The Pathophysiology of Wild-Type Transthyretin Amyloidosis: Implications for Exercise Intolerance

Abstract

Wild-type transthyretin amyloidosis (ATTRwt) is an age-associated protein misfolding disorder marked by extracellular deposition of transthyretin fibrils within the myocardium, peripheral nerves, lungs, blood vessels, and musculoskeletal tissues. ATTRwt typically presents as a restrictive cardiomyopathy with preserved left ventricular ejection fraction which contributes to the development of hallmark symptoms such as exercise intolerance. Amyloid infiltration severely impairs ventricular compliance and diastolic reserve, limiting stroke volume and cardiac output augmentation during exercise, and is frequently accompanied by coronary microvascular dysfunction. These central limitations are compounded by autonomic dysfunction, including chronotropic incompetence and impaired sympathetic vasomotor control, which blunt heart rate responses and disrupt appropriate blood flow responses. Pulmonary hypertension, right ventricular–pulmonary artery uncoupling, and ventilatory inefficiency further constrain oxygen transport and contribute to exertional dyspnea and early fatigue. Other peripheral factors such as amyloid-related derangements in vascular endothelial function and musculoskeletal pathologies likely result in impaired hyperemic responses to exercise and accelerated cardiovascular deconditioning, further limiting physical capacity. Together, these integrated cardiac, pulmonary, autonomic, and peripheral abnormalities convergently impair exercise performance in ATTRwt. Considering the universal presentation of exercise intolerance in ATTRwt, therapies that may have favorable effects on physical capacity are of great interest to patients, physicians, and scientists alike. This review seeks to synthesize current evidence describing the central and peripheral pathophysiological mechanisms underlying exercise intolerance in ATTRwt and discuss the potential of pharmacologic and exercise-based interventions that may improve physical capacity in this population.

INTRODUCTION

Transthyretin Amyloidosis (ATTR) is a progressive systemic disorder caused by the tetrameric dissociation and subsequent monomer misfolding of transthyretin (TTR), a transport protein primarily synthesized in the liver, resulting in the formation and extracellular deposition of insoluble amyloid fibrils in the myocardium, peripheral nerves, blood vessels, and musculoskeletal structures. This progressive, systemic TTR amyloid deposition produces a heterogeneous clinical syndrome with both cardiac and extracardiac manifestations^1,2. While ATTR has historically been considered a rare disease, due to increased recognition, improved diagnostic techniques, and an aging population, diagnoses for ATTR have dramatically increased in recent years. Indeed, emerging evidence demonstrates that the prevalence of ATTR rose from 15.8 per 100,000 individuals in 2010 to 95.8 per 100,000 individuals in 2022³. ATTR exists in two main forms: wild-type ATTR (ATTRwt) and hereditary/variant ATTR (ATTRv). ATTRwt results from age-related instability, misfolding, and proteolysis of otherwise normal TTR protein, whereas ATTRv is caused by pathogenic mutations in the TTR gene that promote protein destabilization and amyloid formation. Although ATTRwt and ATTRv share overlapping pathological features, they differ in their predominant clinical manifestations⁴. ATTRwt commonly affects the myocardium, leading to increased ventricular wall thickness, progressive diastolic dysfunction, and ultimately heart failure (HF), most commonly heart failure with preserved ejection fraction (HFpEF)¹. ATTRv frequently manifests earlier and is associated with a broader clinical phenotype that may include peripheral neuropathy and dysautonomia⁵, although more recent studies suggest that these may be underestimated aspects of ATTRwt pathophysiology^6,7. ATTRwt represents the majority of ATTR cases (~85%) with ATTRv representing the remainder⁸. Given that ATTRwt is the predominant subtype of ATTR and is more strongly associated with cardiac dysfunction, the present review will focus primarily on ATTRwt, whereas detailed discussions of ATTRv are available elsewhere^4,9.

A hallmark physiological feature of ATTRwt is a marked reduction in exercise capacity. Similar to HFpEF and heart failure with reduced ejection fraction (HFrEF), patients with ATTRwt frequently develop exertional dyspnea and fatigue early in the disease course¹⁰. However, the degree of functional limitation is frequently disproportionate to resting measures of cardiac performance and structure, such as ejection fraction and LV wall thickness¹¹, reflecting the complex, multisystem nature of ATTRwt. Indeed, reduced exercise capacity in ATTRwt reflects amyloid-mediated derangements in cardiovascular, cardiopulmonary, and autonomic nervous system function. This marked impairment in exercise capacity not only contributes substantially to reduced quality of life, but also serves as an important prognostic indicator¹², underscoring its clinical relevance and central role in ATTRwt pathology.

Importantly, it should be recognized that ATTRwt is not synonymous with HF. Rather, it is a distinct disease that commonly leads to a cardiomyopathy with a clinical phenotype resembling HFpEF or HFrEF syndromes^1,13. While the mechanisms contributing to exercise intolerance in these broader HF syndromes have been well-characterized elsewhere^14–18, this review synthesizes current evidence for the pathologic factors that may contribute to exercise intolerance in ATTRwt, with particular emphasis on the distinct cardiovascular, pulmonary, and autonomic abnormalities associated with this unique disease (Fig. 1) as well as potential targets for therapeutic intervention (Fig. 2). However, given the overlap of clinical signs and symptoms of ATTRwt and non-amyloid related HF, this review will also highlight parallels and dissimilarities between emerging ATTRwt research and the existing HFpEF and HFrEF literature as a clearer delineation of ATTRwt pathophysiology is essential for improving functional assessment, guiding treatment strategies, and ultimately enhancing quality of life in this growing patient population.

Figure 1.

Conceptual figure summarizing the pathophysiologic factors contributing to exercise intolerance in patients with wild-type transthyretin amyloidosis, including central limitations such as cardiac dysfunction, pulmonary hypertension, chronotropic incompetence, and ventilatory efficiency, and peripheral limitations, such as sympathetic vasomotor dysregulation, vascular dysfunction, and musculoskeletal manifestations. Created in BioRender. Iacovelli, J. (2026) https://BioRender.com/pjt7z26

Figure 2.

Conceptual figure summarizing the amyloid and HF-directed pharmacotherapies and exercise-based interventions that may exert beneficial effects on physical capacity in patients with ATTRwt. Created in BioRender. Iacovelli, J. (2026) https://BioRender.com/0jtxpxm

CARDIAC DYSFUNCTION

Cardiac dysfunction is a central determinant of exercise intolerance in both amyloid- and non-amyloid-related HF, resulting from disease-specific impairments in ventricular mechanics, maximal cardiac output, and myocardial perfusion during physiological stress^19–21. In ATTRwt, while LV ejection fraction is frequently preserved at rest (reduced ejection fraction is also observed, but less common²²), amyloid infiltration markedly reduces ventricular compliance and limits diastolic filling, constraining stroke volume augmentation as metabolic demand increases²³. Thus, structural and functional cardiac abnormalities limit maximal cardiac output during exercise. Indeed, studies have reported that patients with ATTR exhibit relatively smaller augmentation of stroke volume index (rest, 31 mL/m²; exercise, 35 mL/m²) and cardiac output index (rest, 2.3 L/min/m²; exercise, 3.6 L/min/m²)^24,25, compared with similarly aged, healthy adults (stroke volume: rest, 31 mL/m²; exercise, 39 mL/m²; cardiac output index: rest, 2.2 L/m²/min; exercise, 5.8 L/m²/min)²⁶.

Cardiac Remodeling.

While ATTRwt commonly leads to heart failure (HF), most often with preserved ejection fraction^27,28, the pathological basis of ATTRwt differs fundamentally from non-amyloid HFpEF. Indeed, in HFpEF from non-amyloid etiology, ventricular wall thickening primarily reflects concentric cardiomyocyte hypertrophy driven by chronic pressure overload and systemic inflammation²⁹. In contrast, the increased ventricular wall thickness observed in ATTRwt is largely attributable to extracellular TTR amyloid deposition, resulting in so-called “pseudohypertrophy” rather than true myocyte enlargement³⁰. These structural changes profoundly impair ventricular compliance and diastolic filling. Amyloid infiltration of the ventricular myocardium markedly reduces chamber distensibility, leading to elevated filling pressures even at low cardiac volumes^24,31,32. While both ATTRwt and non-amyloid HFpEF are associated with diastolic dysfunction, the degree of ventricular thickness and stiffness in ATTRwt is often more severe, predisposing the ventricle to exaggerated increases in filling pressures during exercise²⁴. Indeed, invasive hemodynamics obtained via right heart catheter studies have reported left ventricular filling pressures (measured using pulmonary arterial wedge pressure) of 17 mmHg at rest, increasing to 30 mmHg at peak exercise²⁴, whereas healthy adults typically report resting and exercising pressures of 10 mmHg and 17mmHg, respectively^33,34.

While ATTRwt is most associated with diastolic dysfunction, echocardiography reveals systolic dysfunction as a pathologic feature of ATTRwt, which may contribute to reduced ejection fraction²². Global longitudinal strain (GLS) is a highly sensitive echocardiographic metric that is abnormal in 88% of ATTRwt at diagnosis and allows for the detection of systolic dysfunction even before left ventricular ejection fraction declines³⁵. GLS has also been identified as a strong prognostic marker in ATTRwt, irrespective of ATTR-modifying pharmacotherapy³⁵. Despite preserved ejection fraction, longitudinal systolic dysfunction reduces stroke volume and maximal cardiac output, thereby further limiting exercise capacity in ATTRwt³⁵.

Atrial remodeling further amplifies the functional consequences of ventricular systolic and diastolic dysfunction. Left atrial enlargement and dysfunction are common in HFpEF, typically arising secondary to the backward transmission of chronically elevated ventricular filling pressures^29,36. In ATTRwt, however, direct amyloid involvement of the atrial myocardium may exacerbate atrial mechanical dysfunction, limiting atrial contribution to ventricular filling during exercise and increasing susceptibility to atrial arrhythmias³⁷. Collectively, these ventricular and atrial abnormalities limit stroke volume augmentation and cardiac output during physical activity, likely contributing to early onset dyspnea and fatigue and severe exercise intolerance^35,37. While disease-related changes in cardiac function have been well-characterized in ATTRwt, mechanistic investigations that directly evaluate the contribution of exercise-induced augmentations in cardiac output to increases in V̇O2 are lacking and should be explored.

Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction (CMD) describes structural and functional alterations which affect the coronary microcirculation³⁸ that can lead to myocardial ischemia, angina, and cardiac dysfunction³⁹. CMD is highly prevalent in patients with HFpEF and occurs independent of obstructive coronary artery disease⁴⁰. CMD in HFpEF is believed to be related to comorbidity-induced increases in systemic inflammation, endothelial dysfunction, and fibrosis²⁹.

More recent evidence demonstrates that CMD is also highly prevalent in ATTRwt and is likely related to amyloid involvement of the myocardial space and coronary vessels⁴¹. Indeed, amyloid deposits have been identified in the interstitium surrounding the cardiac myocytes, the perivascular space, and in the media of the coronary vasculature⁴¹, and is believed to have cytotoxic effects that directly damage endothelial cells^42,43. Dorbala and colleagues found that coronary vasomotor function, quantified by PET/CT-derived myocardial blood flow, was impaired both at rest (0.59 ± 0.15 vs. 0.88 ± 0.23 ml/g/min, P = 0.004) and under vasodilator stress (0.85 ± 0.29 vs. 1.85 ± 0.45 vs. ml/min/g, P < 0.0001) in patients with ATTR compared with subjects with hypertensive LV hypertrophy⁴¹. Interestingly, this study also demonstrated that CMD was nearly universal in the ATTR cohort and was associated with amyloid burden, as quantified by LV mass⁴¹, suggesting that these amyloid-related morphologic changes are related to CMD in this patient population.

From a physiological standpoint, CMD has important implications for exercise tolerance in ATTRwt. During exercise, the ability to augment myocardial blood flow is essential for supporting increases in heart rate and diastolic and contractile performance^39,40. Impaired coronary microvascular function may therefore promote myocardial ischemia during physical stress, further limiting diastolic filling and attenuating stroke volume reserve^39,40. These ischemia-related constraints on ventricular performance likely interact with restrictive mechanics to exacerbate reductions in maximal cardiac output, thereby contributing to exercise intolerance in ATTRwt.

AUTONOMIC DYSFUNCTION

Upon initiation of exercise, the autonomic nervous system (encompassing parasympathetic and sympathetic branches) rapidly modulates cardiac output via elevations in heart rate and LV contractility and elicits systemic vasoconstriction⁴⁴. The integrated effects of increased cardiac output and peripheral vasoconstriction, together with local vasodilatory and sympatho-inhibitory mechanisms within exercising skeletal muscle, are essential for matching oxygen delivery to metabolic demand while maintaining adequate arterial blood pressure⁴⁴. Consequently, autonomic dysregulation can impair the ability to appropriately augment cardiac output and regulate vascular tone during exercise, resulting in exercise-induced hypotension, impaired oxygen delivery, and reduced perfusion of active skeletal muscle^16,45–54. Clinically, these abnormalities may manifest as exercise intolerance, exertional fatigue, and early volitional exhaustion.

Chronotropic Incompetence.

Chronotropic incompetence refers to the inability of the heart to increase rate in proportion with increased activity during either maximal or submaximal exercise⁵⁵. Appropriate autonomic modulation of heart rate during exercise is essential for matching cardiac output to meet the elevated metabolic demands of exercise⁵⁶. Consistent with the Fick principle, heart rate responsiveness is a primary determinant of increases in VO₂, such that disease-related impairments in heart rate augmentation can substantially limit exercise capacity.

Chronotropic incompetence is typically diagnosed by the inability to achieve at least 80% of age predicted maximal heart rate during exercise testing⁵⁶ and has been identified in a range of cardiovascular and neurodegenerative diseases including hypertension⁵⁷, coronary artery disease⁵⁶, HFrEF⁵⁵, HFpEF^56,58, and Parkinson’s Disease⁵⁹. In the context of HF where stroke volume reserve is limited^60,61, patients have a greater reliance on heart rate responsiveness, including both maximal heart rate and heart rate reserve, to achieve appropriate increases in cardiac output⁵⁶. In a study of 332 patients with ATTRwt, Patel and colleagues reported a high prevalence of chronotropic incompetence during cardiopulmonary exercise testing (CPET), independent of cardiac amyloid burden and rate-limiting drug use (e.g., β-blockers)¹². Findings from this investigation suggest that both the prevalence and the severity of chronotropic incompetence are greater than that observed in HF of non-amyloid etiologies and that chronotropic incompetence is one of the primary mechanisms underlying functional impairment in patients with ATTRwt.

The cause of chronotropic incompetence in ATTRwt has yet to be fully elucidated. However, studies in other HF and neurodegenerative populations as well as emerging evidence regarding disease-related changes in autonomic function in ATTRwt may provide insight into possible mechanisms underlying these impairments in heart rate responsiveness. First, we will consider the role of amyloid-mediated nerve fiber damage and loss. Recent case reports have identified ATTRwt deposition in the epineurium, endoneurium⁶, and epineurial vessels^6,62 of peripheral nerves which may result in direct nerve fiber damage or disrupt blood-nerve barriers, contributing to damage and rarefaction of peripheral nerve fibers^43,63. Using meta-iodobenzylguanidine (MIBG) scintigraphy and tomographic imaging techniques, Gimelli and colleagues identified cardiac sympathetic denervation in patients with ATTRwt which tended to worsen in parallel with amyloid burden, albeit this relationship did not reach statistical significance⁶⁴. Therefore, disruptions in cardiac sympathetic innervation may be a key factor underlying chronotropic incompetence in this disease population, affecting peak heart rate and heart rate responsiveness during exercise.

Disease-related changes in cardiac β-adrenergic receptor signaling may also be a pathologic factor contributing to impaired heart rate responsiveness. Indeed, patients with HF have been shown to have reduced heart rate responsiveness to norepinephrine infusion compared with healthy control subjects⁶⁵, suggestive of postsynaptic β-adrenergic receptor desensitization. Additionally, an in vitro study demonstrated a 50–56% reduction in β-adrenergic receptor density in the left ventricles of cardiac transplant patients compared with left ventricles of their prospective donors⁶⁶. Collectively, this evidence suggests that both disease-related reductions in cardiac β-receptor sensitivity and density may contribute to attenuations in the autonomic modulation of heart rate in ATTRwt. While this has yet to be investigated, a recent study from our group demonstrated that heart rate responsiveness to a sympathoexcitatory stimulus (lower-body negative pressure-induced central hypovolemia) was not different between patients with ATTRwt and non-amyloid HF controls, suggesting that disease-related changes in cardiac β-receptor function may be similar in these patient populations⁶⁷. However, more mechanistic investigations of cardiac β-adrenergic receptor sensitivity in ATTRwt are warranted.

Finally, the potential role of disease-related changes in parasympathetic (cardiovagal) nervous system function to exercising heart rate responses in ATTRwt should also be considered. The Valsalva maneuver is a standardized test in which a person forcefully exhales against a closed glottis (typically by blowing into a manometer at ~40 mmHg for 15 seconds), producing predictable changes in heart rate and blood pressure, mediated by the autonomic nervous system. The Valsalva ratio is calculated as the longest R-R interval (or lowest heart rate) after release of the maneuver divided by the shortest R-R interval during strain (or highest heart rate), and is used as an index of parasympathetic cardiac autonomic function, with lower ratios suggesting impaired vagal control⁶⁸. A recent study by Kleinveld et al. demonstrated that 83% of ATTRwt patients exhibited a pathological Valsalva ratio compared with 30% of healthy control subjects⁷. Additionally, two-thirds of the ATTRwt cohort displayed an abnormal expiration-inspiration difference during the deep breathing test⁷. Collectively, these results are suggestive of cardiac parasympathetic dysfunction and implicate dysregulation of cardiovagal outflow as a pathological factor that may contribute to impaired heart rate responsiveness during exercise in patients with ATTRwt.

Sympathetic Vasomotor Dysregulation.

The sympathetic nervous system plays a critical role in the modulation of vascular tone to mediate increases in blood pressure and aid in the redirection of blood flow to the exercising skeletal muscle⁶⁹. Disruptions in this signaling due to disease-related changes in sympathetic activation, sympathetic denervation, or vascular α-adrenergic receptor sensitivity may have critical impacts on exercise hemodynamics.

While neural control of the circulation during exercise has yet to be evaluated in ATTRwt, one study showed that circulating norepinephrine levels are greater in patients with ATTRwt than HF of non-amyloid etiology⁷⁰. While this was not a direct measurement of sympathetic activity (such as muscle sympathetic nerve activity), it is suggestive of greater basal neurohormonal activity in patients with ATTRwt, even compared to a HF population^71,72, which may exaggerate sympathetic restraint of limb blood flow during exercise. In contrast, other investigations point to the possibility of amyloid-mediated attenuations in sympathetic vasoconstrictor signaling. As described above, amyloid involvement of neural tissues may result in rarefaction of peripheral nerves⁴³, thus disrupting vasoconstrictor signaling. Koike et al. demonstrated that ATTRv patients with neuropathy exhibited abnormal decreases in total peripheral resistance (TPR) during a sympathoexcitatory head-up tilt test (TPR increased in all healthy control subjects), however, these patients showed exaggerated responsiveness to a low-dose, intravenous norepinephrine infusion, as determined by changes in systolic blood pressure⁷³. Collectively, this suggests that denervation of peripheral sympathetic efferent nerve fibers may, rather than reduced α-adrenergic receptor sensitivity may impair appropriate vasoconstrictor responsiveness in ATTRv. However, this has yet to be demonstrated in patients with ATTRwt. Because systemic vasoconstriction plays a key role in the redirection of blood flow toward the active skeletal muscle^44,74, impairments in α-adrenergic signaling may also have deleterious effects on exercise capacity.

While disease-related changes in sympathetic vasoconstriction during exercise has not been evaluated in ATTRwt, emerging evidence from our group shows that sympathetic vasomotor responsiveness to a sympathoexcitatory stimulus (lower-body negative pressure-induced hypovolemia) is impaired in patients with ATTRwt compared with non-amyloid HF controls, as demonstrated by attenuated reductions in peripheral blood flow⁶⁷. Although this study did not directly assess the relationship between amyloid involvement of peripheral nerves and vasomotor responsiveness, complementary evidence supports a link between nerve damage and autonomic dysfunction in ATTRwt. Indeed, Campagnolo and colleagues found that of a small cohort of ATTRwt patients, 50% (8/16) met the criteria for orthostatic hypotension, all of which concomitantly presented with an abnormal Neuropathy Impairment Score (NIS), supporting a potential link between nerve damage and neurogenic orthostatic in ATTRwt⁷⁵. Consistent with these findings, a recent investigation demonstrated that patients with ATTRwt exhibit abnormalities in blood pressure counter-regulation during the Valsalva maneuver⁷, supporting the notion of impaired sympathetic vasomotor control.

In summary, autonomic dysfunction appears to represent an important and underrecognized contributor to exercise intolerance in patients with ATTRwt. Although direct assessments of neural control during dynamic exercise are lacking, available evidence suggests heightened basal sympathetic activity, impaired vasoconstrictor responsiveness, and peripheral nerve involvement that may disrupt appropriate blood flow redistribution during physical stress in this patient population.

PULMONARY HYPERTENSION AND RV DYSFUNCTION

Pulmonary hypertension (PH) is a pathophysiological condition characterized by elevated mean pulmonary arterial blood pressure. Elevated pulmonary pressures increase pulmonary vascular resistance and right ventricular (RV) afterload, limiting pulmonary blood flow⁷⁶ and contributing to RV strain and impaired contractile reserve^77,78. In response to cardiopulmonary stressors, such as exercise, PH and RV dysfunction result in ventilation-perfusion mismatch⁷⁹, early exertional dyspnea, and reduced physical capacity⁷⁶. PH and RV dysfunction are hallmarks of HF, particularly the HFpEF phenotype^80,81 and has been associated with reductions in peak oxygen consumption, exercise intolerance, and survival^76,82–84.

Recent studies have sought to characterize PH in ATTRwt pathophysiology. Current estimates regarding the prevalence of PH tend to be higher in ATTRwt (73–90%^85–87) compared with HFpEF (30–88%^82,88,89) cohorts, although these were not direct comparisons. Evidence also demonstrates that the severity of exercise-induced PH, quantified by changes in the mean pulmonary artery pressure/cardiac output slope is higher in patients with ATTRwt (7.2 mmHg/L/min²⁴) compared with healthy (1.8 mmHg/L/min⁸⁰), HFpEF (3.7 mmHg/L/min⁸⁰), and HFrEF (3.5 mmHg/L/min⁸⁰) cohorts. The predominant PH phenotype in ATTRwt is isolated postcapillary PH, although combined pre- and post-capillary PH has also been observed⁸⁶. This postcapillary phenotype predominance suggests that in ATTRwt, PH and RV remodeling are typically secondary to cardiac involvement, wherein elevated LV filling pressures are transmitted backward to the pulmonary circulation and RV^90,91.

In contrast to non-amyloid HFpEF, where PH largely reflects functional and hemodynamic abnormalities⁹², ATTRwt may additionally involve structural pulmonary vascular remodeling secondary to amyloid deposition⁹³, further limiting pulmonary blood flow during exercise. Indeed, a recent autopsy study observed amyloid deposition in the media of the pulmonary blood vessels of a patient with ATTRwt⁹³. These TTR deposits may mechanically stiffen the vessels and vasodilatory capacity in response to increased blood flow during exercise, thereby increasing resistance. Elevated pulmonary vascular resistance can result in an under-perfusion of the lung, effectively increasing physiologic dead space and contributing to ventilation-perfusion mismatch⁷⁹. Additionally, exercise-induced increases in arterial pressure and cardiac output may further elevate pulmonary pressures beyond those observed at rest, resulting in interstitial edema⁹⁴. The development of pulmonary edema, in conjunction with pulmonary amyloid deposits, likely impairs gas exchange by increasing diffusion distance, and worsens ventilation-perfusion mismatch⁹⁴.

Large studies have also demonstrated that RV dysfunction is common in ATTRwt and a strong predictor of hospitalization and mortality in this population^91,95,96. Impairments in contractile function result in the inability of the RV to overcome elevated afterload imposed by PH, creating an imbalance of RV contractile function and elevated RV afterload due to PH known as “right ventricular-pulmonary artery (RV-PA) uncoupling”⁹¹. Beyond isolated RV systolic dysfunction, impaired RV-PA coupling represents a critical and underappreciated mechanism contributing to exercise intolerance in ATTRwt. The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, is evaluated using echocardiography and is a common measure of RV-PA coupling. Studies in older healthy cohorts demonstrate TAPSE/PASP ratios >0.60, whereas values of < 0.40 have been consistently reported in at least one-third of ATTR cohorts^97,98 and indicates that the RV is unable to maintain output against elevated afterload⁹⁹ in a relatively large proportion of this patient population.

Collectively, impaired RV-PA coupling and reduced RV contractile reserve may substantially hinder cardiac output reserve during exercise, thereby contributing to exertional dyspnea and severe exercise intolerance in this population.

VENTILATORY INEFFICIENCY

Ventilatory inefficiency refers to a disproportionate ventilatory response relative to metabolic demand and is represented by the slope of minute ventilation (V̇E) to carbon dioxide production (V̇CO₂), with higher values indicating lower efficiency^100,101. In HF, ventilatory inefficiency reflects impaired cardiac output and abnormal pulmonary hemodynamics leading to ventilation–perfusion mismatch, along with heightened chemoreceptor sensitivity and an exaggerated exercise pressor reflex that augments neural drive to breathe^102,103. As a result, patients must ventilate disproportionately more to eliminate carbon dioxide, even at low workloads. This excessive ventilatory demand directly contributes to respiratory muscle fatigue and pronounced dyspnea, ultimately manifesting as marked exercise intolerance and reduced functional capacity¹⁰⁴.

A recent systematic review and meta-analysis from Willixhofer and colleagues demonstrates that across five studies and 656 patients, individuals with ATTRwt have a mean V̇E/V̇CO₂ slope of 38.4 (CI: 36.9–40.0)¹⁰¹ indicative of impaired ventilatory efficiency (defined as a V̇E/V̇CO₂ > 34)¹⁰⁵. Further, the authors found that the degree of ventilatory inefficiency in ATTRwt was consistently higher than those observed in other forms of HF^11,101,106. Notably, a separate investigation found that ATTRwt patients with V̇E/V̇CO₂ > 40 had a median survival of 38.54 months (95% CI: 32.63–51.47) compared with 88.69 months (95% CI: 56.26–89.49) in patients with V̇E/V̇CO₂ slope ≤ 40, which supports the use of ventilatory efficiency as a powerful prognostic marker in this patient population. Collectively, large-scale studies indicate that ventilatory inefficiency is both more prevalent and more severe in ATTRwt compared with other forms of HF, and that it is independently predictive of mortality, underscoring the critical role of ventilatory dysregulation in ATTRwt pathology¹⁰⁰.

There are several possible pathological mechanisms, including amyloid infiltration of the lung tissues, increased physiologic dead space, and autonomic dysregulation, that may contribute to impaired ventilatory efficiency in ATTRwt. In a study by Eggleston and colleagues, pulmonary function testing revealed that out of twenty-one patients with ATTR, about half presented with restrictive or obstructive lung disease demonstrated by impairments in percent predicted forced vital capacity and diffusing capacity of lung for carbon monoxide (DLCO), respectively¹⁰⁷. This study also showed that in a smaller subset of these participants, eight out of nine (89%) of patients presented with multifocal or diffuse pulmonary vascular involvement on lung biopsy, suggesting that amyloid infiltration of the pulmonary tissues likely plays a role in the development of lung diseases in ATTRwt¹⁰⁷.

Ventilatory inefficiency in ATTRwt may also be related to the influence of autonomic dysregulation. In HF, derangements in chemoreceptor sensitivity and/or exercise pressor reflex responses can result in exaggerated ventilatory drive^102,103. While the functionality of these reflexes have not been evaluated in ATTRwt, a recent study by Monfort and colleagues demonstrated that in patients with ATTRv, ventilatory responses during metaboreflex activation (post exercise muscle ischemia) were elevated compared with controls¹⁰⁸, suggesting that ventilatory component of the metaboreflex is exaggerated in amyloidosis-related HF.

Additionally, it has been proposed that heightened ventilatory responses may be a compensatory mechanism against baroreflex dysfunction^12,109. Bernardi and colleagues demonstrated in patients with primary amyloidosis, another predominant form of cardiac amyloidosis, blood pressure remained relatively stable during head up tilt despite reduced autonomic modulation of vascular resistance¹⁰⁹. Additionally, they found that these patients displayed a persistent hyperventilatory response, as indicated by reduced end-tidal carbon dioxide, and that the breathing rate was inversely correlated with tilting-induced changes in blood pressure. Collectively, this evidence suggests that hyperventilation may compensate for impaired baroreflex control of arterial blood pressure in other forms of cardiac amyloidosis¹⁰⁹. Considering the parallels between ATTRwt and these other cardiac amyloidosis phenotypes, future studies evaluating mechanisms of neural ventilatory control in ATTRwt are warranted.

Importantly, regardless of the contributing mechanisms, impairments on ventilatory efficiency may have several consequential effects on exercising limb blood flow. Firstly, ventilatory inefficiency may contribute to elevated blood flow demand by the respiratory muscles, thus requiring a greater proportion of cardiac out that otherwise could have been distributed to the exercising limbs^104,110. Additionally, fatiguing respiratory muscle contractions may also result in metaboreflex-mediated increases in sympathetic vasoconstrictor activity in the exercising limbs, further compromising exercising limb blood flow and oxygen delivery^104,111.

In summary, ventilatory inefficiency is a prominent and prognostically important feature of ATTRwt that reflects the combined effects of abnormal pulmonary hemodynamics, amyloid involvement of pulmonary tissues, and autonomic dysregulation. These abnormalities impose an excessive ventilatory burden during exercise, contributing to dyspnea, respiratory muscle fatigue, impaired limb blood flow, and severe exercise intolerance.

OTHER CONSIDERATIONS

Mitochondrial Dysfunction.

Aerobic exercise capacity is fundamentally dependent on the ability of skeletal muscle mitochondria to utilize oxygen for ATP production¹¹², Accordingly, both HFpEF and HFrEF cohorts have demonstrated reductions in V̇O_2peak that are strongly associated with impaired skeletal muscle mitochondrial oxidative capacity^113,114. Surprisingly, despite well-documented exercise intolerance in ATTRwt, direct assessments of skeletal muscle mitochondrial function are largely absent. To date, only one study has evaluated mitochondrial oxidative phosphorylation capacity in patients with ATTRwt, using high-resolution respirometry of endomyocardial biopsy specimens. The authors reported that myocardial mitochondrial oxidative phosphorylation capacity declined with increasing disease severity and was associated with greater left ventricular amyloid burden, suggesting that amyloid deposits may directly impact cardiomyocyte mitochondrial function¹¹⁵. However, studies have yet to explore whether impairments in peripheral (skeletal muscle) oxidative metabolism represent an important mechanism underlying reduced aerobic capacity in ATTRwt. Furthermore, because mitochondrial oxidative capacity is highly dependent on adequate oxygen delivery, impairments in skeletal muscle perfusion and mitochondrial function may interact to further limit oxygen utilization during exercise in ATTRwt. Thus, the relationship between skeletal muscle oxygen delivery and utilization represents a potentially important contributor to exercise intolerance in ATTRwt and should be explored.

Peripheral Vascular Dysfunction.

Peripheral vascular dysfunction is characterized by impaired regulation of vascular tone, and may be mediated by endothelial dysfunction, vascular smooth muscle cell dysfunction, arterial stiffening, or dysregulation of autonomic control of the vasculature. In addition to central cardiac impairments, peripheral vascular dysfunction is recognized as a hallmark of HF pathophysiology and has been associated with increased symptom burden²⁰ and reduced limb blood flow during exercise^116,117 in this population.

Peripheral vascular dysfunction in HF may be related, in part, to derangements in redox balance, leading to reduced nitric oxide (NO) bioavailability through endothelial nitric oxide synthase (eNOS) uncoupling, direct NO scavenging, and depletion of essential eNOS cofactors^118–123. However, irrespective of HF development, amyloid involvement of the peripheral vasculature may affect vascular reactivity in ATTRwt. Studies have identified amyloid deposition in the blood vessel walls and in the extravascular space^124,125. Additionally, TTR fibrils have been demonstrated to have cytotoxic effects, likely mediated through increases in reactive oxygen species and oxidative stress^63,126,127, and cause endothelial damage^43,63. Therefore, vascular amyloid deposits may directly result in endothelial cell damage and impaired vasoreactivity, with potential ramifications for vascular control at rest and during exercise.

Surprisingly, using brachial artery flow-mediated dilation (FMD), a measure of endothelial-dependent vasodilation in a conduit artery, several investigations have demonstrated that vascular endothelial function is preserved in patients with ATTRwt compared with age-matched or comorbidity-matched controls^128–130. While the FMD test has been widely described as providing a bioassay for NO availability^131–133, this vascular assessment is performed at rest in a conduit vessel, and thus responses do not reflect the complex regulatory pathways that govern exercise hyperemia in the skeletal muscle microcirculation. Indeed, during exercise, microvasculature vasodilation is the primary determinant of the hyperemic response^134,135, suggesting that measures of microvascular function may be more relevant for assessing the contribution of vascular dysfunction to exercise intolerance. Interestingly, several investigations consistently support the presence of microvascular dysfunction in coronary and retinal vascular beds in patients with ATTRwt^41,128,136. Zampiccoli et al. reported that patients with cardiac amyloidosis exhibited impairments in retinal microvascular function, as determined by flicker-induced dilation, while brachial artery FMD was preserved, compared with healthy controls¹²⁸. Collectively, evidence suggests that ATTRwt pathology may affect the microvascular circulation to a greater degree than the conduit arteries. However, there is a paucity of data regarding microvascular function in the exercising limbs of patients with ATTRwt, and thus remains an unexplored potential contributor to exercise intolerance in this patient population.

Altered mechanical properties of the peripheral vasculature, including increased arterial stiffness, contributes to peripheral vascular dysfunction by limiting the ability of blood vessels to appropriately dilate and buffer pulsatile blood flow¹³⁷. Consequently, arterial stiffness contributes to increased vascular resistance, reduced microvascular perfusion, and ultimately, impairs skeletal muscle perfusion and exercise intolerance^137,138.

While investigations in this area are limited, one study reported that carotid-femoral pulse wave velocity (a measure of aortic stiffness¹³⁹) and augmentation index (a measure of how much reflected pressure waves increase the heart’s workload by calculating the ratio of the reflected wave to the total pulse pressure¹⁴⁰) were not different between ATTRwt and controls, suggesting that central arterial stiffness and wave reflections are not altered in ATTRwt¹²⁹. The same study found that central (aortic) systolic (111 mmHg vs. 128 mmHg, p < 0.001) and diastolic (67 mmHg vs. 73 mmHg, p = 0.007) blood pressures, measured using radial artery tonometry, were lower in patients with ATTRwt compared with age- and sex-matched controls¹²⁹. While lower central blood pressures may suggest reductions in ventricular afterload and vascular compliance, it is possible that disease-related reductions in stroke volume and cardiac output contributed to these findings, rather than changes in the peripheral circulation¹²⁹. While studies have not directly linked lower aortic blood pressure to exercise intolerance in ATTRwt, reduced central blood pressures can potentially decrease perfusion pressure and elicit arterial baroreceptor-mediated peripheral vasoconstriction, both of which may diminish skeletal muscle blood flow^141,142. Therefore, future investigations should explore the contribution of altered central blood pressures in exercise intolerance in patients with ATTRwt.

Musculoskeletal Manifestations.

Due to amyloid involvement of soft tissues (e.g. tendons and ligaments), another unique aspect of ATTRwt phenotype is the prevalence of musculoskeletal manifestations¹⁴³. Carpal tunnel syndrome is the most common musculoskeletal symptom, estimated to affect over 50% of patients with ATTRwt^144,145 and frequently occurring 5–15 years before cardiac symptoms¹⁴⁶. Spinal stenosis is another common manifestation of ATTRwt. Interestingly, Godara and colleagues found that 43 out of 324 patients undergoing spinal stenosis surgery, 13% had ATTR deposition in the ligamentum flavum, a vertebral connective tissue¹⁴⁷, highlighting the prevalence of this musculoskeletal symptom in ATTRwt. Orthopedic symptoms are also present in the lower limbs, as total knee and hip arthroplasties are 3–5 times more common in patients with ATTR compared with age-matched controls¹⁴⁸.

These frequently occurring musculoskeletal manifestations can contribute to immobility and limited capacity to perform physical tasks, and ultimately, a sedentary lifestyle^149,150. Over time, inactivity leads to cardiovascular and skeletal muscle deconditioning, which can result in worsened exercise intolerance and avoidance, feeding into a vicious cycle of inactivity and cardiovascular and skeletal muscle deterioration¹⁵¹. Thus, frequently occurring musculoskeletal manifestations in ATTRwt directly limit mobility and physical activity, promoting deconditioning that compounds central cardiopulmonary limitations and worsens exercise intolerance.

STRATEGIES FOR IMPROVING EXERCISE TOLERANCE IN ATTRwt

Given the ubiquitous presentation of exercise intolerance in patients with ATTRwt and its substantial impact on quality of life and mortality, there is considerable interest in investigating interventions to improve these outcomes. While a substantial body of literature exists exploring potential interventions to improve functional capacity in other forms of HF^14,152–156, much less data is available specific to the ATTRwt phenotype. Although findings from HFpEF- and HFrEF-specific studies may provide insight into potential interventions to improve exercise capacity in amyloid-related HF^157,158, this review will focus on the evidence specific to ATTRwt (Fig. 2). Typical outcomes for studies evaluating strategies for improving exercise tolerance include functional measures, such as peak oxygen consumption (V̇O_2peak) during cardiopulmonary exercise testing (CPET) and 6-minute walk distance (6MWD), or more subjective, but validated, assessments, such as symptom-based questionnaires.

CPET-derived V̇O_2peak is widely utilized toolto evaluate aerobic fitness because it provides a direct, quantitative measure of the integrated cardiovascular, pulmonary, and muscular response to exercise, with high reproducibility and sensitivity to physiological change^159,160. Several studies have demonstrated V̇O_2peak as a robust prognostic marker in patients with ATTRwt¹⁶¹. These investigations also consistently demonstrate that V̇O_2peak is significantly impaired in patients with ATTRwt, with studies commonly reporting a mean V̇O_2peak of 14–16 mL/kg/min^12,162, as compared to 22–39 mL/kg/min in similarly aged healthy cohorts^163,164. Relevant to this aging population, the minimal aerobic power associated with functional independence is estimated to be around 15–18 mL/kg/min¹⁶³.

6MWD is another prognostic functional marker in ATTR, with a 6MWD of <350 m having been shown to be associated with about a 3-fold risk for all-cause mortality in this patient population¹⁶⁵. While 6MWD is a less physiologically specific measure than CPET-derived V̇O_2peak, it may be more reflective of functional activities of daily living and is less resource-intensive, making it a practical measure for routine clinical and research use¹⁶⁶.

Symptom-based questionnaires such as the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) have also been validated in ATTR¹⁶⁷ and are commonly used in clinical trials as a tool to evaluate symptom improvement and functional status. These subjective symptom-based questionnaires add important patient-centered information regarding perceived dyspnea, fatigue, and quality of life, capturing dimensions of functional capacity status not always reflected by more objective testing, such as V̇O_2peak and 6MWD. However, they are more susceptible to placebo effects, recall bias, and variability in patient perception¹⁶⁸.

Pharmacotherapeutics.

While treatment for HFrEF and HFpEF mainly involves treating underlying comorbidities and managing symptoms with pharmacologic and exercise/lifestyle changes, several disease-modifying pharmacotherapies have been developed to prevent TTR destabilization and dissociation (TTR stabilizers) and target hepatic TTR production (TTR gene silencers) to inhibit TTR amyloid fibril deposition, with demonstrated mortality benefit^169–171.

TTR stabilizers, such as acoramidis and tafamidis, have been shown to prevent declines in 6MWD and KCCQ-12 scores^172–175. A study from Shibata et al. demonstrated that six months of treatment with tafamidis preserved V̇O_2peak, peak heart rate, and V̇E/V̇CO₂, suggesting that TTR stabilizers may prevent the decline in markers of exercise capacity, dysautonomia, and ventilatory efficiency, although the lack of a control group precludes the determination of a causal effect¹⁶¹. Interestingly, this study also demonstrated that participants who showed an improvement in V̇O_2peak had a lower baseline (13.7 ± 3.1 mL/kg/min) compared with participants who did not exhibit improvements in peak aerobic performance (17.7 ± 4.1 mL/kg/min; P = 0.009), suggesting that tafamidis may have the most beneficial effects on exercise tolerance in those with low initial tolerance¹⁶¹. TTR gene silencers, including vutrisiran and patisiran, have also showed promise in improving functional capacity, with findings from the HELIOS-B and APOLLO-B trials demonstrating that vutrisiran and patisiran, respectively, preserve 6MWD and KCCQ-12 scores versus placebo^176,177. Thus, like TTR stabilizers, gene-silencing therapies appear to exert clinically meaningful benefits on functional outcomes, underscoring their role in mitigating exercise intolerance in ATTRwt.

While these ATTR pharmacotherapies have demonstrated benefits in slowing functional decline, future studies are needed to elucidate the mechanisms by which ATTRwt-modifying therapies influence cardiac performance, pulmonary function, autonomic regulation, and vascular function, and how these effects translate into meaningful improvements in exercise capacity in this unique HF population.

In addition to ATTR-modifying therapies, optimization of heart failure (HF) medications is critical for improving exercise tolerance in this patient population. Although β-blockers have demonstrated mortality benefits in HFrEF^178,179, evidence supporting their use in HFpEF remains inconsistent^180–182. In patients with ATTRwt, discontinuation of non-selective β-blockers has been associated with improved survival¹⁸³. Furthermore, β-blockers are often poorly tolerated in this population, with up to 43% of patients discontinuing therapy because of worsening HF symptoms, including profound hypotension, syncope, and fatigue¹⁸³. This poor tolerability is likely related to exacerbation of chronotropic incompetence and autonomic dysfunction¹⁸⁴, both hallmark features of ATTRwt that contribute to reduced functional capacity. Consequently, reducing or discontinuing β-blocker therapy may be appropriate in selected patients with ATTRwt¹⁸⁴ and could potentially improve physical capacity.

Additional HF-directed therapies include mineralocorticoid receptor antagonists (MRAs) and loop diuretics for the management of fluid overload. Careful control of volume status is essential for alleviating symptoms of pulmonary congestion, such as dyspnea, while maintaining adequate preload through modulation of filling pressures¹.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have also emerged as a promising HF therapy and have been associated with improved functional capacity¹⁸⁵ and reduced hospitalization and mortality risk in patients with ATTRwt¹⁸⁶. Recent evidence further suggests that SGLT2i may improve exercise capacity in ATTRwt, particularly among patients with lower baseline functional capacity¹⁸⁷. Collectively, optimization of heart failure therapy is essential in ATTRwt, with evidence suggesting that reducing poorly tolerated β-blockers and incorporating therapies such as MRAs, diuretics, and SGLT2 inhibitors may improve symptoms, exercise capacity, and clinical outcomes.

Exercise Training Interventions.

Exercise training represents a promising nonpharmacological strategy to improve exercise tolerance in ATTRwt by targeting peripheral and autonomic limitations that contribute to impaired cardiovascular reserve during physical activity. Thus, exercise training may provide a targeted means of improving functional capacity beyond pharmacologic therapy alone.

Randomized controlled trials demonstrate that aerobic exercise training, including continuous moderate-intensity training and high-intensity interval training, improves peak oxygen consumption, submaximal exercise capacity, and quality of life in patients with HFpEF^188–193. Notably, evidence suggests that improvements in exercise capacity following aerobic exercise training are attributed primarily to improvements in peripheral mechanisms rather than changes in resting cardiac structure¹⁹⁴. Indeed, Haykowski et al. demonstrated that in patients with HFpEF, exercise training-induced changes in peak cardiac output only accounted for 16% of the observed improvements in V̇O_2peak, thus 84% of improvements in achieved V̇O_2peak were attributed to non-cardiac factors, such as improved microvascular and/or skeletal muscle function¹⁹⁴. Resistance training in HFpEF populations further enhances skeletal muscle composition and functional capacity by improving muscle strength, mass, and neuromuscular efficiency, thereby supporting greater tolerance for both daily activities and aerobic exercise¹⁹⁵.

Given the substantial physiological overlap between ATTRwt and non-amyloid HFpEF, particularly with respect to impaired diastolic reserve and limited cardiac output augmentation during exercise^20,26,196, similar training-induced adaptations may be achievable in ATTRwt. Thus, while direct evidence remains limited, exercise training is likely to be feasible and beneficial in ATTRwt when appropriately tailored to disease severity and comorbidities¹⁹⁷. However, when considering the potential for exercise-based therapies, it is important to also consider the unique, extra-cardiac manifestations of ATTRwt that may hinder the ability of these patients to participate in an exercise training program. As discussed earlier, ATTRwt is characterized by the high prevalence of musculoskeletal manifestations, including carpal tunnel syndrome, spinal stenosis, biceps tendon rupture, trigger finger, and knee, hip, and shoulder arthropathies, which may severely limit functional ability¹⁴³. Additionally, sensorimotor dysfunction may significantly hinder exercise by causing muscle weakness, poor balance, numbness, and limited dexterity¹⁹⁸. Collectively, given the unique aspects of ATTRwt pathology discussed throughout this review, studies examining the impact of exercise training on functional capacity in this specific amyloidosis-related HF is warranted and ongoing trials¹⁹⁷ will be critical for defining efficacy and best practices in this population.

CONCLUSIONS

Exercise intolerance is a defining physiological limitation in ATTRwt and reflects the combined effects of cardiac, vascular, pulmonary, and autonomic dysfunction that constrain coordinated cardiopulmonary and vascular responses during physical stress. Amyloid infiltration of the myocardium produces a restrictive cardiomyopathy characterized by impaired ventricular compliance, limited stroke volume augmentation, and coronary microvascular dysfunction, all of which restrict cardiac output during exercise. These central limitations are further compounded by abnormalities in autonomic regulation, including chronotropic incompetence and dysregulated sympathetic vasomotor control, which impair heart rate responsiveness and appropriate redistribution of blood flow to active skeletal muscle. PH and ventilatory inefficiency further hinder maximal cardiac output and pulmonary gas transfer by increasing RV strain and exacerbating ventilation–perfusion mismatch. Together, these abnormalities elevate the metabolic cost of breathing and further limit systemic oxygen delivery during exertion. Additionally, musculoskeletal manifestations promote physical inactivity and likely contribute to deconditioning, amplifying functional impairment over time. Together, these interacting pathophysiological mechanisms converge to markedly impair exercise capacity in patients with ATTRwt.

While recent work has substantially advanced our understanding of the central and peripheral mechanisms limiting exercise capacity in ATTRwt, the role of peripheral vascular dysfunction in exercise intolerance remains incompletely defined. Given the established role of peripheral vascular dysfunction in limiting limb blood flow during exercise in other forms of HF, future studies should examine microvascular reactivity in ATTRwt, as this remains a poorly characterized aspect of the disease. Additionally, more information is needed regarding the impact of exercise-based therapies on physical function in patients with ATTRwt. Studies combining CPET with direct measures of autonomic and peripheral vascular function will be essential for defining therapeutic targets to restore exercise capacity in patients with ATTRwt.