IJCS | Volume 32, Nº2, March/April 2019

186 Ribeiro et al. CMR and amyloidosis Int J Cardiovasc Sci. 2019;32(2)177-189 Review Article to stabilize amyloid precursor protein. Despite its low availability, heart transplantation can be a very successful approach in carefully selected patients. 17 Standard supportive therapy for heart failure is of limited benefit and occasionally deleterious to cardiac amyloidosis patients. Since cardiac amyloidosis leads to a classical phenotype of restrictive cardiomyopathy, cardiac output can be dependent on heart rate. In this case, patients can be intolerant to beta-blockers, in contrast to heart failure patients with reduced or preserved ejection fraction. There is scarce evidence for the use of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) in patients with myocardial amyloid deposition, and in dysautonomic patients, these drugs can even aggravate the symptoms of delayed orthostatic hypotension. Medications such as calcium channel blockers and digitalis should be avoided as they can selectively concentrate in myocardial tissue with amyloid deposition, causing increased toxicity. The use of anticoagulants should be considered in atrial fibrillation or intracavitary thrombus, which is not infrequent in these patients, even in sinus rhythm. 16,17 Preservation of adequate filling pressures is vital because of the restrictive physiology of this heart disease, to achieve the balance between the treatment of peripheral edema and the development of prerenal kidney failure caused by water-salt depletion and careful use of diuretics. In contrast to other types of heart failure, maintenance of blood pressure, often requiring the use of alpha-agonists such as Midodrine, can make the use of high doses of diuretics possible, especially in patients with autonomic neuropathy. 3,17,58 Pacemakers and implantable defibrillators may not prevent suddendeath, since it is known that themechanism of death in these patients involves electromechanical dissociation. Given the lack of robust evidence, indication of these devices is similar to that in other heart diseases. High defibrillation threshold may be present in cardiac amyloidosis patients and the benefit of these devices remain uncertain. 33 Biventricular pacemakers seem to be the ideal therapeutic option to prevent worsening of cardiac function resulting from desynchrony caused by excessive stimulation of the right ventricle. 59 Currently, amyloidosis treatment is based on reducing the provision of amyloid precursor protein. In immunoglobulin light chain amyloidosis, therapy is focused on plasma cell clones, and combines chemotherapy with autologous bone marrow transplantation. Most chemotherapeutic regimens include dexamethasone combined with an alkylating agent (melphalan or others), which, although they are very useful in the treatment of immunoglobulin light chain amyloidosis, they should be used with caution by patients with cardiac disease due to the high risk of volume overload. New therapeutic strategies include bortezomib, a proteasome inhibitor, and novel immunomodulators (lenalidomide and pomalidomide). Regarding transthyretin amyloidosis, based on the fact that transthyretin is a transport proteinmostly produced in the liver, scientists have developed studies on RNA interference therapies, two recently investigated in phase III trials, 61,62 which showed that small interfering RNA (patisiran) or “antisense” (inotersen) constructs, can reduce levels of TTR messenger RNA, the amount of transthyretin synthesized, the serum concentrations of transthyretin, and the amount of misfolded monomer available to aggregate and form deposits. In both trials, the patients who received the active drug had a lower mean rate of progression of the manifestations of the neuropathy (as determined by the modified Neuropathy Impairment Score+7 [NIS+7]) than did the patients who received placebo. 3,13,17 Liver transplantation has been used in some cases as a strategy to eliminate transthyretin variants from the circulation. However, although the therapy has been shown to be effective for the amyloidogenic variant Val30Met, disappointing results have been reported with other genetic variants, which frequently involves the heart, since cardiac disease continues toprogresswith continuous deposition of wild-type transthyretin amyloid. 58 Strategies for the inhibition of amyloid fibril formation assume a massive change of precursor protein into a completely different form. The key stage of transthyretin amyloid fibril formation is the transthyretin tetramer dissociation into monomers prone to self-aggregation. Diflunisal, a nonsteroidal anti-inflammatory drug rarely used nowadays, binds to plasma transthyretin, increasing the structural stability of this soluble protein. Studies involving diflunisal are in progress. Tafamidis, a novel drug with no analgesic or anti-inflammatory properties but with similar mechanisms of action, can selectively bind to thyroxine binding sites, and is currently the most promising drug for amyloidosis treatment. The drug was approved for use by ANVISA in November 2016 for the treatment of transthyretin familial amyloidotic polyneuropathy. Although not worldwide approved yet, the recently published the ATTR-ACT trial showed