Wild-type (senile) amyloidosis medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]
Overview
Medical Therapy
- There is no treatment for wild-type amyloidosis; the mainstay of therapy is supportive treatment aimed at symptoms of the disease.
- Since wild-type amyloidosis commonly presents with symptoms of right-sided heart failure and carpal tunnel syndrome, treating amyloid deposits in the heart is important.[1]
- Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where supraventricular arrhythmias are present, and an avoidance of digoxin and calcium channel blockers.
- Antihypertensives are usually poorly tolerated as these patients can be profoundly hypotensive
- For some patients with severe wild-type (senile) ATTR amyloidosis, a heart transplant may be the best option.
- In ATTRwt amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated.
- In patients with transthyretin amyloid cardiomyopathy, Tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo.[2]
Limitations in treatment due to insufficient evidence-based approaches While there are great advances in the treatment of AL amyloidosis by chemotherapy (71,72) and emerging new therapies for ATTRm-CA aimed at the reduction of mutant gene expression (73), TTR tetramer stabilization (74,75) and dissolution (76), currently there are no proven curative or disease modifying therapies for ATTRwt-CA. There are several possible reasons why ATTRwt-CA does not have any proven therapies: (I) it is a underrecognized and underdiagnosed leading to small patient cohorts to study and incomplete understanding of its natural history of the disease (13); (II) the disease presents late in life with multitude of age related comorbidities and mortality (13,14); and (III) the disease process is likely gradual thus curative or disease modifying therapeutic effects are difficult to measure (13). Consequently, most of the therapeutic considerations for ATTRwt-CA are based on expert opinion and observations from therapeutic effects on the other type of amyloidosis affecting the heart.
Symptomatic relief and supportive care The mainstay of therapy is supportive care aimed at symptomatic relief. The main symptoms of patients with ATTRwt-CA are congestion, fatigue, peripheral nerve pain, and hypotension. Relief of congestive symptoms and associated fatigue can be accomplished with the use of diuretics, including loop diuretics and thiazides in combination with mineralocorticoid receptor antagonist to help with potassium reabsorption. Diuretics should be used sparingly as these patients are preload dependent due to high filling pressures and can be used with weight-based parameters. Other medications typically used in cardiomyopathies, such as β-blockers, ACE-i and angiotensin receptor blockers (ARB), do not seem to modify the disease progression and often result in worsening fatigue and hypotension. B-blockers are usually not tolerated as they can reduce the inotropy of the heart resulting in decreased stroke volume and have a maladaptive blunting of chronotropy on which ATTRwt-CA patients relay for augmentation of their cardiac output. ACE-i and ARB medications often worsen hypotension in ATTRwt-CA patients due pre-existing peripheral neuropathy affecting the autonomic nervous system of these patients. Hypotension can be managed with α-1 blocker midodrine and compression stockings.
Atrial arrhythmias The symptoms associated with ATTRwt-CA are further exacerbated by atrial arrhythmias which are frequently associated with the condition (15). Rate control is difficult in these patients as β-blockers can worsen hypotension at higher doses, calcium channel blockers are contraindicated as they bind to the amyloid fibrils causing sustained worsening of CHF (77-79) and digoxin can cause cardiac toxicity due to progressive accumulation in the amyloid rich heart despite normal serum levels (80). Antiarrhythmic medications, such as amiodarone, can be used for rhythm control as patients are older and is overall well tolerated because it is usually not associated with deleterious hemodynamic changes. Symptomatic relief from atrial arrhythmias has been reported in a small cohort of ATTRwt-CA patients with catheter ablation (81). However, catheter ablation for atrial arrhythmias have high recurrence rate, necessitating AV ablation with permanent pacemaker placement in refractory cases.
Investigational medications Currently there are no known curative or disease modifying agents for the treatment of ATTRwt-CA. However, there are several investigational medications that may have the potential to modify or even reverse the disease process. The strategies employed are ATTR disruption to reduced amyloid fibril aggregation, ATTR destabilization, and ATTR suppression. The combination of bile acid tauroursodeoxycholic acid (TUDCA) and doxycycline have been shown to reduce ATTR aggregation in a mouse model of TTR V30M transgenic mouse model (82) as well as to be tolerated in a phase II clinical trial (75) and currently being evaluated [with un-reported results from a phase III clinical trial (clinicaltrials.gov; NCT01855360)]. Tafamidis meglumine, a ATTR destabilizing agent has been shown to reduce the progression of peripheral neuropathy in patients with TTR V30M TTRm-CM with ongoing clinical trials to evaluate its long-term cardiac effects in ATTRm as well as ATTRwt cardiomyopathies (clinicaltrials.gov; NCT00935012 and NCT02791230). Patisiran is a siRNA, inhibiting ATTR mRNA translation, which has shown significant reduction of serum ATTR levels when administered intravenously in patients with familial amyloid polyneuropathy in a phase II clinical trial (83) with an ongoing long-term clinical trial in patients with familial ATTR (clinicaltrials.gov; NCT01960348).
Permanent pacemaker and defibrillator implantation Cardiac infiltration with amyloid fibrils can precipitate conduction system abnormalities, like bundle branch blocks and AV node dysfunction (84). A significant portion of patients with ATTRwt-CA have pacemakers at the time of diagnosis or have one implanted for high degree AV block (13). ACC/AHA guidelines suggest a case by case consideration for implantable cardioverter-defibrillator (ICD) implantation in patients for primary and secondary prevention due to limited clinical trials to show associated outcomes (85).
Advanced therapies: left ventricular assist devices (LVAD) and heart transplantation ATTRwt-CA patients have advanced heart failure symptoms and reduced life expectancy, findings which may qualify them to be considered for advanced heart failure options such as LVAD and/or heart transplantation. In a small single center report of 9 patients, LVAD implantation is technically feasible for ATTRwt-CA but it was associated with higher 24-month mortality and morbidity compared to other indications for LVAD implantation (86). A review of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database is necessary to be able to better evaluate outcomes of LVAD implantation for ATTRwt-CA. Patients with ATTRwt-CA are usually not considered for heart transplantation due to their advanced disease presentation, age, and associated comorbidities. Indeed, in a literature review there was a single case report found of a 68-year-old patient who underwent heart transplantation for biopsy proven ATTRwt-CA who was reported to have a good 3-year outcome
References
- ↑ Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J; et al. (2008). "Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study". Ann Med. 40 (3): 232–9. doi:10.1080/07853890701842988. PMID 18382889.
- ↑ Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M; et al. (2018). "Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy". N Engl J Med. 379 (11): 1007–1016. doi:10.1056/NEJMoa1805689. PMID 30145929.