree of cardiac involvement. A widely utilized staging system published in relied solely on two cardiac biomarkers: troponin T or I and N-terminal pro-B-type natriuretic peptide.
The staging system successfully produced distinct survival curves, though overall survival remained dismal in all 3 arms, with median survival of A revised staging system was published by the same group in , adding the absolute difference in free light chains as a third variable, thus separating patients into 4 stages. With ongoing improvements in chemotherapy since the study period of even this second manuscript, it is likely that survival has continued to substantially improve. Treatment of AL amyloidosis follows two parallel paths: treating the consequences of the organ dysfunction while concomitantly attempting to slow progression of the disease by killing the clonal plasma cells and hence reducing the circulating pathologic light chains with chemotherapy.
Neurohormonal antagonists typically used in HF are often poorly tolerated and counterproductive. In particular, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers often lead to hypotension due to autonomic dysfunction and the presence of a small left ventricular cavity with an inability to augment stroke volume in response to vasodilation , and beta-blockers often exacerbate bradyarrhythmias.
Digoxin binds to amyloid fibrils, leading to the potential of digoxin toxicity even with normal circulating levels, and should generally be avoided. Pacemakers are frequently needed due to a high prevalence of conduction disease particularly in ATTR amyloidosis. Ventricular arrhythmias and sudden cardiac death are common as well. Because cardiac amyloidosis is not reversible and can often be associated with severe symptoms and high mortality rates, cardiac transplantation should be considered in well-selected patients.
In ATTR amyloidosis, it is important to rule out significant neurologic involvement for patients with familial forms.
Cardiac Amyloidosis - American College of Cardiology
In all cases, we would recommend that transplantation only be performed in centers that are experienced with transplanting patients with amyloidosis. Over the last decade, chemotherapy options for AL amyloidosis have markedly improved, such that most patients can achieve large reductions in and sometimes complete normalization of their circulating pathologic light chains. Chemotherapy typically involves the combination of multiple classes of antineoplastics, including alkylators e. An alternative strategy involves auto-stem-cell transplant utilizing high-dose chemotherapy with an alkylating agent.
Although auto-stem-cell transplant can be an effective method of lowering light chains and is used by many centers, the only randomized trial comparing it to standard chemotherapy found auto-stem-cell transplant to have inferior outcomes. Because ATTR amyloidosis is not a malignant process, chemotherapy has no role.
These include the following: Diflunisal. This nonsteroidal anti-inflammatory drug that is approved for arthritis pain stabilizes the tetrameric form of transthyretin. A randomized trial demonstrated slowing of disease progression among patients with polyneuropathy due to mutant ATTR amyloidosis. This agent is approved in some parts of the world Europe and Japan for mutant ATTR amyloidosis causing polyneuropathy, but it is not approved in the United States. Two agents that work via small-interfering RNA or RNA interference decreasing production of transthyretin by the liver are in Phase 3 trials for ATTR amyloidosis, including both polyneuropathy and cardiomyopathy forms.
Regional strain imaging is a very useful technique for the early diagnosis of patients with ATTR.
In patients with ATTR, longitudinal strain is depressed in basal and midventricular segments but is preserved in apical segments 18 Figure 2C. This typical pattern can be useful in the differential diagnosis of ATTR from other heart diseases. Recently, the Mayo Clinic group proposed a stratification system similar to that in force for AL. In a cohort of patients with ATTRwt, both biomarkers were shown to be predictors of mortality. Cardiac magnetic resonance imaging CMRI can be used to obtain structural and functional information and characterize the composition of myocardial tissue.
Other patterns, such as transmural the most common or patching, are also compatible Figure 3. Diversity of late enhancement patterns by cardiac magnetic resonance imaging in transthyretin amyloidosis. A and B: late enhancement sequences, 4-chamber plane and short axis at the mid level, respectively, of a patient with mutant transthyretin amyloidosis ATTRm , showing diffuse pathological transmural gadolinium deposition.
C and D: late enhancement sequences, 4-chamber and short-axis basal level, respectively, of patients with ATTRm showing pathological gadolinium deposition with a patched pattern, with lower inferoseptal and inferolateral basal focal area. E and F, late enhancement sequences, 4-chamber plane and short axis at the apical level, respectively, of patients with ATTRm, showing extensive pathological transmural deposition, except in basal and middle anterolateral segments. Long T 1 times: T 1 mapping is a technique in which a quantitative myocardial signal is measured before native T 1 or after contrast administration.
Native T 1 times are very long in cardiac amyloidosis. T 1 times may even be abnormal before LVH is observed. Contrast administration can be used to calculate extracellular volume ECV and assess increases of extracellular space. ECV values in cardiac amyloidosis are higher than in other heart disease, except in myocardial infarct zones. T 1 mapping, before and after contrast, with modified look-locker inversion-recovery MOLLI in 3T cardiac magnetic resonance imaging in healthy control, patient with transthyretin amyloidosis, and patient with primary light-chain amyloidosis.
C and D: native T 1 mapping and EV, respectively, in a patient with mutant transthyretin amyloidosis with neurologic damage and incipient cardiac involvement, elevated native T 1 , and slightly elevated EV 0. E and F: native T 1 mapping and EV, respectively, in a patient with wild-type transthyretin cardiac amyloidosis, elevated native T 1 , and very high EV 0.
In the s, observation of cardiac uptake of several bone diphosphonate tracers was histologically correlated to the presence of cardiac amyloidosis. Similar findings were subsequently reported by our group and others. Given its high sensitivity and specificity, this technique is extremely useful for establishing a diagnosis of ATTR and may show cardiac involvement even when echocardiography and MRI findings are still normal.
In fact, after scintigraphy for oncologic or rheumatologic indications, incidental findings of ATTR are not uncommon. Other radiotracers are currently under study. For example, 18 F-florbetapir, which has already been approved for brain beta-amyloid imaging, 4 has been studied in patients with AL and ATTR. The definitive diagnosis of ATTR is based on the histological demonstration of amyloid fibrils. Although there may be extracardiac deposition, the likelihood of demonstrating amyloid by histology varies by organ. However, a negative biopsy of a clinically unaffected organ does not exclude a diagnosis of ATTR.
As in ATTRwt, endomyocardial biopsy is indicated in patients with no extracardiac involvement or with heart disease alone.
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After histological confirmation of amyloidosis, which may sometimes require interpretation by trained personnel, 6 correct classification of the subtype is crucial. Although the results of this technique are typically definitive, it is less sensitive in the recognition of light chains. This limitation can be overcome by the use of mass spectrometry, which provides definitive results and is the criterion standard in the confirmation of the amyloid subtype.
The finding of a causative mutation can be of importance for offering genetic counseling and follow-up to asymptomatic carriers, 4,30 who could benefit from forthcoming therapies that delay or even prevent the onset of the disease. Until recently, histological studies were considered essential in the diagnosis of ATTR. The study analyzed the results of patients. Diagnostic algorithm for patients with suspected cardiac amyloidosis.
A key feature this algorithm is the absence of a monoclonal protein that could cause AL on serum chain assay Freelite, The Binding Site, UK and on immunofixation electrophoresis of blood and urine. Of interest, our hospital has documented 2 cases of patients with multiple myeloma and concomitant ATTRwt on mass spectrometry..
Treatment of patients with ATTR has 2 objectives: to provide medical support and, if possible, to stop or delay amyloid deposition by the use of specific treatments.. The following sections describe supportive cardiac care for patients with ATTR.. Euvolemia must be maintained in patients with cardiac amyloidosis.
Diet and lifestyle measures are very important. However, because excessive use of diuretics can lead to hypotension frequently due to autonomic dysfunction and worsen the clinical situation, especially in ATTRm, extreme care must be exercised in its management.. In the treatment of HF in ATTR, it must be taken into account that impaired diastolic dysfunction and reduced stroke volume lead to compensatory tachycardia to maintain cardiac output.
Therefore, beta-blockers must be used with care and individualized for each patient. Standard practice is to remove them in the absence of difficulties in controlling heart rate. This approach is even more important, if possible, in ATTRwt because of the frequent presence of conduction disorders. In contrast to HF with systolic dysfunction due to other etiologies, there is no evidence in support of a prognostic benefit due to the use of beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor antagonists in cardiac amyloidosis.
In fact, their use may lead to clinical worsening due to hypotension and low output: a recent publication has reported worse prognosis in ATTRm and a neutral effect in ATTRwt. Maintaining long-term sinus rhythm is difficult. However, electrical cardioversion may be attempted because it can lead to clinical improvement..