**Table 2.**

*Prognostic staging system for cardiac amyloidosis.*

*Cardiac Amyloidosis*

*DOI: http://dx.doi.org/10.5772/intechopen.109522*

#### **Figure 7.**

*AL-cardiomyopathy pharmacological therapeutic treatment flowchart. IMiDs, immunomodulator drugs; Afib, atrial fibrillation; DOA, direct oral anticoagulants; VKA, vitamin K antagonist; PPM, permanent pacemaker; ICD, internal cardiac defibrillator; CRT, cardiac resynchronization therapy; VT, ventricular tachycardia; SCD, sudden cardiac death; ARNI, angiotensin receptor-neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitor; BB, betablocker; OTH, orthotropic heart transplant.*

#### **Figure 8.**

*ATTR-amyloidosis pharmacological therapeutic treatment flowchart. Afib, atrial fibrillation; DOA, direct oral anticoagulants; VKA, vitamin K antagonist; PPM, permanent pacemaker; ICD, internal cardiac defibrillator; CRT, cardiac resynchronization therapy; VT, ventricular tachycardia; SCD, sudden cardiac death; ARNI, angiotensin receptor-neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitor; BB, betablocker; OTH, orthotropic heart transplant.*

Angiotensin-converting enzyme inhibitors (ACEI), aldosterone receptor blockers (ARB), and aldosterone receptor/Neprilysin inhibitors (ARNI) often lead to hypotension. Moreover, beta-blockers are known to exacerbate bradyarrhythmias in this

#### *Cardiac Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.109522*

population. Digoxin binds to amyloid fibrils, leading to potential drug toxicity even when circulating levels are within normal range, and should be avoided unless there is difficulty controlling atrial fibrillation. Similarly, calcium blockers should be avoided as well since they tend to bind irreversibly to amyloid fibers, thus causing bradycardia.

Orthostatic hypotension is a common debilitating symptom in patients with cardiac amyloidosis, often leading to significant deterioration and poor quality of life. Its management include pharmacological interventions such as the use of sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine, or the norepinephrine transporter inhibitor atomoxetine along with use of compressions stockings. A retrospective study of patients with AL-CM showed droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine. Slow titration may be important to minimize rapid changes in blood pressure [60].

Cardiac arrhythmias are commonly secondary to infiltration of amyloid proteins to cardiac conduction system as well as fibrosis at the sinoatrial node and atrioventricular nodes which disrupts the transmission of electrical impulses along the conduction fibers, additional direct cytotoxic effects of amyloid fibers have been described in AL-CA [61]. Atrial fibrillation (AF) is the most common rhythm disturbance seen among patients, with a prevalence ranging between 10 and 69% [41, 62]. When it comes to treatment and rhythm control options, patients with cardiac amyloidosis have limited strategies due to intolerance to most of the rate control medications, leading to low output states and hemodynamic deterioration. Nevertheless, AF does not significantly affect the overall survival of patients with ATTR cardiomyopathy. Rhythm control strategies including antiarrhythmic treatment, synchronized cardioversion, and AF ablation are more effective when performed earlier during the disease course [63]. Amiodarone can be used to safely restore heart rhythm and can be considered the agent of choice in those patients with beta blocker intolerance requiring both rhythm and rate control. Anticoagulation is highly recommended in these patients because of higher rates if thrombi and thromboembolic events when compared to aged-matched population without the disease [64]. A retrospective study showed no difference on thrombotic events or major bleeding events between both groups [65]. Hence anticoagulation prescription is indicated to all patient with CA and atrial fibrillation unless prohibitive risk of bleeding. In a comparative study in patients who underwent Left atrial appendage devise placement, it was demonstrated that devise reduce the risk of bleeding complications and ischemic cerebrovascular events in a similar fashion than patients without CA [66]. Sinus bradycardia and bifasicular block are common and progression to complete AV block is not infrequent requiring permanent pacemaker implantation [67]. Biventricular pacing is recommended over regular permanent pacemaker due to risk of induced desynchrony by the last one. It has been found that CRT response was associated with lower rates of cardiac events in this population especially in younger patients [68]. Although sudden cardiac death is common in AL amyloidosis, most of the times it has been the result of electromechanical dissociation rather than ventricular arrhythmias. Therefore, defibrillator implantation is recommended in cases in which a sudden death event has been aborted and it is understood that the patient has a survival of ≥12 months.

#### **7.1 Cardiac amyloidosis disease specific treatment**

### *7.1.1 AL-cardiomyopathy*

Patients with amyloid cardiomyopathy due to AL amyloidosis need identification and management with chemotherapeutic regimens that will control production of

light chain gammopathy and/or autologous cell transplantation (ASCT) [7]. The goal of treatment in patients with cardiac involvement is to achieve complete resolution or normalization of serum kappa and lambda free light chain (FLC) and FLC ratio. Staging is paramount as the risk of treatment-related mortality associated with ASCT in AL amyloidosis restricts the use of this procedure to a small group of selected patients. Multiple prognostic models have been proposed for patients with amyloidosis, most simple staging models incorporate NT-proBNP and cardiac troponin that can be easily used in clinical settings (**Table 2**) [69]. There are several different choices of anti-plasma cell medications (alkylating agents, immunomodulatory drugs (IMiDs) and proteosomes inhibitors) approved for treatment of myeloma multiple and can be used off-label for the treatment of AL amyloidosis. Daratumumab is the first monoclonal Ab that has been demonstrated to be highly effective in the treatment of AL-CA [70]. The intensity and type of therapy chosen is affected by the number and extent of organ involvement. Patients with AL cardiomyopathy with New York Heart Association (NYHA) functional class 3 and above are not considered for autologous stem cell transplant (ASCT). The treatment goal is to achieve a complete hematological response or extremely low levels of serum FLCs. For those patients who are candidates for stem cell transplantation, ASCT involves administration of high-dose melphalan followed by stem cell rescue (**Figure 7**).

#### *7.1.2 Transthyretin cardiomyopathy*

ATTR amyloidosis which was previously managed only by treating symptomatology and volume congestion, is now treated with disease modifying therapies targeted at the level of synthesis, stabilization and/or elimination of the TTR protein. Thus, avoiding overproduction of abnormal TTR protein. Strategies for management are divided in transthyretin tetramer stabilizers, synthesis inhibitors and clearance of amyloid deposits (**Figure 8**).

### *7.1.2.1 Transthyretin stabilizers*

Tafamidis is a transthyretin stabilizer which works by binding to the thyroxine site of TTR with high affinity, thus slowing dissociation of TTR tetramers into monomers and preventing aggregation in amyloid fibrils. It is indicated in ATTR-CM and heart failure with functional class 1–3 (NYHA). The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled 441 patients allocated in a 2:1:2 to Tafamidis 80 mg, Tafamidis 20 mg, or placebo [71]. Tafamidis improved survival, reduced cardiovascular (CV)-related hospitalizations, as well as measures of functionality and health-related quality of life (HRQoL) in patients with ATTR-CM. The study was not designed to assess the relative efficacy between study drug dosages, but it showed a significant reduction in the increased NT-pro BNP and troponin I over time in patients with the 80 mg dose over the ones using 20 mg, with higher number of patients with stable or reduced NT-proBNP levels at 30-months. This was better analyzed in the ATTR-ACT long term study treated for additional 60 months using the 80 mg dose. Demonstrating a 30% relative risk reduction of death when compared to the 20 mg dose [72].

In a similar fashion, Diflunisal, a nonsteroidal anti-inflammatory, is known to have capability to stabilize TTR protein by increasing its dissociation barrier by binding to the thyroxine site. It could be used off-label for the treatment of ATTR. Diflunisal has been shown to reduce neurologic deterioration in patients with familial amyloid polyneuropathy due to hereditary transthyretin amyloidosis [73–75].

#### *Cardiac Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.109522*

Additionally, in patients with cardiac involvement, diflunisal treatment resulted in measurable differences in cardiac troponins as well as pro-BNP and echocardiographic parameters of cardiac structure and function after only 1 year of administration [73, 74]. Nevertheless, the medication has been associated the usual side effects seen with NSAIDS such as gastric disturbances, nephrotoxicity as well as cardiac toxicity.

There are other medications in development with ATTR stabilization capabilities, Acoramidis (AG10) and mds84. Acoramidis (AG10) appeared to be safe and well tolerated during phase 2 clinical trial and completely stabilized TTR [76]. The ATTRibute-CM Study is an undergoing phase 3 study with main aim to demonstrate Acoramidis usefulness in improvement of exercise capacity, survival, and secondary end point of improvement of health-related quality of life, all-cause mortality, and rate of cardiovascular-related hospital events when compared to placebo [73]. Lastly, mds84 is bivalent ligand TTR that can bind to the binding groove as well as central protein channel pockets. In vitro studies have demonstrated higher potency capabilities when compared to other TTR stabilizers [73, 74]. So far, there is no evidence of undergoing available clinical trials.

#### *7.1.2.2 Transthyretin gene silencers*

Patisiran is a double-stranded small interfering RNA which decreases the production of abnormal TTR by binding to the RNA-induced silencing complex mediating cleavage of the protein's mRNA to prevent TTR synthesis by the liver. It has FDA approval for treatment of ATTRv polyneuropathy. The APOLLO trial demonstrated improvement in the biomarker NT-proBNP as well as echocardiographic parameters such as LV-wall thickness, end-diastolic volume, cardiac output, and global longitudinal strain in those patients with cardiac involvement. Further sub analysis demonstrated improvement in functional capacity, decreased hospitalizations and mortality when compared to placebo [77]. These findings provided off-label alternative use for hereditary (variant) ATTR-CM.

The APOLLO-B, a randomized placebo control trial for treating both types of ATTR-CM designed to determine usefulness of siRNA to improve functional capacity and decrease hospital admissions and MACE. Inotersen, an antisense oligonucleoside inhibitor that causes degradation of TRR mRNA through binding to the TTR mRNA produced by the liver. The medication is administered by subcutaneous injection weekly. Similarly, to Patisiran, it is indicated for treatment of ATTRv polyneuropathy. Dasgupta et al., presented data from a single center which demonstrated long-term treatment in ATTR CM was safe and effective at inhibiting progression and potentially reverting amyloid burden accompanied by increased exercise tolerance and decrease in mean LV mass measured by CMR [78].

There are two ongoing investigational drugs that target gene silencing of TTR undergoing evaluation with phase 3 trials. Eplontersen CARDIO-TTRansform and Vutrisiran (HELIOS-A and HELIOS-B) [73]. In the HELIOS-A, Vutrisiran, preliminary results showed improvement on the exploratory cardiac biomarkers, NT-pro-BNP endpoints when compared to placebo (*P* < 0.05).

#### *7.1.2.3 Transthyretin degraders*

Doxycycline is a tetracycline derivative which poses anti-amyloidogenic properties, disrupting pre-formed TTR fibrils in vitro [79, 80]. Tauroursodeoxycholic acid (TUDCA), a biliary acid has similar effect in reducing non−/pre-fibrillary TTR deposits. This was demonstrated in transgenic mice where the combination of both drugs had a synergistic effect and have shown disease stabilization, good tolerability, and low toxicity profile with 1-year of treatment [80].

Monoclonal anti-serum amyloid protein is an antibody targeting normal non fibrillar glycoprotein SAP promoting a giant cell reaction that will remove visceral amyloid deposits. Medication is administered intravenously. This drug is still undergoing evaluation and a clear utility in amyloid cardiomyopathy has not been demonstrated [73, 74].

#### **7.2 Advanced heart failure therapies**

Cardiac amyloidosis is a progressive disease with significant risk of progression of heart failure and mortality associated to a restrictive physiology along with characteristically small, hypertrophied LV ventricle. This leads to a significant anatomic concern as a small LV cavity could lead to suction events by obstructing the inflow cannula thereby predisposing the patient to low flow, hypotension, pump thrombosis as well as arrhythmias and worsening RV dysfunction. Furthermore, this population has frequent RV involvement with associated pulmonary hypertension and right heart failure which would further limit ventricular assistant devise use feasibility. There are only a few small studies with overall conflicting results to draw conclusions. Hence consideration of treatment should be done on a patient-to-patient basis. One small study suggest left ventricular assist device (LVAD) implantation is technically feasible for patients with severe heart failure due to advanced cardiac amyloidosis [81]. Another single-center case series highlighted the feasibility of supporting highly selected CA patients with continuous flow-left ventricular assist devise (CF-LVAD) as bridge to transplant (BTT) or destination therapy (DT including the HeartMate 3 pump) with reasonable outcomes, principally for those with a reduced LVEF and an absence of significant pre-implant RV dysfunction or pulmonary artery pulsatile index (PAPI) ≤ 1.5 [81, 82].

Improvement in treatment options in patients with cardiac amyloidosis has opened the possibility for heart transplant in carefully selected patients with advanced heart failure including those that require combined heart-liver or heart-kidney. Barrette et al. analyzed 31 patients who underwent heart transplants for cardiac amyloidosis (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) that were carefully selected for the procedure. His findings disclosed there was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications [83].

#### **7.3 Transthyretin cardiomyopathy in aortic stenosis**

Aortic stenosis (AS) is the most prevalent valvular disease seen in over 4% of octogenarian patients. Multiple studies have described a prevalence of cardiac amyloidosis in patients with aortic stenosis which range from 4% up to 29% [84]. Hence, AS-CA frequently coexists in this population. Aortic stenosis should be graded according to guidelines but taking into consideration that in these settings the patient will present with low flow/low gradient patterns (i.e., AVA <1.0 cm2 , mean gradients <40 mm Hg and stroke volume index <35 ml/m2 ). A multicenter prospective of close to 400 patients referred for aortic valve replacement mostly through transcatheter

*Cardiac Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.109522*

aortic valve replacement (TAVR) showed that even though dual pathology of severe AS-CA conferred overall worse disease by functional capacity, cardiac remodeling and biomarkers, the patients had improved outcome when procedure was performed. Furthermore, their data confirmed AS-CA was common and affected 1 in 8 patients referred for TAVR [85].
