For many years, the treatment of cardiac hereditary transthyretin amyloidosis (hATTR) relied on liver transplantation to remove the source of aberrant transthyretin (TTR). However, several studies have shown that liver transplantation provided an incomplete cure. Hence, combined liver/heart transplantation has emerged as an alternative.

In addition to obvious transplant-associated limitations, such as the dependence on organ donors, a recent study also showed limited success of this approach in some patients.

The retrospective study concluded that 40% of patients with Val142Ile-associated cardiac hATTR who underwent heart transplantation developed progressive extracardiac manifestations. These patients required the initiation of TTR silencer therapy with patisiran (Onpattro®), a small interfering RNA (siRNA).

TTR gene silencers, tetramer stabilizers, and amyloid fibril disruptors have emerged as target-specific approaches. However, only tafamidis (Vyndamax™) is approved by the US Food and Drug Administration (FDA) for the treatment of cardiac ATTR, with both wild-type ATTR and hATTR, with New York Heart Association (NYHA) functional classification I or II. In addition, patisiran and inotersen (Tegsedi®), an antisense oligonucleotide, are used in hATTR patients with polyneuropathy and might be soon approved for cardiac ATTR.

Learn more about hATTR therapies

According to Tschöpe and Elsanhoury, patients with contraindications to tafamidis may benefit from supportive therapy with epigallocatechin-3-gallate (green tea) or from the off-label use of diflunisal, an FDA-approved non-steroidal anti-inflammatory agent, or tolcapone, a catechol-O-methyltransferase inhibitor.

Green tea acts as a disaggregator of amyloid fibrils and was shown to reduce left ventricular wall mass and thickness in patients with cardiac ATTR. However, a single-center retrospective study reported no survival benefit in patients who received a 675 mg daily dose of green tea when compared to patients on symptomatic treatment.

Symptomatic treatment of cardiac ATTR is challenging. “In general, the symptomatic management of ATTR-CM [transthyretin amyloid cardiomyopathy] follows the CHAD-STOP concept: conduction and rhythm disorders prevention, high heart rate maintenance, anticoagulation, diuretics, and STOP ß-receptor and calcium-channel blockers, digoxin, and renin-angiotensin-aldosterone,” Tschöpe and Elsanhoury wrote.

However, the use of heart failure therapies in cardiac ATTR is limited due to the challenging clinical presentation of the disorder.

Traditional Heart Failure Therapies: Yes or No?

“Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output,” Tschöpe and Elsanhoury explained.

Several heart failure medications are poorly tolerated by patients with cardiac ATTR and are generally not recommended due to concerns about hypotension, bradyarrhythmias, and other adverse effects. For instance, renin-angiotensin system-acting agents exacerbate hypotension, particularly in patients with autonomic dysfunction. Beta-blockers have a known negative chronotropic effect.

A study conducted by Cheng et al enrolled 309 patients with cardiac ATTR taking heart failure medications, including beta-blockers (49.8%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (35%), and mineralocorticoid receptor antagonists (23.9%). The results of the study showed no benefit for these therapies in cardiac ATTR and suggested that stopping beta-blockers may even improve survival.

Promising Strategies to Improve hATTR Treatment

In vitro studies showed that calcium channel blockers and digoxin bind to amyloid fibrils, which enhances their pharmacological effects. Therefore, they are generally avoided in patients with cardiac ATTR due to the risk of disturbances in cardiac rhythm or sudden death. However, low-dose digoxin might be used in situations of uncontrollable tachyarrhythmia absoluta.

Loop diuretics are especially important for patients with right ventricular congestion and pulmonary edema. They are usually used in combination with aldosterone antagonists to prevent hypokalemia. However, these therapeutics must be strictly monitored due to potential alterations in renal perfusion and cardiac output.

Alpha-1-adrenoreceptor agonists might be useful when higher doses of diuretics are needed as they treat orthostatic hypotension. Oral anticoagulants are particularly required for patients with atrial fibrillation to prevent thromboembolic events.

Up to 25-36% of patients with hATTR need a pacemaker. However, pacemaker implantation has been associated with high risk and worse survival in patients with cardiac ATTR.

Prophylactic implantable cardioverter-defibrillator (ICD) therapy is only recommended for patients who suffer from sustained ventricular tachycardias (VAs). A recent retrospective study conducted by a team of experts from Emory University’s Cardiac Amyloidosis Center, Atlanta, Georgia, did not find any survival difference between patients with ejection fraction of 35% or less with and without ICDs. The study enrolled 130 patients, 88 of whom were diagnosed with hATTR (89% with the Val122Ile mutation).

“High rates of VAs and appropriate ICD therapy were found among a unique cohort of largely hereditary ATTR-CM patients with a high rate of systolic heart failure,” the authors wrote.

Reference

Tschöpe C, Elsanhoury A. Treatment of transthyretin amyloid cardiomyopathy: the current options, the future, and the challenges. J Clin Med. 2022;11(8). doi:10.3390/jcm11082148

Warner AL. Advances in the treatment of transthyretin cardiac amyloidosis: current and emerging therapies. Pharmacother J Hum Pharmacol Drug Ther. 2021;41(12):1081-1091. doi:10.1002/phar.2639

Cheng RK-H, Vasbinder A, Levy W, et al. Association of traditional heart failure therapies with survival in transthyretin cardiac amyloidosis. J Am Coll Cardiol. 2021;77(18):526. doi:10.1016/S0735-1097(21)01885-4

Lyle MA, Brown MT, Morris AA, et al. Heart transplantation in Val142Ile mutation in the modern era: a single center experience. Clin Transplant. Published online July 18, 2022. doi:10.1111/ctr.14780

Brown MT, Yalamanchili S, Evans ST, et al. Ventricular arrhythmia burden and implantable cardioverter-defibrillator outcomes in transthyretin cardiac amyloidosis. Pacing Clin Electrophysiol. 2022;45(4):443-451. doi:10.1111/pace.14458