What’s new in cardiac amyloidosis? Pharmacological treatment,physical activity,and care of patients with transthyretin cardiac amyloidosis

Abstract

Awareness, proper diagnosis and treatment of cardiac amyloidosis have increased, but there are still several unmet needs that have to be addressed for the optimal care of the disease. In this comprehensive review, we describe current and future treatments for both hereditary and wild-type TTR cardiac amyloidosis and also review lifestyle, including current challenges and opportunities for specific dietary concerns and exercise sports for these patients.

Keywords

cardiac amyloidosis cardiomyopathy disease-modifying agents heart failure small interfering RNA

Introduction

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by the deposition of amyloid, a proteinaceous material derived from misfolded products. Depending on the origin of the precursor protein, different types of amyloidosis exist: light chains produced by plasma cell dyscrasia result in amyloid light chain (AL) amyloidosis, mutations in transthyretin generate the familial subtype (ATTR-h, hereditary transthyretin amyloidosis, also called “v” variant), or amyloidosis due to spontaneous mutations, “wild type” (ATTRwt, previously known as senile systemic amyloidosis).^1,2

Transthyretin (TTR) is a tetrameric plasma protein primarily synthesized in the liver. Its function is to transport thyroxine and retinol-binding proteins. It is composed of monomers and dimers that are typically found in tetrameric form in circulation. However, in the presence of specific mutations, it tends to destabilize, separate into monomers, and then assemble into fibers that deposit in the interstitium of various tissues.³ The majority of TTR mutations generate variant forms that are less stable than the wild-type protein, increasing the likelihood of tetramer dissociation. This process, including dissociation and aggregation of TTR, is also believed to occur under normal physiological conditions, leading to the deposition of wild-type TTR. Moreover, a different pathway involving the proteolytic cleavage of TTR has been suggested as a mechanism for amyloid fibril formation in patients with ATTR (transthyretin amyloidosis).⁴

The exact prevalence of ATTRwt is not known, but data are estimating that it is an underdiagnosed disease. The average age of onset is approximately 70 years. Traditionally described in males, its diagnostic incidence in females has increased in recent years. Although the TTR protein can be deposited in various organs, it primarily affects the heart, making it the main organ involved. Cardiac manifestations are diverse, ranging from arrhythmias due to conduction system involvement to progressive biventricular heart failure (HF; Table 1).⁵

Table 1.

Cardiovascular manifestations of amyloidosis.

Diastolic with or without concomitant systolic dysfunction

Conduction abnormalities (involvement of the sinoatrial and/or atrioventricular node; bundle branch blocks; etc.)

Atrial arrhythmias

Ventricular hypertrophy

Biatrial dilation

Heart failure

Valvular thickening, aortic stenosis

Restrictive or hypertrophic cardiomyopathy phenotype

Cardiac involvement is a prognostic factor in amyloidosis. In the AL type with cardiac involvement, survival can extend up to 3 years, but in severe cases, it is reduced to 6–12 months. Patients with familial TTR and ATTRwt have a survival of approximately 6 years, although more recent cohorts reflect a median survival of 3.5 years. However, when cardiac amyloid deposits are extensive, they can lead to fatal biventricular HF.

Transthyretin cardiac amyloidosis (ATTR-CA) is associated with a reduced stroke volume index, which correlates with increased mortality. As a result, beta-blockers may be harmful by further reducing cardiac output. Given the unproven benefit and potential adverse effects of beta-blockers, de-escalation should be considered in patients with bradycardia and symptomatic hypotension. The management of HF in ATTR-CA is expected to evolve with earlier diagnosis and accumulating clinical experience. In addition, the detection of atrial fibrillation (AF) requires adjustments in treatment, as anticoagulation is critical due to the elevated risk of intracardiac thrombus formation. Current guidelines recommend anticoagulation for all patients with ATTR-CA and AF, irrespective of the CHA₂DS₂-VASc score, and advise transesophageal echocardiography-guided direct current cardioversion regardless of anticoagulation status.¹³

Methods

We performed a comprehensive nonsystematic review of the literature published in indexed journals from inception to 2023. This review included peer-reviewed articles from databases such as PubMed, Scopus, and Web of Science, as well as a selection of gray literature sources including conference abstracts, guidelines, health entities regulations, and policies. We also reviewed regulatory frameworks and policies from relevant health entities. Reference lists from key studies were manually screened to identify additional sources.

Our search strategy focused on studies that addressed various aspects of management and interventions for the pathology. We classified the information into three primary categories: dietary interventions, physical activity guidelines, and pharmacological treatments. We assessed and organized the data according to its consistency, relevance, and methodological quality. In addition, we synthesized the findings where relevant to emphasize emerging trends and identify gaps in the literature.

Pharmacological treatment of cardiac amyloidosis

Genetic silencer of TTR

Patisiran (siRNA)

A lipid-encapsulated small interfering ribonucleic acid (siRNA) nanoparticle targeting TTR, specifically ALN-TTR02 (Patisiran), has been developed. A phase III trial, APOLLO (NCT01960348), an 18-month randomized trial, assessed the efficacy and safety of Patisiran (0.3 mg/kg intravenous, once every 3 weeks) versus placebo in 225 patients with ATTR-FAP. In comparison with the placebo group, Patisiran significantly improved the quality of life, clinical neuropathy scores, and disease progression in patients with ATTR-FAP (familial amyloidosis polineuropathy). The drug was well tolerated, with no relevant adverse events.

In a subgroup of patients who also had cardiomyopathy, Patisiran significantly improved the left ventricle basal longitudinal strain, reduced the levels of natriuretic peptides (NT-pro-BNP), and improved left ventricular geometric patterns, including left ventricular hypertrophy.⁶ The data provided by APOLLO-A then suggest that for ATTR-FAP, the use of SiRNA may halt cardiac amyloid infiltration, but the low power to confirm it, based on a subset of patients and without specific long-term cardiac outcomes, as well as Patisiran difficult administration and safety profile, are barriers for escalating cardiovascular trials with this indication.

The APOLLO-B trial was designed to evaluate the effect of Patisiran versus placebo in patients with wild-type or hereditary ATTR amyloidosis with cardiomyopathy. While Patisiran demonstrated benefit in the 6-minute walking test (6MWT) at month 12 of treatment, all composite outcomes were not significant in the same time interval. This trial is being continued as an open-label extension to assess security and efficacy. It should be noted that despite being Food and Drug Administration (FDA) approved for ATTR neuropathy, this treatment has not achieved approval for ATTR-CA.⁷

Vutrisiran (siRNA)

Vutrisiran is a TTR gene silencer that differs from Patisiran as it is conjugated with GalNAc, granting it a longer half-life and enabling subcutaneous administration. HELIOS-A, a phase III study, demonstrated its beneficial effects on amyloid neuropathy. Recently, the results from HELIOS-B were published. This phase III, double-blind, randomized clinical trial followed 655 transthyretin amyloid cardiomyopathy (ATTR-CM) patients (with or without tafamidis treatment) in a 1:1 randomization to receive Vutrisiran 25 mg or placebo every 12 weeks for up to 36 months.⁸

The efficacy of Vutrisiran was demonstrated by reductions of 28% and 33% in the composite of all-cause mortality and recurrent cardiovascular events in the overall and monotherapy populations, respectively. It also lowered all-cause mortality by 36% and 35% in the overall and monotherapy populations, respectively. Clinically significant improvements were observed in the 6-Minute Walk Test, the Kansas City Cardiomyopathy Questionnaire, and the New York Heart Association (NYHA) class by month 30, even in patients not treated with tafamidis. Vutrisiran showed consistent efficacy across the primary composite endpoint and all secondary endpoints in key subgroups, including those defined by baseline tafamidis use, ATTR disease type, and disease severity. Adverse events occurred at a similar frequency in both the placebo and siRNA groups. These results represent an important step toward a longer and better quality of life for ATTR-CM patients.⁸

For the primary outcome measures, they applied the Andersen-Gill model.⁹ The model assumes that the risk of experiencing an event at a specific time, from the point of study entry, remains constant regardless of whether previous events have occurred. This assumption implies that recurrent events are considered independent. If this assumption holds true, the all-cause hazard can be estimated using the event times of every observed event. However, if the assumption of independent recurrent event times is not met, the Andersen-Gill model can still be applied but will no longer estimate the all-cause hazard ratio. Instead, the treatment effect estimator derived from the model reflects a hazard ratio that combines both direct and indirect effects.¹⁰

In addition, participants may experience the event of interest multiple times (recurrent events). However, most analyses concentrate solely on the time to the first event, disregarding any subsequent occurrences. Even considering the challenges in interpreting the selected statistical approach, this trial brings for the first time in amyloidosis history a strong support for the combination therapy. It finds no adverse interactions between Vutisiran and Tafamidis with potential long-term additive benefits.¹¹

Inotersen (antisense oligonucleotide)

Inotersen is an antisense oligonucleotide targeting TTR, which interferes with hepatic TTR synthesis. A phase III trial,¹² a 66-week randomized study, assessed the efficacy and safety of subcutaneous inotersen (300 mg, once a week) in 172 patients with ATTR-FAP and concomitant cardiomyopathy. The trial demonstrated that inotersen improved clinical manifestations and neurological scores in patients with ATTR-FAP. The most frequent adverse events were glomerulonephritis (3%) and severe thrombocytopenia (3%). Therefore, frequent laboratory monitoring is necessary to avoid these potential side effects.

Even with a safety profile that requires specific monitoring, this drug is attractive due to its subcutaneous (SC) administration and efficacy in neurologic outcomes, being labeled currently in several countries, with reports from real-world data showing similar safety and efficacy profiles to the trial.

Eplontersen

Eplontersen is a second-generation ligand-conjugated antisense oligonucleotide that targets the mRNA of TTR in the hepatocyte. Its conjugation with GalNac means that lower doses can still be effective while diminishing the frequency of dose-related adverse effects. Currently, this drug is being studied in ATTR neuropathy. Also, the CARDIO-TTRansform phase III RCT is evaluating cardiovascular (CV) mortality and recurrent cardiovascular events in patients suffering from ATTR-CA.^13,14

Several aspects of this drug make it a potential candidate for leading ATTR treatment: its self-administration subcutaneous administration and safety profile, as well as primary efficacy outcomes in neurologic variables from NEURO-TTRansform phase III randomized clinical trial. This drug is developed by IONIS^® and sent for regulatory approval in the United States and Europe. Also, AstraZeneca^® acquired the rights to commercialize the drug in several countries. The results of the cardiac long-term efficacy trial are expected by 2025.

TTR tetramer stabilizers

Tafamidis

Tafamidis is an oral drug that can bind to a thyroxine-binding site on the TTR tetramer, resulting in the inhibition of its dissociation into monomers, a crucial step in the TTR amyloid formation cascade. It is a diflunisal analog, possessing TTR stabilization characteristics but is not a nonsteroidal anti-inflammatory drug (NSAID). It is the only FDA-approved medication for both types of ATTR-CA since May 2019, after demonstrating positive results in the ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) study.¹⁵ In that trial, 441 patients with ATTR-CA (wild-type or variant) were randomly assigned in a 2:1:2 ratio to receive oral tafamidis 80 mg, 20 mg, or placebo every 24 h for 30 months. Patients with NYHA class IV HF or an estimated glomerular filtration rate <25 ml/min/1.73 m² were excluded.

In a combined analysis of both doses, using win ratio analysis, tafamidis was associated with a reduction in all-cause mortality (29.5% vs 42.9%, HR 0.70; 95% CI 0.51–0.96) and cardiovascular hospitalizations (RR 0.68; 95% CI 0.56–0.81) at 30 months. There was a lesser increase in NT-proBNP levels and less worsening of circumferential and radial global strain without affecting other echocardiographic parameters, with no significant safety issues reported.¹⁵ Furthermore, it significantly delayed the decline in functional capacity assessed by the 6-minute walk and the quality of life evaluated by the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score/KCCQ-OS.

In a recent subanalysis,¹⁶ tafamidis improved all-cause mortality and hospitalizations related to cardiovascular diseases in all subgroups (TTR genotype, initial NYHA class, and tafamidis dose). This trial suggests that the severity of initial cardiac dysfunction influences the outcome. The study demonstrated the dose-dependent effects of tafamidis on TTR tetramer stability in plasma.

Subsequently, an extended follow-up was published using a dose of 61 mg of tafamidis acid (equivalent to the 80 mg dose of tafamidis meglumine in a single tablet), and in long-term follow-up, the benefits were further confirmed: At an average of 58 months, there were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (p < 0.001). Mortality was also reduced in the continuous tafamidis (vs placebo to tafamidis) subgroups of variant ATTR (risk reduction 43%, p = 0.05) and ATTRwt (risk reduction 39%, p = 0.006).¹⁶

One important discussion was raised due to the analysis of NYHA class III patients in the trial: the number of them was low compared to class I and II patients, and in the primary results, death outcomes did not achieve statistical significance. However, emerging data from the 5-year follow-up of that cohort did show benefits: At the baseline of ATTR-ACT, 55/176 (31.3%) patients receiving tafamidis 80 mg and 63/177 (35.6%) receiving placebo had NYHA class III symptoms. After 30 months of treatment, patients could roll over to the long-term extension (LTE) study to receive open-label tafamidis. In an interim analysis of the LTE study (August 2021), all-cause mortality was lower among patients with NYHA class III symptoms who received continuous tafamidis in ATTR-ACT and the LTE study (death risk reduction of 36% at a median follow-up: 60 months), reassuring its benefit for patients with a more advanced disease stage.

Although in the first 1.5 years of treatment, no difference in mortality was observed in the ATTR-ACT trial, it is expected, due to its mechanism of action, that by preventing continuous amyloid deposition and slowing the rate of LV thickening—along with improving surrogates like cardiac biomarkers—these effects will take months to years to translate into clinical endpoints, primarily improvements in HF symptoms (NYHA class and 6MWT).¹⁷ Eventually, this will lead to significant results in stronger cardiovascular endpoints, such as HF hospitalization or death, which were shown to be significant after the expected time frame. During the LTE, an open-label study, it was demonstrated that the mortality reduction seen in patients initially treated with tafamidis in the ATTR-ACT trial is maintained in both ATTRwt and ATTRv patients, with a more substantial reduction in patients with NYHA class I or II (44%) compared to those with NYHA class III (35%).

Authors remark that this is currently the only FDA-approved therapy that showed a reduction in death for patients with cardiac amyloidosis, but current accessibility and affordability are low for most patients. However, by 2024–2025, the patent for the original drug expires, and several generics are in development, which may cause a fall in the cost of the intervention.

Diflunisal

Diflunisal is a NSAID that can stabilize TTR tetramers in vitro. In a randomized phase III trial, 130 patients with ATTR-FAP and symptomatic neuropathy were randomly assigned to receive 250 mg of diflunisal or placebo orally twice daily for 2 years. This trial demonstrated a significant reduction in the progression of neurological deterioration and preservation of quality of life compared to placebo. However, diflunisal did not have beneficial effects on improving cardiac status.¹⁸

Although the overall dose of diflunisal was well-tolerated in this trial, its cyclooxygenase inhibitory activity can lead to renal and gastrointestinal adverse events, such as renal failure, gastric mucosal injury, volume overload, and hypertension. The possibility of severe, potentially life-threatening adverse events remains a significant concern.^19,20 Therefore, diflunisal is not yet used in the authorized indication for the treatment of ATTR-CA.

Acoramidis (AG10)

Acoramidis (AG10) is a novel stabilizing compound that specifically binds to the TTR tetramer to inhibit TTR dissociation. An in vitro study demonstrated that AG10 had greater tetrameric stability of TTR compared to tafamidis and diflunisal. A randomized, double-blind, placebo-controlled phase II trial²¹ confirmed the safety and efficacy of AG10 in patients with ATTR-CA (wild-type or variant). A phase III trial²² in ATTR-CA has been developed.

ATTRibute-CM was a double-blind trial that randomly assigned 632 patients with ATTR-CM in a 2:1 ratio to receive acoramidis 800 mg twice daily or placebo for 30 months. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in NT-proBNP level, and the change from baseline in the 6-min walk distance (using the Finkelstein–Schoenfeld method win-ratio analysis) had a win ratio of 1.8 (p < 0.001), meaning 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Also, death from any cause and cardiovascular-related hospitalization were improved with the intervention.

Some emerging data from the trial are remarkable: Authors evaluated serum TTR levels, and at 30 months, the change from baseline in the least-squares mean difference in the serum TTR level was 7.01 mg/dl in favor of acoramidis. However, some concerns were raised regarding partial efficacy as death from any cause could not be confirmed and it was a key secondary endpoint. With current information, this drug may probably be added to the treatment options for cardiac amyloidosis.

Tafamidis treatment was not permitted during the first 12 months of the trial but was allowed afterward. Then, a total of 107 patients received tafamidis (61 of 409 (14.9%) in the acoramidis group and 46 of 202 (22.8%) in the placebo group), accounting for 17.5% of the 611 patients included in the primary analysis. The median time to tafamidis initiation was 17.2 months, with a median exposure duration of 11.4 months. These figures were consistent between the acoramidis and placebo groups (17.8 and 16.1 months for initiation time, and 11.6 and 10.8 months for exposure duration, respectively). Since the trial was double-blind, investigators were allowed to administer tafamidis in an open-label format after 12 months, which could have influenced the outcomes (Figures 1 and 2).²²

Figure 1.

Actual therapies for ATTR-CM.

Figure 2.

Pharmacological therapies.

Disruptors of ATTR

Doxycicline/tauro-ursodesoxicholic acid

These agents are effective in degrading non-fibrillar TTR deposits. Limited clinical trials have verified that concurrent treatment mitigates disease progression in patients with ATTR amyloidosis. Only three prospective, non-comparative, single-group studies have investigated this combined therapy, demonstrating modest results with a high dropout rate (~10%) due to esophageal and dermatological intolerance to doxycycline. However, given the high cost of other disease-modifying therapies, the combination of doxycycline with tauro-ursodesoxicholic acid/doxycicline (TUDCA/UDCA) remains a desirable and more cost-effective option.¹⁵ A phase I/II open-label clinical trial²³ evaluated the tolerability and efficacy of the doxycycline and TUDCA combination in the progression of ATTR-CA (wild-type or variant). Thirty-eight ATTR-CA patients were treated with TUDCA (250 mg orally three times a day) and doxycycline (100 mg orally twice a day) for 18 months. This trial was recently completed, but results have not yet been published.

Serum amyloid P component

The serum amyloid P (SAP) component is a normal plasma protein found in all types of amyloid deposits, stabilizing their formation. The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) has been developed to act as a competitive drug inhibitor of SAP binding to amyloid fibrils, efficiently depleting circulating SAP but leaving some residual SAP in amyloid deposition. Subsequent treatment with CPHPC followed by anti-SAP monoclonal antibodies efficiently triggered immunotherapeutic removal of amyloid deposits from key organs, including the liver, in animal studies and patients with systemic amyloidosis in early-phase clinical trials (NCT01777243).²⁴

Amyloid P is a glycoprotein component, found in all types of amyloid, that binds to and stabilizes the fibrils. This glycoprotein circulates as an SAP component in plasma, before reaching the deposits where it will bind to the amyloid fibrils. Therefore, finding a way to avoid SAP reaching the amyloid deposits might prove beneficial in the treatment of this disease. A competitive inhibitor of SAP binding to the fibrils, CPHPC, is effective in depleting the circulating SAP. Combining the CPHPC with an anti-SAP monoclonal antibody (dezamizumab) that triggers immune-mediated clearance of amyloid deposits has been tested in patients with systemic amyloidosis during early-phase clinical trials.⁶

Specific monoclonal antibodies against amyloid

The monoclonal antibody NNC6019/PRX004 targets non-native TTR aggregates associated with the natural course of wATTR (wild type transthyretin amyloidosis) and hATTR (hereditary transthyretin amyloidosis) disease, without affecting the normal tetrameric form of TTR. This antibody is a misTTR depleter designed to eliminate existing deposits and prevent new ones. In preclinical studies, it inhibited amyloid fibril formation, neutralized soluble misTTR aggregates, and promoted the clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis.²⁵

This therapy could be used as monotherapy or complement existing therapeutics. Prothena completed phase I with PRX004 in patients with hereditary forms of ATTR, where PRX004 was safe and well tolerated. In July 2021, Novo Nordisk acquired the drug and initiated phase II of the clinical trial of NNC6019/PRX004 in patients with ATTR cardiac amyloidosis.²⁶

Similarly, NI006 is an antibody designed specifically to remove cardiac amyloid. The first human study in amyloidosis demonstrated safety and potential efficacy signals at 12 months.²⁵

The concept of interstitial removal of the amyloid deposits is ambitious, and we raise some concerns as amyloid initial harm provokes a secondary inflammatory-fibrotic reaction which is the final responsibility of the cardiovascular and neurologic complication rather than the fibrils themselves, so this particular physiopathology may halt the potential benefit of an antibody-based strategy to remove the fibrils from interstitium. Even while the above early-stage trials showed potential benefit, we are cautious and awaiting long-term cardiovascular outcomes trials with evidence of removal (e.g., reversal of Perugini’s stage or H/L (heart/lung) ratio on nuclear imaging tests, LV “un-thickening” on echocardiography), and even parameters of improvement rather than slowing the worsening of clinical manifestations as what is seen with TTR stabilizers.

NTLA-2001

Hereditary ATTR amyloidosis, a monogenic disease, represents an attractive target for in vivo gene-editing approaches utilizing CRISPR-Cas9 technology. NTLA-2001 is a novel CRISPR-Cas9-based therapy administered intravenously, aimed at editing the TTR gene within hepatocytes.²⁷

Systemic administration of NTLA-2001 in six patients with hATTR amyloidosis and polyneuropathy resulted in sustained reductions in serum TTR levels. The NTLA-2001 platform utilizes a proprietary lipid nanoparticle delivery system with liver specificity, containing a single guide RNA targeting human TTR and a codon-optimized mRNA encoding the Streptococcus pyogenes Cas9 protein. Further investigation regarding cardiac benefits is expected in the next years.

Lifestyle in patients with ATTR amyloidosis

Dietary aspects: Green tea

Epigallocatechin gallate, a well-known polyphenol in green tea, can inhibit the formation of TTR amyloid fibrils and disaggregate amyloid deposits. Two observational studies^28,29 revealed that 12 months of green tea consumption significantly reduced the left ventricular mass by 6%–13%, as assessed by cardiac magnetic resonance imaging in ATTRwt-CA patients. This suggests that green tea extract consumption has an inhibitory effect on the progression of the disease. However, these studies have limitations, being open-label, observational, and limited to small sample sizes.¹⁵

In the context of scarce availability or unaffordable treatments for most patients currently suffering cardiac amyloidosis, and considering its safety profile, clinicians usually prescribe green tea to patients and our opinion is for this recommendation.

Green tea is rich in epigallocatechin gallate, a polyphenol capable of inhibiting the formation of the TTR fibrils and also degrading amyloid deposits. One study found that drinking 1.5–2 l of green tea (taking the equivalent content of the polyphenol in pills) improved ventricular ejection fraction and NYHA Functional Class when paired with standard treatment for amyloidosis. The left ventricular mass reduction achieved was between 6% and 13%, measured with cardiac magnetic resonance images. While the results seem very promising, it has to be taken into account that the studies have limitations since they are open-label, observational, and limited to small sample sizes.^6,15

Physical activity in patients with amyloidosis

Consequences of amyloidosis in physical activity

There are several consequences of amyloid deposits regarding physical performance and tolerance, affecting patients’ ability to perform certain types of exercise. Amyloidosis results in myocardial involvement, leading to symptoms of retrograde HF, dyspnea, and fatigue, even at low exertion levels.² In addition, alterations in deformation and subsequent contractile deficits cause a potential low antegrade volume, resulting in peripheral hypoperfusion. Patients with cardiac amyloidosis have been shown to have lower inotropic reserve than controls, along with increased biventricular filling pressures and reduced pulmonary artery compliance. A direct cytotoxic effect on cardiomyocytes has been demonstrated in AL amyloidosis, indicating that not only interstitial infiltration but also circulating proteins contribute to hemodynamic alterations.

Autonomic dysfunction is present in most patients, even preceding myocardial involvement in individuals with ATTR-v or AL. This dysautonomia manifests as marked postural hemodynamic changes and orthostatism, partly contributing to exercise intolerance. Tendon involvement is described, usually in ATTR-wt patients, with the possibility of spontaneous or marked effort-induced tendon rupture (e.g., the “Popeye’s sign” with biceps tendon rupture).³⁰ Bilateral carpal tunnel syndrome is common in these patients, which points out the possibility of cardiac amyloidosis screening in patients subjected to bilateral carpal tunnel syndrome surgery.³¹

Peripheral polyneuropathy can cause numbness, pain, and burning in the lower limbs, interfering with the ability to engage in physical activity. These manifestations are more commonly observed in patients with hereditary ATTR. Moreover, most amyloidosis patients require anticoagulant treatment due to a high thromboembolic risk, limiting the possibility of engaging in contact sports or even predisposing to hemarthrosis.

Patients with ATTR-v amyloidosis typically experience disabling neuropathy before significant cardiac involvement, while those with ATTR-wt are diagnosed at an advanced age, often with concomitant bradyarrhythmias and aortic stenosis. All these factors contribute to sarcopenia, frailty, and other non-cardiac issues that limit the ability to engage in physical activity.

The studies summarized in Table 2 showcase important information about the consequences of the disease in physical exercise tolerance and response. In a 2022 study, tafamidis showed an improvement in the physical performance of NYHA Functional Class II patients, measured by CPET but not detected with the 6MWT (Table 2). In 2023 patients followed for a year, under treatment with tafamidis, were found to have less physical exercise tolerance which was linked to not only ATTR-CM but progression of frailty, mostly in elderly patients. Finally, Bartolini et al. found that right ventricular function is an independent predictor of exercise capacity and ventilatory efficiency in these patients.

Table 2.

Studies assessing exercise response in ATTR amyloidosis.

Author/year	Population	Control	Intervention	Outcome	Results
Badr Eslam/2022³⁵	78 patients. Age 78 ± 6 years. 87% of males with ATTR amyloidosis. All in NYHA Functional Class II.	24 patients did not receive tafamidis, and there was no reduction in beta-blocker dosage.	54 patients received tafamadis, and there was a reduction in beta-blocker dosage.	29 patients (54%) in the intervention group showed an increase in the predicted percentage of peak VO₂ (p < 0.001), improvement in peak VO₂ (p < 0.001), and better physical performance in the follow-up (p < 0.001).	Improvement in physical performance was measured by CPET in patients who received tafamidis, especially in those with less advanced disease at the study’s initiation. Significant changes can be identified through CPET that are not detected with the 6MWT.
Nakaya/2023³⁶	8 patients with ATTR-CM Average age: 77 years; 7 men	—	1 year of treatment with tafamidis	Frailty had progressed in seven out of eight patients (88%; p < 0.01), and in CPET, anaerobic threshold, and peak oxygen consumption significantly decreased (19.2% and 22.3%, respectively; p < 0.05). The VE/VCO₂ slope and maximum O₂ pulse decreased by approximately 20%, but the changes were not statistically significant (p = 0.47 and p = 0.16, respectively). In successive echocardiograms, the structure of the ventricles and atria, as well as the left ventricular ejection fraction, did not change significantly over time.	Exercise tolerance in patients with ATTR-CM decreased after 1 year. Not only the progression of ATTR-CM but also the progression of frailty in this particularly elderly population may influence this decrease in exercise tolerance.
Bartolini/2012³⁷	72 patients with cardiac ATTR	—	They evaluated the correlation of clinical, humoral, and echocardiographic parameters with CPET parameters such as peak oxygen consumption (VO₂ peak) and the VE/VCO₂ slope.	In the CPET assessment, a significant proportion of patients exhibited an abnormal blood pressure response and heart rate variation during exercise. They reached an average peak VO₂ of 14 ml/kg/min and an average VE/VCO₂ slope of 31. The blood pressure response to exercise was inadequate in 26 (36%) patients (flat in 25 and hypotensive in 1), while 49 patients (69%) showed an inadequate heart rate recovery.	When analyzing and correlating with echocardiographic parameters, the multivariate analysis found that the TAPSE was the only parameter independently related to VO₂ peak. In the two test models performed to avoid collinearity, both TAPSE and TAPSE speed (s′ tricuspid) were the strongest independent predictors of the VE/VCO₂ slope. This study demonstrated that right ventricular function is an independent predictor of exercise capacity and ventilatory efficiency in subjects with ATTR amyloidosis.

ATTR, transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; CPET, cardiopulmonary exercise testing; 6MWT, 6-minute walk test; NYHA, New York Heart Association; TAPSE, tricuspid annular plane systolic excursion; VE/VCO₂, minute ventilation/carbon dioxide production; VO₂, oxygen consumption.

Evaluation of exercise response

Patients with HF secondary to cardiac amyloidosis (CA) experienced higher hospitalization rates compared to HF controls and exhibited significantly lower values in nearly all cardiopulmonary exercise test (CPET) parameters. These included exertional variables: peak oxygen consumption (VO₂ peak), the difference between resting and peak heart rate (ΔHR), O₂ pulse max, and the difference between end-tidal carbon dioxide at rest and peak exercise (ΔPETCO₂); compound variables: circulatory power (CP) and ventilatory power (VP); and non-exertional variables: minute ventilation to carbon dioxide production (VE/VCO₂), oxygen uptake efficiency slope (OUES), percent of predicted oxygen uptake at the first ventilatory threshold (% predicted VO₂ at VT1), and oxygen equivalent at the first ventilatory threshold (EqO₂ at VT1).³²

Furthermore, the observed reductions in VO₂ at VT1 and increases in EqO₂ at VT1 indicate an earlier transition from aerobic to anaerobic metabolism, highlighting a critical factor in the impaired exercise capacity seen in patients with CA. In addition, although they showed improved performance in VO₂ peak, OUES, CP, and VP, CA patients had elevated resting heart rate, stroke volume, and cardiac output. By contrast, HF patients did not exhibit this pattern; however, they had higher VP, which correlated with increased left ventricular mass index and left atrial volume index.

In addition to providing valuable prognostic information, the use of CPET in patients with cardiac amyloidosis could have therapeutic implications for promoting physical activity and exercise. Regular exercise has been shown to improve peak oxygen consumption (VO₂), reduce the risk of hospitalization, and enhance the quality of life in HF patients. Thus, by assessing a patient’s functional capacity through CPET, physicians can design personalized exercise programs that are safe and effective, improving clinical outcomes and quality of life.^{33, 34}

Given the aforementioned considerations, before considering a drug as the sole variable in the long-term follow-up of exercise-related events (e.g., 6-minute walk, CPET), it is crucial to take into account that parameters of frailty and sarcopenia have likely worsened concomitantly over these months of follow-up. This interference should be considered in the interpretation of prognostic parameters.

The disease has a devastating prognosis, and limitations in physical activity are not solely attributed to cardiac infiltration but are multifactorial. On the other hand, the utility of the 6-minute walk and CPET in prognostic classification has been demonstrated, with limited usefulness in assessing treatment response. However, Badr-Eslam, Nakaya, and Bartolin, among other investigators, reviewed and developed specific protocols to assess exercise response in patients with cardiac amyloidosis. Their publications are summarized in Table 2.

Benefits of physical activity

The amount of information published about the benefits of physical activity is not vast. One pilot study (33) consisting of five individuals diagnosed with ATTR-wt found that aerobic and strength training over 16 weeks improved VO_{2 peak}, KCCQ-12 score, and mean achieved predicted peak heart rate. Another publication (34) enrolled eight patients with ATTR-CA with reduced ejection fraction and assessed amyloid-like protein aggregate levels after 18 weeks of moderate-intensity aerobic and resistance exercises twice per week. It was found that physical activity in that time period decreased amyloid-like aggregates and may reduce the formation of ThT-positive aggregates.

Given the scarcity of data regarding the characteristics of the recommended exercise program we cannot define a standard routine. Nevertheless, both publications included aerobic and strength exercises in their training prescriptions. The article from Rivera-Theurel et al. evaluated the response to a plan consisting of two sections. First, preconditioning of twice a week 45 min of a treadmill or cycle ergometer at a maximum of 70% VO_{2 peak}, for 2 weeks. Then, twice a week of aerobic high-intensity interval training consisting of four sets of 2–4 min over 85% VO_{2 peak} and strength training (one set of 10–15 repetitions of 3–5 exercises involving the major muscular groups) spanning a 14-week period.

Emerging drugs under development for various forms of amyloidosis aim at reversing cardiac and neurological infiltration and may become available in the coming years. Therefore, even in patients currently functionally limited, we cannot neglect offering tailored physical activity programs to them, given the significant cardiovascular health benefits associated with physical activity (Table 3).

Table 3.

Cardiovascular, neurological, and orthopedic impairments interfering with physical activity in patients with amyloidosis.

Congestive heart failure	Dysautonomia
Chronic low cardiac output	Carpal tunnel
Bradycardias and atrioventricular blocks	Lumbar stenosis
Atrial fibrillation	Sensory-motor neuropathy
Pulmonary hypertension	Tendon rupture
Aortic stenosis	Involvement of fingers and rotator cuff
Coronary artery disease	Hematomas
Orthostatic hypotension	Sarcopenia

Conclusion

We have reviewed several aspects of the therapeutic approach to patients with ATTR-CA, highlighting the limited benefits associated with diet and physical activity. On the other hand, there is currently a rise in the development of drugs for the treatment of ATTR-CA, with tafamidis already demonstrating a reduction in mortality, and several molecules in development aiming to prevent amyloid synthesis, modify its folding, or even remove it from the interstitium with potential disease reversal. The prohibitive cost of available treatments is a current barrier, but the future is promising for patients with this devastating disease who until very recently had no treatment.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Sol C. Song

Juan J. Sterba

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