Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis

Rishi K Patel; Francesco Bandera; Lucia Venneri; Aldostefano Porcari; Yousuf Razvi; Adam Ioannou; Liza Chacko; Ana Martinez-Naharro; Muhammad U Rauf; Daniel Knight; James Brown; Aviva Petrie; Ashutosh Wechalekar; Carol Whelan; Helen Lachmann; Vivek Muthurangu; Marco Guazzi; Philip N Hawkins; Julian D Gillmore; Marianna Fontana

doi:10.1001/jamacardio.2024.0022

. 2024 Mar 6;9(4):367–376. doi: 10.1001/jamacardio.2024.0022

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis

Rishi K Patel ¹, Francesco Bandera ^2,³, Lucia Venneri ¹, Aldostefano Porcari ^1,⁴, Yousuf Razvi ¹, Adam Ioannou ¹, Liza Chacko ¹, Ana Martinez-Naharro ¹, Muhammad U Rauf ¹, Daniel Knight ¹, James Brown ¹, Aviva Petrie ⁶, Ashutosh Wechalekar ¹, Carol Whelan ¹, Helen Lachmann ¹, Vivek Muthurangu ⁵, Marco Guazzi ^2,³, Philip N Hawkins ¹, Julian D Gillmore ¹, Marianna Fontana ^1,^✉

¹National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London, United Kingdom

²Cardiac Rehabilitation and Heart Failure Unit, Cardiology University Department, Scientific Institute for Research, Hospitalization and Healthcare MultiMedica, Sesto San Giovanni, Milan, Italy

³Department of Biomedical Sciences for Health, University of Milano, Milan, Italy

⁴Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina, University of Trieste, Italy, Trieste, Italy

⁵Institute of Cardiovascular Science, University College London, London, United Kingdom

⁶Eastman Dental Institute, University College London, University Street, London, United Kingdom

Accepted for Publication: December 26, 2023.

Published Online: March 6, 2024. doi:10.1001/jamacardio.2024.0022

^✉

Corresponding Author: Marianna Fontana, MD, PhD, National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, Pond Street, London, NW3 2QG, UK (m.fontana@ucl.ac.uk).

Author Contributions: Drs Patel and Bandera had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Patel and Bandera are co–first authors. Drs Gillmore and Fontana are co–last authors.

Concept and design: Patel, Bandera, Porcari, Wechalekar, Lachmann, Guazzi, Hawkins, Gillmore, Fontana.

Acquisition, analysis, or interpretation of data: Patel, Bandera, Venneri, Razvi, Ioannou, Chacko, Martinez-Naharro, Rauf, Knight, Brown, Petrie, Whelan, Lachmann, Muthurangu, Fontana.

Drafting of the manuscript: Patel, Bandera, Ioannou, Chacko, Petrie, Guazzi, Hawkins, Fontana.

Critical review of the manuscript for important intellectual content: Patel, Bandera, Venneri, Porcari, Razvi, Ioannou, Martinez-Naharro, Rauf, Knight, Brown, Wechalekar, Whelan, Lachmann, Muthurangu, Hawkins, Gillmore, Fontana.

Statistical analysis: Patel, Bandera, Porcari, Petrie, Fontana.

Obtained funding: Lachmann, Hawkins.

Administrative, technical, or material support: Patel, Razvi, Ioannou, Chacko, Martinez-Naharro, Brown, Lachmann, Muthurangu, Gillmore.

Supervision: Bandera, Venneri, Martinez-Naharro, Knight, Wechalekar, Whelan, Gillmore, Fontana.

Conflict of Interest Disclosures: Dr Knight reported grants from the British Heart Foundation during the conduct of the study and personal fees from Janssen Pharmaceuticals outside the submitted work. Dr Gillmore reported consulting fees from Alnylam, BridgeBio, AstraZeneca, Ionis, Attralus, Intellia, Lycia, and Pfizer outside the submitted work. Dr Fontana reported consulting fees from and/or serving on advisory boards for Attralus, Alnylam, Prothena, Akcea, Pfizer, Ionis, Intellia, Alexion, Novo Nordisk, Jannsen, AstraZeneca, Lexeo, and Cardior and research grants from Pfizer, Eidos, and Alnylam outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Fontana is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/21/33447). Dr Knight is supported by a British Heart Foundation Clinical Research Leave Fellowship (FS/CRLF/20/23004).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

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Corresponding author.

PMCID: PMC10918582 PMID: 38446436

Key Points

Question

What is the spectrum of functional phenotypes in transthyretin amyloidosis and how are they associated with amyloid burden?

Findings

This cohort study of 506 patients found that peak oxygen consumption, oxygen pulse, and ventilatory efficiency were impaired in cardiac phenotypes, while chronotropic incompetence and exercise oscillatory ventilation were prevalent across all phenotypes. Worsening amyloid burden was associated with decline in multiple cardiopulmonary exercise testing (CPET) parameters, and peak oxygen consumption and peak systolic blood pressure independently associated with prognosis.

Meaning

The findings indicate that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and in predicting outcomes.

This cohort study examines the use of cardiopulmonary exercise testing in evaluating patients with transthyretin amyloidosis.

Abstract

Importance

Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis.

Objective

To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis.

Design, Setting and Participants

This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months.

Main Outcomes and Measures

Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis.

Results

Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO₂], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO₂ and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO₂: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]).

Conclusions and Relevance

In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO₂, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Introduction

Transthyretin (ATTR) amyloidosis is a multisystem, life-threatening disease resulting from the deposition of transthyretin amyloid fibrils.^1,2,3 There are 2 distinct forms: hereditary or variant (ATTRv) amyloidosis, caused by pathogenic transthyretin mutations, and wild-type amyloidosis, where transthyretin accumulates in its wild-type form.^2,3 The phenotypic presentation of ATTRv amyloidosis can be predominantly neurologic (ATTR-PN), predominantly cardiac (ATTR-CM), or a mix of both (ATTR-mixed),^2,4 while ATTR wild-type presents almost exclusively with a cardiomyopathic phenotype.

Impaired physical performance is a hallmark of ATTR amyloidosis, with the 6-minute walk test being increasingly used as primary and secondary end points in recent clinical trials.^4,5 However, the 6-minute walk test provides a simple estimation of exercise tolerance, without insights into the functional phenotype. Cardiopulmonary exercise testing (CPET) is the gold standard for the evaluation of putative mechanisms that underlie exercise intolerance in heart failure,⁶ and CPET-derived indices of cardiovascular and respiratory limitation have repeatedly emerged as strong predictors of mortality.^7,8,9,10

Recent studies of CPET in amyloidosis have highlighted the clinical and prognostic significance of peak oxygen consumption (VO₂) and ventilatory efficiency.^{11,12,13,14,15,16,17,18,19} However, many of these studies are limited by small patient numbers,^11,13,15,17 while others have analyzed cardiac amyloidosis of different etiologies collectively.^11,12,13 Furthermore, many studies have only reported on a limited number of CPET variables,^11,13,14,16 such that the comprehensive metabolic, ventilatory, and cardiovascular indices that can be measured by CPET remain largely unexplored. Our study used CPET in a large cohort of patients to characterize the spectrum of functional capacity in ATTR amyloidosis, characterize functional decline with respect to amyloidotic burden, and assess prognosis.

Methods

Patients referred to the National Amyloidosis Centre, United Kingdom, from May 2019 to September 2022 in whom ATTR amyloidosis was confirmed were invited to participate in a prospective protocolized clinical follow-up program comprising serial clinical assessments and systemic evaluation of cardiac parameters. We included in this study all patients who underwent CPET assessment as part of the clinical assessment. Disease phenotype was classified as either ATTR-CM with no evidence of PN, ATTR-PN with no evidence of CM, or ATTR-mixed, in accordance with validated diagnostic criteria for ATTR-CM²⁰ and recommended diagnostic algorithms for ATTR-PN.²¹ Histological proof was reserved in cases of diagnostic uncertainty. Transthyretin gene sequencing was performed in all patients and biomarker staging determined based on current guidelines.²² Patients were treated in accordance with the Declaration of Helsinki and provided informed written consent for retrospective analysis and publication of their data with approval from the Royal Free Hospital ethics committee.

All participants underwent a symptom-limited CPET with data acquired using a metabolic cart (Ultima CardioO2, MGC Diagnostics) and tiltable cycle ergometer.²³ Habitual therapy was maintained. Lung spirometry was performed before the test, according with current European Respiratory Society requirements.^24,25 With the patient in a left semirecumbent position, an incremental ramp protocol of 10 watts per minute was used to obtain a standard of exercise.^12,26 Peak VO₂ and respiratory exchange ratio were defined as the highest 10-second averaged sample obtained during the final 20 seconds of exercise. Weight-adjusted Wasserman-Hansen equations were used to define percentage predicted peak VO₂. Ventilatory efficiency (VE) / volume of carbon dioxide expired (VCO₂) slope was calculated as the regression line of VCO₂ measurements plotted against minute ventilation (VE) values, excluding the earliest and latest segments.²⁷ Exercise oscillatory ventilation (EOV) was defined as the presence of cyclic fluctuations in VE that endure for at least 60% of the exercise test at an amplitude of 15% or more of the average resting value²⁸ and characterized dichotomously as being either present or absent. Maximal ventilatory capacity (MVV) was estimated as forced expiratory volume in 1 second × 40. Breathing reserve was defined as (MVV − peak VE) / MVV, where peak VE is the minute ventilation at peak. Maximum predicted heart rate (HR) was defined as 220 – age in years. To explore the chronotropic response taking into account resting HR, a chronotropic index was calculated as (peak HR – resting HR) / [{220 – age} – resting HR]).²⁹ Heart rate reserve was defined as peak HR – HR at 1 minute into recovery. Other CPET variables were measured according with current recommendations.²⁸

Echocardiography was performed using a GE machine (5S probe) and analyzed offline using EchoPAC software by qualified operators (R. K. P. and L. V.) blinded to disease phenotype and in accordance to current guidelines (eMethods in Supplement 1).³⁰ Patients with no contraindications underwent cardiovascular magnetic resonance (CMR) at 1.5-T (Magnetom Aera, Siemens Healthcare) comprising localizers, cine imaging, precontrast and postcontrast T-1 mapping to quantify extracellular volume (ECV) as a measure of cardiac amyloid burden (eMethods in Supplement 1).³¹

Statistical Analysis

Numerical variables are summarized by means (SDs) or medians (IQRs) where appropriate. A Kruskal-Wallis test was used to compare the distributions of each variable between subgroups and, if significant, was followed by a Bonferroni-corrected pairwise comparison to establish where differences lay. Categorical variables are summarized by frequencies (percentages) and groups compared using the χ² test. Standardized box plots, scatterplots, and radar plots were obtained to compare functional phenotypes according with clinical presentations and degree of left ventricular ejection fraction (LVEF). A linear regression model was used to identify clinical, biomarker, and echocardiographic variables that were associated with peak VO₂. The association between amyloid burden and CPET parameters was explored using myocardial ECV brackets as follows: less than 30.0%, 30.0% to 39.9%, 40.0% to 49.9%, 50.0% to 59.9%, 60.0% to 69.9%, and greater than 70.0%.^6,32

Mortality data was obtained via the UK Office of National Statistics. Survival was evaluated with Cox proportional hazards regression analysis and presented as hazard ratios, Kaplan-Meier survival graphs, and restricted cubic spline curves. The proportional hazards assumption was checked and confirmed. Univariable and multivariable analyses were used to determine which covariates were independent predictors of mortality, with variables selected a priori based on clinical relevance (eMethods in Supplement 1). Time-dependent receiver operating characteristic (ROC) curves were used to determine cutoff values for significant parameters for Kaplan-Meier Survival curves. All data were analyzed using SPSS Statistics version 29 (IBM). Figures were constructed using Stata Statistical Software Release 17 (StataCorp). P values were 2-sided with a significance level of <.05.

Results

Characteristics of the Entire Cohort

In total, 506 patients with ATTR amyloidosis were included (mean [SD] age, 73.5 [10.2] years; 457 [90.3%] male and 49 [9.7%] female). Among them, 394 had ATTR-CM (mean [SD] age, 76.7 [6.6] years; 377 [95.7%] male and 17 [4.3%] female), 92 had ATTR-mixed phenotype (mean [SD] age, 65.3 [9.5] years; 69 [75.0%] male and 23 [25.0%] female), and 20 had ATTR-PN (mean [SD] age, 48.3 [14.1] years; 11 [55.0%] male and 9 [45.0%] female). Baseline characteristics and echocardiography of each clinical presentation are shown in eTable 1 in Supplement 1. In terms of genotypes: 332 patients (65.6%) had ATTR wild-type; 60 (11.9%) had the V122I-associated ATTRv, 58 (11.5%) had T60A-associated ATTRv, and 56 (11.1%) had neither V122I- or T60A-associated ATTRv (24 with V30M; 7 with S77Y; 4 with G47V; 2 with A1775, A97S, E42D, F33V, and H90D; and 1 with E54L, E89K, E89Q, G53A, I107V, I68L, I84S, R34G, S23N, and S50R variants). A total of 309 patients (61%) underwent CPET when naive to any clinical trial enrollment or disease-modifying treatment; a further 101 (20%) underwent CPET within 6 weeks of enrollment into a clinical trial or commencing disease-modifying therapy.

Comparison of CPET Parameters According to Clinical Presentation

Parameters are presented in Table 1 and Figure 1. Mean (SD) peak VO₂, percentage predicted peak VO₂, and peak workload in patients with ATTR-CM (14.5 [4.3] mL/kg/min, 68.5% [18.6], and 72.3 watts [26.2], respectively) and ATTR-mixed (15.7 mL/kg/min [6.2], 64.8% [24.2], and 73.7 watts [32.5], respectively) were significantly lower than in patients with ATTR-PN (22.4 mL/kg/min [8.1], 79.2% [16.7], and 112.8 watts [42.9], respectively). Similarly, percentage predicted peak O₂ pulse was preserved only in patients with ATTR-PN (mean [SD], 103.5% [19.5]). Mean (SD) percentage predicted peak heart rate and chronotropic index, respectively, were abnormal in all subgroups (ATTR-CM: 79.9% [16.7] and 0.60 [0.32]; ATTR-mixed: 70.9% [14.9] and 0.43 [0.27]; ATTR-PN: 76.4% [9.5] and 0.55 [0.17]). Heart rate reserve was mostly reduced in patients with ATTR-PN and ATTR-mixed. Mean (SD) VE/VCO₂ slope was significantly higher on average in patients with ATTR-CM (38.1 [8.6]) compared to those with ATTR-mixed (34.0 [9.7]) and ATTR-PN (28.7 [2.8]). Distribution of both Weber Class of peak VO₂ and ventilatory class of VE/VCO₂ were more favorable in the ATTR-PN cohort compared to the ATTR-CM and ATTR-mixed cohorts (eFigure 1 in Supplement 1). A high prevalence of EOV was observed in all phenotypes (64.4% in ATTR-CM, 63% in ATTR-mixed, and 75% in ATTR-PN).

Table 1. Cardiopulmonary Exercise Test (CPET) Findings by Clinical Phenotype.

Variable	Mean (SD)			P value^a
Variable	ATTR-CM (n = 394)	ATTR-mixed (n = 92)	ATTR-PN (n = 20)	P value^a
Baseline lung function
FEV1, % predicted	80.6 (17.1)	77.5 (18.0)	95.8 (11.5)^b	.03
FVC, % predicted	86.2 (20.0)	83.1 (20.6)^c	86.8 (8.8)	.03
FEV1/FVC ratio	80.6 (10.0)^d	83.3 (11.3)	88.6 (8.6)^b	<.001
Metabolic
Peak work, W	72.3 (26.2)	73.7 (32.5)^c	112.8 (42.9)^b	<.001
VO₂, mL/kg/min
Anaerobic threshold	11.7 (3.2)	12.6 (4.4)^c	15.9 (4.6)^b	<.001
Peak exercise	14.5 (4.3)	15.7 (6.2)^c	22.4 (8.1)^b	<.001
% Predicted	68.5 (18.6)	64.8 (24.2)^c	79.2 (16.7)^b	.001
Respiratory exchange ratio
Peak exercise	1.09 (0.11)	1.10 (0.12)	1.15 (0.15)	.17
Ventilatory
VE/VCO₂ slope	38.1 (8.6)^d	34.0 (9.7)^c	28.7 (2.8)^b	<.001
VE, L/min
Rest	12.60 (3.28)	12.07 (3.11)	12.61 (3.19)	.37
Peak exercise	50.34 (15.25)	47.25 (18.20)^c	62.34 (23.88)	.007
VT, L
Rest	0.66 (0.18)	0.62 (0.15)	0.63 (0.13)	.20
Peak exercise	1.55 (0.43)	1.45 (0.48)^c	1.78 (0.52)	.01
Respiratory rate, breaths per min
Rest	20 (5.9)	20 (5.4)	21 (6.0)	.97
Peak exercise	33 (7.1)	33 (8.4)	35 (8.8)	.51
Breathing reserve, %	46.2 (13.5)	50.1 (17.1)	50.7 (13.7)	.07
EOV, No. (%)	253 (64.4)	58 (63.0)	15 (75.0)	.59
PETCO₂, mm Hg
Rest	31.0 (7.0)^d	33.4 (5.4)	34.7 (3.8)^b	<.001
Peak exercise	32.1 (8.3)^d	36.2 (10.2)^c	38.9 (3.9)^b	<.001
Cardiovascular
Heart rate, bpm
Rest	72 (12.8)^d	76 (12.6)	79 (12.1)	.002
Anaerobic threshold	103 (19.7)	99 (19.6)^c	114 (16.3)^b	.02
Peak exercise	115 (22.7)	111 (25.7)^c	131 (22.3)^b	.004
% Predicted	79.9 (16.7)^d	70.9 (14.9)	76.4 (9.5)	<.001
Chronotropic index	0.60 (0.32)^d	0.43 (0.27)	0.55 (0.17)	<.001
Heart rate reserve at 1 min recovery, bpm	15 (16.2)^d	11 (17.3)	12 (8.6)	<.001
VO₂/work slope, mL/min/W	10.3 (4.8)	10.0 (1.9)	10.7 (1.4)	.10
VO₂/heart rate, mL/min/bpm
Rest	4.2 (1.2)	4.1 (1.4)	4.6 (1.5)	.16
Peak exercise	10.1 (2.9)	10.8 (3.9)^c	13.0 (4.1)^b	.003
% Predicted	82.1 (23.0)	82.1 (33.4)^c	103.5 (19.5)^b	<.001
SBP, mm Hg
Rest	136 (20.7)	136 (17.1)	130 (13.1)	.34
Peak exercise	155 (28.3)	153 (33.3)^c	179 (25.2)^b	<.001
DBP, mm Hg
Rest	79 (13.8)	79 (10.3)	80 (6.3)	.73
Peak exercise	86 (17.4)	82 (17.3)^c	98 (23.3)^b	.003

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Abbreviations: ATTR, transthyretin; CM, cardiomyopathy; DBP, diastolic blood pressure; EOV, exercise oscillatory ventilation; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PETCO₂, end tidal carbon dioxide; PN, polyneuropathy; SBP, systolic blood pressure; VE, minute ventilation; VCO₂, volume of carbon dioxide expired; VO₂, oxygen consumption; VT, tidal volume.

^{^a}

Statistical significance is represented by P values <.05.

^{^b}

Bonferroni-corrected P values from pairwise comparison: P < .05 for CM vs PN.

^{^c}

Bonferroni-corrected P values from pairwise comparison: P < .05 for PN vs mixed.

^{^d}

Bonferroni-corrected P values from pairwise comparison: P < .05 for CM vs mixed.

Figure 1. — Comparison between disease phenotypes presented as Tukey box plots and radar plots. Central lines in these boxes indicate the median values, extremities the 25th and 75th percentiles; out of the box, lines extend to the minimum and maximum values. CM indicates cardiomyopathy; EOV, exercise oscillatory ventilation; HR, heart rate; HRR, heart rate reserve; PN, polyneuropathy; VCO_2, volume of carbon dioxide expired; VE, ventilatory efficiency; VO₂, oxygen consumption.

Linear regression analysis showed that age, estimated glomerular filtration rate, N-terminal prohormone of brain natriuretic peptide, LVEF and E/e′ were significant predictors for peak VO₂ (eTable 2 in Supplement 1). Comparison of CPET parameters between three common genotypes of ATTR (wild-type, V122I-associated ATTRv, and T60A-associated ATTRv) and by cardiac rhythm (sinus rhythm, atrial arrhythmia, and paced rhythm) can be seen in eTables 3 and 4 in Supplement 1, respectively.

Association of Amyloid Burden With CPET Parameters

In total, 326 (64.4%) patients underwent CMR with ECV mapping and were divided into groups based on myocardial ECV (Figure 2) as a measure of cardiac amyloid infiltration. Percentage predicted peak VO₂ was reduced in all patients, but the degree of reduction was progressively more severe with increasing cardiac amyloid infiltration. Percentage predicted O₂ pulse was preserved in patients with either no or mild to moderate cardiac amyloid infiltration but was significantly reduced in those with severe infiltration. Ventilatory efficiency was preserved in patients with no cardiac infiltration, was reduced even in mild infiltration, and became progressively more severe with increasing infiltration. Percentage predicted peak HR was impaired in all patients, irrespective of the degree of cardiac infiltration. Heart rate reserve was frequently impaired, and unrelated to the degree of cardiac infiltration. EOV was highly prevalent in all patients with a trend to be higher in patients with less severe degree of cardiac infiltration. The data are also presented as scatterplots with equations of linear correlation (eFigure 2 in Supplement 1).

Patients with ATTR-CM or mixed phenotype who underwent CMR (n = 311) were dichotomized based on LVEF and shown in eFigures 3, 4, and 5 in Supplement 1. In patients with LVEF>55% (n = 107), abnormal values of percentage predicted peak VO₂ was observed in patients with ECV values above 40%. Percentage predicted peak HR was reduced across the spectrum of ECV values above 40%, whereas percentage predicted peak O₂ pulse was normal (>85% of predicted) across the range of ECV values. Ventilatory efficiency was impaired in all patients with ECV above 40%, with the degree of impairment being progressively more severe with increasing ECV. EOV was highly prevalent in all patients. Heart rate reserve was progressively more impaired with increasing ECV.

In patients with LVEF<55% (n = 204), abnormal values of percentage predicted peak VO₂ were observed in all patients with a trend for lower values with progressively higher degree of cardiac amyloid infiltration. Percentage predicted peak O₂ pulse was reduced (<85% of predicted) across the range of ECV values and those with a higher degree of cardiac amyloid infiltration displayed a more severe reduction. Percentage predicted peak HR was mildly reduced across the spectrum of ECV. Ventilatory efficiency was impaired in all patients, even for mild degrees of cardiac infiltration. EOV was highly prevalent in all patients. Heart rate reserve was normal across the spectrum of ECV.

CPET Parameters and Prognosis

At follow-up (mean 22.4 months [SD 11.6]), 72 (14.2%) patients had died. Univariable Cox regression analysis demonstrates all CPET variables were predictive of mortality except for EOV, and peak respiratory exchange ratio (eTable 5 in Supplement 1). The multivariate model (Table 2) demonstrates that peak VO₂, whether expressed as the absolute value (hazard ratio, 0.89; 95% CI, 0.81 to 0.99; P = .03) or as percentage predicted (hazard ratio, 0.97; 95% CI, 0.95 to 0.99; P = .01), and peak SBP (hazard ratio, 0.98; 95% CI, 0.97 to 0.99, P < .001) were independently associated with patient survival in the overall population. The same analysis with standardized hazard ratios is presented in eTable 6 in Supplement 1. Kaplan-Meier survival curves and restricted cubic spline curves for peak VO₂ and peak SBP are shown in Figure 3. Separate multivariable models were repeated to include the use of rate-limiting medication and disease-modifying therapies or enrollment in a clinical trial, and both show similar results (eTable 7A and 7B in Supplement 1). Kaplan-Meier survival curves dividing patients by Weber Classification (peak VO₂) or ventilatory class (VE/VCO₂) are shown in eFigure 6 in Supplement 1. Time-dependent receiver operating curves gave cutoff values for peak VO₂ (14 mL/kg/min) and peak SBP (145 mm Hg) and Kaplan-Meier survival curves dichotomizing patients using each cutoff value are shown in eFigure 7 in Supplement 1.

Table 2. Multivariate Cox Regression Analysis of Risk of Death in Patients With Transthyretin (ATTR) Amyloidosis.

Variable	Peak VO₂ model, HR (95% CI)^a	P value^b	% Predicted peak VO₂ model, HR (95% CI)^a	P value^b
Peak VO₂, mL/kg/min	0.89 (0.81-0.99)	.03	NA	NA
% Predicted peak VO₂	NA	NA	0.97 (0.95-0.99)	.01
VE/VCO₂ slope	0.99 (0.97-1.02)	.59	0.99 (0.97-1.02)	.54
Chronotropic index	0.85 (0.35-2.03)	.71	0.91 (0.37-2.23)	.83
Peak VO₂/heart rate, mL/min/bpm	0.90 (0.78-1.02)	.10	0.89 (0.78-1.01)	.08
Peak SBP, mm Hg	0.98 (0.97-0.99)	<.001	0.98 (0.97-0.99)	<.001
VO₂/work slope, mL/min/W	0.98 (0.86-1.13)	.80	1.00 (0.87-1.16)	.97
Biomarker stage
1 vs 2	2.29 (1.34-3.93)	.002	2.59 (1.50-4.48)	<.001
1 vs 3	3.78 (1.65-8.66)	.002	4.42 (1.92-10.16)	<.001

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Abbreviations: HR, hazard ratio; NA, not applicable; SBP, systolic blood pressure; VE, ventilatory efficiency; VCO_2, volume of carbon dioxide expired; VO_2, oxygen consumption.

^{^a}

Hazard ratios represent the comparison of the risk of mortality for a unit increase in the variable of interest.

^{^b}

Statistical significance is represented by P values <.05.

Discussion

To our knowledge, this cohort study is the first using CPET to characterize the functional capacity of a large cohort of patients with ATTR amyloidosis. The main findings are: (1) Impairment of functional capacity was highly prevalent in all patients, with each disease phenotype demonstrating distinctive patterns of functional impairment, (2) chronotropic incompetence, EOV and ventilatory inefficiency were highly prevalent in all disease phenotypes, with the prevalence being higher than in heart failure from different etiologies; and (3) peak VO₂ and peak SBP emerged as independent predictors of prognosis, after adjusting for known predictors.

Functional capacity was invariably reduced in patients with ATTR amyloidosis, and the mechanisms contributing to functional impairment were observed to be different across each clinical phenotype. Patients with ATTR-PN showed the greatest preservation in exercise tolerance and ventilatory efficiency, with chronotropic incompetence observed as the main mechanism underlying the reduction in functional capacity. The preservation of O₂ pulse augmentation during exercise in ATTR-PN represents the ability for patients with no cardiac involvement to adequately increase their stroke volume when metabolic demand is increased. In contrast, patients with ATTR-CM and ATTR-mixed phenotypes showed a variety of mechanisms contributing to functional impairment with reduced O₂ pulse, chronotropic incompetence, and ventilatory inefficiency being present in most patients, with typically a more severe phenotype in ATTR-CM compared to ATTR-mixed disease. Differences in peak VO₂ between each clinical phenotype are likely to relate to the disease stage in terms of presence and severity of cardiac involvement. Baseline characteristics (eTable 1 in Supplement 1) show many differences between each group, with ATTR-CM patients having the most advanced disease in terms of cardiac involvement and the lowest peak VO₂.

Linear regression analysis demonstrated that age, estimated glomerular filtration rate, N-terminal prohormone of brain natriuretic peptide, left ventricular ejection fraction (LVEF), and E/e’ were all significantly associated with peak VO₂, highlighting the complex nature of underlying pathophysiological mechanisms contributing to functional impairment in ATTR amyloidosis. Subgroup analysis of genotypes (eTable 3 in Supplement 1) demonstrated the greatest degree of functional impairment in patients with V122I-associated ATTRv, mediated by low peak VO₂ and O₂ pulse, suggesting a predominant cardiomyopathic phenotype, while functional impairment in T60A-associated ATTRv was mediated by chronotropic incompetence, more akin to ATTR-mixed and in keeping with a milder degree of cardiac involvement. Subgroup analysis of cardiac rhythm (eTable 4 in Supplement 1) highlighted the high prevalence of arrhythmia in ATTR disease and that remaining in sinus rhythm is associated with the most favorable functional phenotype compared to those with atrial arrhythmia or paced rhythm.

Cardiac amyloid infiltration is known to cause left ventricular stiffening and reduced compliance, leading to restrictive physiology.³³ Our study shows that during exercise, cardiac involvement limits the normal physiological increase in stroke volume. Categorizing the disease based on the degree of cardiac amyloid infiltration on CMR demonstrates 2 distinctive phenotypes based on LVEF. When LVEF is reduced, impairment in both peak O₂ pulse (inotropic reserve) and chronotropic incompetence are both important contributing mechanisms in driving functional impairment. As amyloid burden increases, the progressive decrease in peak O₂ pulse with no comparable trend in chronotropic response indicates that impaired inotropic reserve is the predominant mechanism for functional impairment. In contrast, when LVEF is preserved, the progressive decrease in chronotropic incompetence suggests this as the predominant mechanism for functional limitation, while the preservation of peak O₂ pulse indicates that inotropic reserve is maintained in these patients.

Despite the presence of important differences between each clinical phenotype as outlined above, we also observed abnormalities in CPET that were consistent across all ATTR disease phenotypes, with distinguishing features compared to heart failure from nonamyloid etiologies. First, chronotropic incompetence was highly prevalent in all phenotypes and was independent from the degree of cardiac amyloid infiltration (as measured by ECV) and β-blocker use, most likely reflecting the high prevalence of cardiovascular autonomic dysfunction that characterizes this population.³⁴ In studies of heart failure with reduced ejection fraction, the prevalence of chronotropic incompetence has been reported as widely ranging between 23% and 72%, although it was less prevalent in those with preserved ejection fraction (30%-50%).^35,36 In patients with ATTR-PN and ATTR-mixed phenotypes, abnormal heart rate reserve was also observed after exercise, possibly reflecting a more severe degree of autonomic dysfunction manifesting with parasympathetic imbalance.³⁷

Second, abnormal ventilatory efficiency emerged as a distinctive feature in ATTR-CM and ATTR-mixed phenotypes. Despite worsening ventilatory inefficiency being observed with increasing cardiac amyloid burden, both the prevalence and severity of ventilatory inefficiency were higher than reported in patients with heart failure from different etiologies.^9,38,39,40 This may suggest additional disease-specific mechanisms contributing to ventilatory inefficiency, such as primary amyloid infiltration of the alveolar-capillary membrane^41,42 and compensatory mechanisms against abnormal vascular autonomic modulation and baroreflex function.⁴³ Impaired diffusion of CO₂ across the alveolar-capillary membrane secondary to lung amyloid infiltration⁴⁴ could explain the higher degree of ventilatory inefficiency observed in this population.

Third, the prevalence of EOV was extremely high in all ATTR patients and similar across each phenotype, compared to a much lower reported prevalence of between 12% and 58% in heart failure with reduced ejection fraction.⁴⁵ The prevalence of EOV was not associated with the degree of cardiac involvement, such that autonomic dysfunction, compensatory hyperventilation, and lung amyloid deposition may be important contributing mechanisms.

All CPET parameters except EOV and peak respiratory exchange ratio were associated with prognosis, demonstrating the important value of metabolic stress testing in predicting outcomes in ATTR amyloidosis. Peak VO₂ and peak SBP were the only variables independently associated with survival in multivariable analysis, after adjusting for other CPET parameters, biomarkers, and treatment. This finding is consistent with the Fick equation, which suggests that peak VO₂ is highly dependent on physiological mechanisms, including chronotropic and inotropic reserve, both of which were significantly impaired in the ATTR population, and correlates with existing literature in favor of peak VO₂ being independently prognostic.^11,12,17 Similarly, the inability to adequately increase blood pressure during exercise is a known marker of adverse prognosis in advanced heart failure,⁴⁶ reflecting the loss of cardiac inotropic reserve and sympathetic-mediated vascular tone adaptation. Notably, we observed only a limited increase in mean SBP of less than 20 mmHg at peak exercise. Unlike heart failure from other etiologies, ventilatory efficiency was not an independent predictor in ATTR patients, which likely reflects the different pathogenic processes that contribute to the increase in the VE/VCO₂ slope, driven not only by heart failure–related mechanisms but also direct lung amyloid infiltration.

Limitations

ATTR amyloidosis is a multisystem disease with lung mechanisms potentially affecting the exercise tolerance. Our study was limited in using only simple spirometry, such that measurement of alveolar gas diffusion would be required to explore the hypothesis of possible lung amyloid infiltration. Additional pathways linked to peripheral, mitochondrial, and neuropathic function are not fully explored by simple CPET, requiring combined and invasive approaches. Patients with ATTR-PN were underrepresented in this study, limiting the ability to explore the association between the functional capacity and the severity of the functional phenotype. While β-blocker use was not associated with the presence or degree of chronotropic incompetence, future prospective studies assessing the direct impact of β-blockers on functional capacity are missing. The prognostic significance of CPET has been demonstrated for all-cause mortality as the outcome, but association of CPET variables with heart failure hospitalization could provide additional and clinically relevant information.

Conclusions

In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment across all disease phenotypes, attributable to multiple physiological mechanisms. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic features of this population. Multiple CPET parameters were associated with amyloid burden by CMR and using multivariable analysis, peak VO₂, and peak SBP were demonstrated to be independently associated with mortality after adjusting for known predictors. The findings suggest that CPET potentially offers a more comprehensive method of evaluating functional capacity compared to existing measures for future prospective studies.

Supplement 1.

eMethods

eTable 1. Baseline characteristics and echocardiography split by ATTR clinical presentation

eTable 2. Linear regression model of clinical and echocardiographic determinants of peak VO2

eTable 3. CPET findings in ATTR split by genotype

eTable 4. CPET findings in ATTR split by cardiac rhythm

eTable 5. Univariable Cox proportional hazards regression analysis of risk of death in patients with ATTR

eTable 6. Multivariate Cox regression analysis of risk of death in patients with ATTR with Standardised Hazard Ratios

eTable 7a. Multivariate Cox regression analysis of risk of death in patients with ATTR with the addition of rate-limiting medication

eTable 7b. Multivariate Cox regression analysis of risk of death in patients with ATTR with the addition of disease-modifying treatment or enrolment in a clinical trial

eFigure 1. Bar charts showing proportion of patients in each Weber Class and Ventilatory Class according to phenotype

eFigure 2. Distribution of CPET variables according with myocardial ECV in ATTR using scatterplots

eFigure 3. Distribution of CPET variables according with myocardial ECV in ATTR-CM with preserved LVEF (>55%)

eFigure 4. Distribution of CPET variables according with myocardial ECV in ATTR-CM with reduced LVEF (<55%)

eFigure 5. Radar plot showing patterns of functional impairment in ATTR-CM according to LVEF

eFigure 6. Kaplan-Meier Survival Curves for patients with ATTR based on Weber and Ventilatory Class

eFigure 7. Kaplan-Meier Survival Curves for patients with ATTR based on CPET parameters

jamacardiol-e240022-s001.pdf^{(1.9MB, pdf)}

Supplement 2.

Data sharing statement

jamacardiol-e240022-s002.pdf^{(6.5KB, pdf)}

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