Right Ventricular to Pulmonary Artery Uncoupling Is Associated With Impaired Exercise Capacity in Patients With Transthyretin Cardiac Amyloidosis

Toru Hashimoto; Kei Ikuta; Shoei Yamamoto; Tomoaki Yoshitake; Tomoyasu Suenaga; Shunsuke Nakashima; Takashi Kai; Kayo Misumi; Takeo Fujino; Keisuke Shinohara; Shouji Matsushima; Rina Atsumi; Takuro Isoda; Shintaro Kinugawa; Kohtaro Abe

doi:10.1253/circj.CJ-24-0402

Abstract

Background: Exercise capacity is related to mortality and morbidity in heart failure (HF) patients. Determinants of exercise capacity in transthyretin cardiac amyloidosis (ATTR-CA) have not been established.

Methods and Results: This single-center study retrospectively evaluated ATTR-CA patients and patients with non-amyloidosis HF with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF) (n=32 and n=51, respectively). In the ATTR-CA group, the median age was 75.5 years (interquartile range [IQR] 71.3–78.8 years), 90.6% were male, and the median left ventricular (LV) ejection fraction was 53.5% (IQR 41.4–65.6%). Cardiopulmonary exercise tests revealed a median peak oxygen consumption and anaerobic threshold of 15.9 (IQR 11.6–17.4) and 10.6 (IQR 8.5–12.0] mL/min/kg, respectively, and ventilatory efficiency (minute ventilation/carbon dioxide production [V̇_E/V̇_CO2] slope) of 35.5 (IQR 32.0–42.5). Among exercise variables, V̇_E/V̇_CO2 slope has the greatest prognostic value. Univariate analysis revealed a significant correlation between V̇_E/V̇_CO2 slope and age, LV global longitudinal strain, tricuspid annular plain systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) ratio, and mixed venous oxygen saturation. In multivariate analyses, the TAPSE/PASP ratio was an independent predictor of V̇_E/V̇_CO2 slope (95% confidence interval −44.5, −10.8; P=0.0067). In non-amyloidosis HFpEF/HFmrEF patients, the TAPSE/PASP ratio was not independently correlated with V̇_E/V̇_CO2 slope.

Conclusions: Right ventricular–pulmonary artery coupling estimated by the TAPSE/PASP ratio determines exercise capacity in ATTR-CA patients. This highlights the importance of early therapeutic intervention against underappreciated right ventricular dysfunction associated with ATTR-CA.

Cardiac amyloidosis (CA) is characterized by the extracellular deposition of misfolded fibrillary proteins in the myocardium, leading to a secondary restrictive cardiomyopathy.¹ Although considered a rare disease, recent evidence suggests that CA is underappreciated as a cause of various cardiac diseases.¹^,² Among 36 proteins that have been identified as precursors, 9 amyloidogenic proteins accumulate in the myocardium to cause cardiac disease.²^,³ Immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) are major causes of CA.¹ ATTR-CA has been recognized as one of the major causes of heart failure, especially heart failure with preserved ejection fraction (HFpEF) in elderly people.⁴ ATTR can be inherited as an autosomal dominant trait caused by pathogenic mutations in the transthyretin gene (variant ATTR [ATTRv]) or it can be caused by the deposition of wild-type transthyretin protein (ATTRwt), previously called senile systemic amyloidosis.¹ Although ATTRv-CA is highly associated with polyneuropathy and autonomic dysfunction, ATTRwt-CA is characterized by comorbid orthopedic disorders such as carpal tunnel syndrome, spinal canal stenosis, and tendon rupture.⁴

Exercise intolerance is a hallmark of heart failure and is associated with reduced quality of life and increased mortality.⁵ Systolic dysfunction, diastolic dysfunction, left ventricular (LV) to arterial coupling, left atrial dysfunction, mitral regurgitation, and chronotropic incompetence contribute to reduced cardiac reserve.⁵ Reduced pulmonary reserve, skeletal muscle dysfunction, anemia, peripheral vascular dysfunction, dysautonomia, obesity, and inflammation are also determinants of exercise intolerance in patients with heart failure.⁵^,⁶ Impaired physical performance is also a hallmark of ATTR-CA.⁷

Cardiopulmonary exercise testing (CPET) is an evidence-based technique for assessing exercise capacity.⁸ Serial monitoring of electrocardiograms, hemodynamics, oxygen saturation, and measurement of ventilatory gas exchange combined with exercise provocation enable accurate quantification of cardiorespiratory physiology in patients.⁶^,⁸ Patel et al. recently demonstrated that reduced peak oxygen consumption (V̇_O2), impaired oxygen pulse, high ventilatory efficiency (minute ventilation/carbon dioxide production [V̇_E/V̇_CO2] slope), and chronotropic incompetence were highly prevalent in patients with ATTR-CA.⁷ These impaired CPET parameters were associated with myocardial amyloid burden assessed quantitatively by extracellular volume using cardiac magnetic resonance.⁷ Although reduced peak V̇_O2 or decreased exercise duration are reported to be correlated with mortality in patients with ATTR-CA,⁷^,⁹ determinants of impaired exercise capacity in ATTR-CA have not been comprehensively explored. In the present study, we sought to reveal the determinants of exercise capacity in patients with ATTR-CA.

Methods

Study Population

The present study is a retrospective analysis of consecutive patients who were diagnosed with CA and with non-amyloidosis HFpEF or heart failure with mildly reduced EF (NA-HFpEF/HFmrEF) at the Department of Cardiovascular Medicine, Kyushu University Hospital between January 2002 and November 2023. The diagnosis of ATTR-CA was established from endomyocardial biopsy with immunohistochemical confirmation of transthyretin in the amyloid deposits. All NA-HFpEF/HFmrEF patients also underwent endomyocardial biopsy and were histopathologically proven not to have ATTR-CA. Of the 150 patients with ATTR-CA, CPET data were available for 32 (Supplementary Figure 1). Clinical data were obtained from patients’ medical records. Because serum N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration data were available for a limited number of patients, we used the conversion formula to convert B-type natriuretic peptide (BNP) to NT-proBNP.¹⁰

This study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board at Kyushu University Hospital (Approval no. 21113-01). Patients were offered the opportunity to opt out of the study.

CPET

CPETs were performed on a cycle ergometer in a temperature-controlled (20–25℃) room. The CPET ramp protocol started with a 3-min rest on the bike followed by a 3-min warm-up cycle at 60 r.p.m. Resistance then increased incrementally by 5–10 W/min and the test terminated when recommendations from the European Society of Cardiology (ESC) were met.⁶ When the exercise stopped, the bicycle load was decreased to the lowest level used and patients kept on pedaling for at least 1 min prior to stopping completely. Heart rate (HR) was monitored continuously throughout the CPET via a 12-lead electrocardiogram. CPET variables were measured breath-by-breath during exercise using an aero-monitor (AE-310S; Minato Medical Science, Osaka, Japan). V̇_O2, V̇_CO2, V̇_E, the respiratory exchange ratio (RER; V̇_CO2/V̇_O2), ventilatory efficiency (V̇_E/V̇_CO2 slope), the ratio of oxygen consumption to HR (V̇_O2/HR; O₂ pulse), and functional V̇_O2 gain (∆V̇_O2/∆workload [W]) were measured. Patients with atrial fibrillation or atrial tachycardia during exercise stress were excluded from the analysis of O₂ pulse because atrial fibrillation blunts the increase in O₂ pulse by the increase in HR during exercise.¹¹ Age-predicted maximum HR (APMHR) was calculated as 220-age.¹² The HR reserve (HRR) was calculated as the difference between HR at peak exercise (HR_peak) and HR at baseline (HR_baseline), and the percentage HRR (%HRR) was calculated as follows:¹³

%HRR = (HR_peak − HR_baseline) / (APMHR − HR_baseline) × 100

Chronotropic incompetence was defined as HR_peak <85% of APMHR or %HRR <80%.¹³

Hemodynamic Measurements

Right heart catheterization was done at baseline in the catheterization laboratory at rest in the supine position. A Swan-Ganz catheter was used to obtain mean right atrial pressure (RAP), right ventricular (RV) pressure, systolic and diastolic pulmonary artery pressure, as well as pulmonary artery wedge pressure (PAWP). All measurements were obtained at end expiration at steady state with the patient in a supine position. PAWP was measured at the end of expiration during spontaneous breathing. Cardiac output (CO) was measured using thermodilution (or Fick’s method in case of severe tricuspid regurgitation) and the cardiac index was calculated as CO divided by body surface area. Stroke volume index (SI) was derived from cardiac index using instantaneous heart rate. Mixed venous oxygen saturation (SvO₂) was measured using blood samples from pulmonary artery. Systolic and diastolic blood pressures were obtained using a digital sphygmomanometer at the time of the procedure. Additional hemodynamic parameters, namely systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), pulmonary artery pulsatility index (PAPi), and RV stroke work index (RVSWI) were calculated as follows:

SVR = ((1 / 3 × SBP+2 / 3 × DBP) − RAP) / CO

where SBP and DBP are systolic and diastolic blood pressure, respectively.

PVR = (mPAP − PAWP) / CO

where mPAP is mean pulmonary artery pressure.

PAPi = (sPAP − dPAP) / RAP

where sPAP and dPAP are systolic and diastolic pulmonary artery pressure, respectively.

RVSWI = (mPAP − RAP) × SI

Echocardiography

A standardized transthoracic echocardiogram protocol was used. Variables of interest included LV parameters (LV internal dimension at diastole, LV mass index, LV global longitudinal strain [GLS], mitral E/A ratio, mitral E wave deceleration time, and mitral E/e′ ratio) and RV parameters (tricuspid annular plane systolic excursion [TAPSE], tricuspid annular peak systolic velocity [RV s′], estimated pulmonary artery systolic pressure [PASP], and the TAPSE/PASP ratio). PASP was calculated as RAP + (RV − RA pressure gradient).¹⁴ All these parameters were measured at the timing of diagnosis and before the start of disease-modifying agents such as transthyretin stabilizers and transthyretin gene-silencing agents.

Technetium-99 m Pyrophosphate (^{99 m}Tc-PYP) Myocardial Scintigraphy

Planar cardiac imaging of the chest was performed using gamma cameras with low-energy, high-resolution collimators. Three hours after intravenous administration of 740 MBq ^{99 m}Tc-PYP, anterior and lateral planar views of the heart were acquired. Cardiac retention was assessed by a quantitative heart-to-contralateral (H/CL) ratio.¹⁵ An H/CL ratio ≥1.3 is thought to indicate ATTR-CA for scans with a 3-h incubation.¹⁶ Single-photon emission computed tomography was performed after planar scans to evaluate the distribution of myocardial uptake and to correct bone activity.

Statistical Analysis

Data are presented as the median with interquartile range (IQR). Comparisons between 2 groups were made using Student’s t-test or the Mann-Whitney U test, if appropriate, for continuous variables and Fisher’s exact test for categorical variables. Univariate linear regression analysis was performed to describe relationships. A multiple linear regression model was used for multivariate analysis of the predictors of each parameter. Statistical analyses were performed using JMP Pro Version 17.0.0 (JMP Statistical Discovery LLC, Cary, NC, USA). Significance was defined as two-tailed P value <0.05.

Results

Baseline Characteristics

The baseline characteristics of the patients included in this study are presented in Table 1. We did not observe any significant differences between the present cohort and the total ATTR-CA patients except for body mass index (Supplementary Table 1). As indicated in Table 1, the median age of our ATTR-CA cohort was 75.5 years (IQR 71.3–78.8 years) and 90.6% were male. Three (10%) patients were New York Heart Association Class I, 17 (53.1%) were Class II, and 12 (37.5%) were Class III. The median plasma BNP concentration was 179.3 pg/mL (IQR 118.6–373.3 pg/mL). Thirteen (40.6%) patients had atrial tachyarrhythmia (paroxysmal or persistent), and the median estimated glomerular filtration rate was 53.7 mL/min/1.73 m² (IQR 46.0–65.8 mL/min/1.73 m²), LVEF was 53.5% (IQR 41.4–65.6%), LV GLS was low as −9.8% (IQR −13.7%, −7.8%), and the LV mass index was increased at 151.4 g/m² (IQR 116.1–174.7 g/m²).

Table 1.

Baseline Characteristics of Patients With ATTR-CA (n=32)

Variables	Median [IQR]	Variables	No. patients (%)
Age (years)	75.5 [71.3, 78.8]	Male sex	29 (90.6)
BMI (kg/m²)	24.2 [22.2, 26.7]	Heart failure class
Hemoglobin (g/dL)	14.1 [12.6, 14.4]	HFrEF	9 (28.1)
Albumin (g/dL)	4.0 [3.8, 4.3]	HFmrEF	7 (21.9)
BUN (mg/dL)	22 [17.5, 30.8]	HFpEF	16 (50.0)
Serum creatinine (mg/dL)	1.0 [0.8, 1.2]	NYHA functional class
eGFR (mL/min/1.73 m²)	53.7 [46.0, 65.8]	I	3 (9.4)
Serum sodium (mmol/L)	140.0 [137.0, 142.0]	II	17 (53.1)
Serum potassium (mmol/L)	4.3 [3.9, 4.5]	III	12 (37.5)
Total bilirubin (mg/dL)	0.9 [0.6, 1.1]	IV	0 (0)
AST (U/L)	26.0 [21.0, 33.8]	ATTRv	2 (6.3)
ALT (U/L)	18.0 [13.0, 29.0]	NAC stage
LDH (U/L)	225.5 [194.8, 292.8]	1	23 (71.9)
Troponin T (ng/mL)	0.053 [0.027, 0.088]	2	7 (21.9)
BNP (pg/mL)	179.3 [118.6, 373.3]	3	2 (6.3)
Echocardiography		Comorbidities
LVEF (%)	53.5 [41.4, 65.6]	Atrial tachyarrhythmias	13 (40.6)
LVIDd (mm)	44.0 [40.3, 48.5]	Chronic kidney disease	21 (65.6)
LVMI (g/m²)	151.4 [116.1, 174.7]	Hypertension	17 (53.1)
GLS (%)	−9.8 [−13.7, −7.8]	Diabetes	8 (25)
E/A ratio	1.5 [0.9, 3.2]	Dyslipidemia	9 (28.1)
Deceleration time (ms)	188.0 [156.0, 216.8]	Ischemic heart disease	3 (9.4)
E/E′ ratio	17.7 [14.1, 24.6]	Carpal tunnel syndrome	17 (53.1)
TAPSE (mm)	14.5 [12.2, 19.5]	Lumbar canal stenosis	8 (25)
RV s′ (cm/s)	9.1 [6.4, 11.3]	Chronic lung diseases	6 (18.8)
TAPSE/PASP (mm/mmHg)	0.55 [0.32, 0.78]	Medications
Hemodynamics		ACEi/ARB/ARNI	20 (62.5)
RAP (mmHg)	5.0 [4.0, 7.0]	β-blockers	15 (46.9)
RVSP (mmHg)	32.5 [26.3, 41.0]	MRA	14 (43.8)
mPAP (mmHg)	21.5 [15.3, 26.0]	SGLT2i	10 (31.3)
PAWP (mmHg)	13.5 [9.0, 18.0]	Diuretics (any class)	21 (65.6)
Cardiac index (L/min/m²)	2.2 [1.9, 2.8]	Antiarrhythmics	2 (6.3)
Stroke index (mL/m²)	34.3 [25.9, 41.4]	Calcium channel blockers	7 (21.9)
SvO₂ (%)	65.9 [62.0, 72.5]	Oral anticoagulants	12 (37.5)
PVR (Wood units)	2.1 [1.3, 2.7]	CIED	4 (12.5)
PAPi	4.0 [3.1, 4.8]	Pacemaker	2
RVSWI (g/m²)	7.6 [5.9, 9.1]	CRT-P	1
RAP/PAWP ratio	0.38 [0.33, 0.47]	CRT-D	1
SVR (Wood units)	22.3 [17.4, 26.0]	ICD	0

ACEi, angiotensin-converting enzyme inhibitors; ALT, alanine aminotransferase; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor-neprilysin inhibitor; AST, aspartate aminotransferase; ATTR-CA, transthyretin cardiac amyloidosis; ATTRv, variant transthyretin amyloidosis; BMI, body mass index; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CIED, cardiac implantable electronic devices; CRT-P, cardiac resynchronization therapy-pacemaker; CRT-D, cardiac resynchronization therapy-defibrillator; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; IQR, interquartile range; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal dimension at diastole; LVMI, left ventricular mass index; mPAP, mean pulmonary artery pressure; MRA, mineralocorticoid receptor antagonists; NAC, National Amyloidosis Centre (UK); NYHA, New York Heart Association; PAPi, pulmonary artery pulsatility index; PASP, pulmonary artery systolic pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV s′, right ventricular tricuspid annular systolic velocity; RVSP, right ventricular systolic pressure; RVSWI, right ventricular stroke work index; SGLT2i, sodium-glucose cotransporter 2 inhibitor; SvO₂, mixed venous oxygen saturation; SVR, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion.

With regard to RV function, TAPSE was 14.5 mm (IQR 12.2–19.5 mm), RV s′ was 9.1 cm/s (IQR 6.4–11.3 cm/s), and the TAPSE/PASP ratio was decreased at 0.55 mm/mmHg (IQR 0.32–0.78 mm/mmHg). Right heart catheterization revealed that RAP was 5.0 mmHg (IQR 4.0–7.0 mmHg), mPAP was 21.5 mmHg (IQR 15.3–26.0 mmHg), PAWP was mildly elevated at 13.5 mmHg (IQR 9.0–18.0 mmHg), and the cardiac index at rest was mildly reduced at 2.2 L/min/m² (IQR 1.9–2.8 L/min/m²). PVR was 2.1 Wood units (IQR 1.3–2.7 Wood units), and other RV function-related parameters, such as PAPi, RVSWI, and RAP/PAWP ratio, were within normal ranges (Table 1).

Of the different medications for heart failure, 15 (46.9%) patients were on β-blockers, 20 (62.5%) were on an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin blocker neprilysin inhibitor (angiotensin receptor–neprilysin inhibitor), 14 (43.8%) were on a mineralocorticoid receptor antagonist, and 10 (31.3%) were on a sodium–glucose cotransporter 2 inhibitor. Twenty (62.5%) patients were prescribed diuretics (Table 1). Cardiac implantable electronic devices (CIEDs) were implanted in 4 (12.5%) patient (Table 1). Two patients had ATTRv; 1 had an E61K mutation and the other harbored a T60A mutation. According to the UK National Amyloidosis Centre (NAC) staging system,¹⁷ most patients (n=23; 71.9%) were in Stage I, 7 (21.9%) were in Stage 2, and 2 (6.3%) were in Stage 3 (Table 1).

Impaired Exercise Capacity in Patients With ATTR-CA

The peak work rate was 71.0 W (IQR 49.3–88.8 W) and peak RER was 1.17 (IQR 1.12–1.22), indicating adequate exercise effort. Exercise parameters were presented in Table 2. Peak V̇_O2 was decreased at 15.9 mL/min/kg (IQR 11.6–17.4 mL/min/kg; % predicted 72.5% [IQR 54.8–79.3%]). V̇_O2 at the anaerobic threshold (AT) was also reduced at 10.6 mL/min/kg (IQR 8.5–12.0 mL/min/kg). Peak O₂ pulse was decreased at 7.7 mL/min/beat (IQR 6.8–10.4 mL/min/beat), suggesting reduced stroke volume at peak exercise. V̇_E/V̇_CO2 slope was elevated at 35.5 (IQR 32.0–42.5). ∆V̇_O2/∆W was reduced at 8.6 mL/min/W (IQR 7.1–10.5 mL/min/W), suggesting impaired cardiac output reserve during exercise. ∆V̇_O2/∆W was not significantly different among ramp protocols (P=0.53). %HRR was 66.8% (IQR 42.9–83.6%), and chronotropic incompetence (%APMHR <85% or %HRR <80%) was observed in 23 (74.2%) patients. The use of β-blockers was not significantly correlated with either chronotropic incompetence (P=0.24) or other CPET parameters, such as peak V̇_O2 (P=0.65), V̇_E/V̇_CO2 slope (P=0.26), or AT (P=0.15). Patients with chronotropic incompetence had lower peak V̇_O2 and higher V̇_E/V̇_CO2 slope than those without incompetence (Figure 1). The patients with CIEDs generally shows a poor rate response to low-vibration exercise such as ergometer because of the characteristics of inherent accelerometer. When excluding the patients with CIEDs, chronotropic incompetence was observed in 19 of 28 (67.9%) patients. The associations between chronotropic incompetence and peak V̇_O2 and V̇_E/V̇_CO2 slope remained significant in this population (peak V̇_O2, P=0.044; V̇_E/V̇_CO2 slope, P=0.049).

Table 2.

Exercise Variables of Patients With ATTR-CA and NA-HFpEF/HFmrEF

Variables	ATTR-CA (n=32)	NA-HFpEF/HFmrEF (n=51)	P value
Peak V̇_O2 (mL/min/kg)	15.9 (11.6, 17.4)	16.8 (11.5, 18.8)	0.521
% Predicted peak V̇_O2	72.5 (54.8, 79.3)	74.0 (57.5, 85.0)	0.699
Peak RER	1.17 (1.12, 1.22)	1.2 (1.11, 1.22)	0.248
Peak V̇_O2/HR (O₂ pulse)^A (mL/min/beat)	7.7 (6.8, 10.4)	7.5 (5.7, 9.3)	0.229
Anaerobic threshold (mL/min/kg)	10.6 (8.5, 12.0)	11.3 (9.5, 12.8)	0.299
V̇_E/V̇_CO2 slope	35.5 (32.0, 42.5)	33.2 (30.0, 39.3)	0.257
ΔV̇_O2/ΔW (mL/min/W)	8.6 (7.1, 10.5)	7.4 (5.6, 9.1)	0.008
Peak heart rate (beats/min)	121.5 (99.3, 136.3)	126.0 (100, 139)	0.469
% Age-predicted maximum heart rate	83.4 (71.0, 90.5)	82.5 (69.7, 94.6)	0.764
HRR (beats/min)	47.5 (29.5, 63.0)	48.0 (37, 65)	0.455
%HRR	66.8 (42.9, 83.6)	69.9 (44.7, 88.1)	0.964

Unless indicated otherwise, data are presented as the median (interquartile range). ^APatients with atrial fibrillation or atrial tachycardia during exercise stress (n=6 for ATTR-CA; n=4 for non-amyloidosis [NA]-HFpEF/HFmrEF) were excluded from the analysis of oxygen pulse. HRR, heart rate reserve; %HRR, percentage heart rate reserve; RER, respiratory exchange ratio; V̇_CO2, carbon dioxide production; V̇_E, minute ventilation; V̇_O2, oxygen consumption; ΔV̇_O2/ΔW, relationship between V̇_O2 and workload (Watts). Other abbreviations as in Table 1.

Figure 1.

Exercise capacity in transthyretin cardiac amyloidosis (ATTR-CA) patients with or without chronotropic incompetence. More severe exercise intolerance was observed in patients with chronotropic incompetence (n=23) than in those without (n=9). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. V̇_CO2, carbon dioxide production; V̇_E, minute ventilation; V̇_O2, oxygen consumption.

Predictors of Exercise Intolerance in Patients With ATTR-CA

Although peak V̇_O2 and V̇_E/V̇_CO2 slope are well-studied CPET variables in patients with heart failure and both provide independent prognostic value, the evidence indicates that V̇_E/V̇_CO2 slope is a greater predictor of prognosis than peak V̇_O2.⁸^,¹⁸ Therefore, we focused on V̇_E/V̇_CO2 slope in further analyses. Univariate analysis demonstrated that age, LV GLS, E/A ratio, TAPSE, RV s′, TAPSE/PASP ratio, and SvO₂ were significantly correlated with V̇_E/V̇_CO2 slope (Table 3). Of the 26 patients undergoing ^{99 m}Tc-PYP scintigraphy, quantitative data were available for 10 patients. The median H/CL ratio was 1.58 (IQR 1.36–1.89). In this limited subpopulation, the H/CL ratio was not significantly correlated with V̇_E/V̇_CO2 slope (95% confidence interval −10.20, 19.92; P=0.54). The TAPSE/PASP ratio has been accepted as a marker of RV-pulmonary artery (PA) coupling because TAPSE reflects RV contractility and PASP serves as a surrogate of afterload.¹⁹ The TAPSE/PASP ratio was significantly correlated with plasma BNP concentrations and the cardiac index in patients with ATTR-CA (Supplementary Figure 2). None of the invasive hemodynamics-related parameters was significantly correlated with V̇_E/V̇_CO2 slope in the present analysis. Interestingly, RV function-related parameters, such as TAPSE, RV s′, and TAPSE/PASE ratio, were strongly correlated with V̇_E/V̇_CO2, whereas LVEF or LV dimension were not. Multiple linear regression analysis was performed incorporating age, sex, GLS, TAPSE/PASP ratio, and SvO₂. Because TAPSE, RV s′, and the TAPSE/PASP ratio were thought to be strongly interrelated, the TAPSE/PASP ratio was chosen for analysis considering the highest coefficient of determination. Multivariate analysis demonstrated that only the TAPSE/PASP ratio was an independent predictor of V̇_E/V̇_CO2 slope (Table 3). As shown in Figure 2, peak V̇_O2 and peak O₂ pulse were significantly correlated with the TAPSE/PASP ratio, as well as V̇_E/V̇_CO2 slope. The AT also showed a nearly significant association with the TAPSE/PASP ratio. Together, these findings suggest that the TAPSE/PASP ratio (RV-PA coupling) determines exercise capacity in patients with ATTR-CA.

Table 3.

Univariate and Multivariate Analyses of V̇_E/V̇_CO2 Slope in Patients With ATTR-CA

Variables	Univariate analysis				Multivariate analysis
Variables	Regression coefficient	95% CI	R²	P value	Regression coefficient	95% CI	P value
Age	0.419	0.054, 0.784	0.145	0.0314	0.1261	−0.376, 0.628	0.6311
Sex	2.413	−2.197, 7.023	0.034	0.3100	−1.6413	−6.882, 3.600	0.5499
BMI	−0.755	−1.535, 0.025	0.107	0.0673
Hemoglobin	−0.248	−1.575, 1.079	0.004	0.7163
Albumin	−4.376	−11.099, 2.347	0.055	0.2125
LVEF	−0.168	−0.354, 0.018	0.095	0.0857
LVIDd	−0.285	−0.677, 0.107	0.063	0.1645
LVMI	0.044	−0.023, 0.111	0.055	0.2111
GLS	1.072	0.327, 1.817	0.241	0.0093	0.1387	−0.959, 1.236	0.8082
E/A ratio	2.322	0.170, 4.474	0.163	0.0455	−2.7864	−5.809, 0.236	0.0939
Deceleration time	−0.005	−0.076, 0.066	0.001	0.8903
E/E′ ratio	0.241	−0.016, 0.498	0.102	0.0753
TAPSE	−0.855	−1.304, −0.406	0.340	0.0009
RV s′	−1.198	−1.960, −0.436	0.260	0.0047
TAPSE/PASP	−20.130	−28.956, −11.304	0.435	0.0001	−27.685	−44.545, −10.825	0.0067
RAP	0.226	−0.811, 1.263	0.006	0.6723
RVSP	0.167	−0.090, 0.424	0.051	0.2119
mPAP	0.173	−0.158, 0.504	0.034	0.3118
PAWP	0.225	−0.171, 0.621	0.040	0.2737
Cardiac index	−2.556	−6.421, 1.309	0.053	0.2047
SvO₂	−0.511	−0.930, −0.092	0.165	0.0235	0.0626	−0.612, 0.737	0.8586
PVR	2.124	−0.373, 4.621	0.085	0.1057
PAPi	0.117	−1.077, 1.311	0.001	0.8490
RVSWI	−0.310	−1.106, 0.486	0.015	0.5090
RAP/PAWP ratio	−17.163	−41.287, 6.961	0.061	0.1734
SVR	0.347	−0.067, 0.761	0.086	0.1104
ACEi/ARB/ARNI	−0.061	−2.885, 2.763	0.000	0.9666
β-blockers	1.562	−1.119, 4.243	0.042	0.2627
MRA	−0.290	−3.044, 2.464	0.001	0.8378
SGLT2i	−0.320	−3.266, 2.626	0.002	0.8327
Diuretics	−2.356	−5.182, 0.470	0.092	0.1127

H/CL, heart-to-contralateral lung. Other abbreviations as in Tables 1,2.

Figure 2.

Relationship between exercise variables and the tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio in patients with transthyretin cardiac amyloidosis (ATTR-CA). Linear regression analysis of the minute ventilation (V̇_E)/carbon dioxide production (V̇_CO2) slope, peak oxygen consumption (V̇_O2), anaerobic threshold (AT), and peak oxygen pulse to the TAPSE/PASP ratio. Sold line: linear regression; shaded areas: 95% condfidence intervals.

Although age, the TAPSE/PASP ratio, and SvO₂ were significantly associated with peak V̇_O2 in univariate analysis, none of these parameters was an independent predictor of peak V̇_O2 in multivariate analysis (Supplementary Table 2).

Exercise Capacity and Its Predictors in Patients With NA-HFpEF/HFmrEF

We further investigated the exercise capacity in patients with NA-HFpEF/HFmrEF to clarify whether the TAPSE/PASP ratio determines exercise intolerance exclusively in patients with ATTR-CA. The baseline characteristics of patients with NA-HFpEF/HFmrEF and in comparison to those with ATTR-CA are presented in Supplementary Tables 3 and 4. Compared with ATTR-CA patients, those with NA-HFpEF/HFmrEF were younger, less likely to be taking diuretics, more likely to be female, and had lower serum troponin T and plasma BNP concentrations. LV hypertrophy was advanced in ATTR-CA patients compared with NA-HFpEF/HFmrEF patients. The E/A ratio, E/e′ ratio, mPAP, and PAWP were significantly higher in ATTR-CA than NA-HFpEF/HFmrEF patients, suggesting advanced restrictive physiology. Conversely, the TAPSE/PASP ratio, stroke index, and SvO₂ were higher in NA-HFpEF/HFmrEF than ATTR-CA patients. Exercise variables obtained through CPET were comparable between the 2 groups, except for ∆V̇_O2/∆W (Table 2). Univariate analysis demonstrated that LV internal dimension at diastole, mitral E wave deceleration time, E/e′ ratio, TAPSE/PASP ratio, SvO₂, PAPi, RAP/PAWP ratio, and SVR were significantly correlated with V̇_E/V̇_CO2 slope in NA-HFpEF/HFmrEF patients (Table 4). However, multiple linear regression analysis incorporating age, sex, and the above parameters revealed that none of the variables had significant correlation with V̇_E/V̇_CO2 slope in NA-HFpEF/HFmrEF patients. The TAPSE/PASP ratio was not an independent predictor of V̇_E/V̇_CO2 slope in NA-HFpEF/HFmrEF patients, in contrast with ATTR-CA patients.

Table 4.

Univariate and Multivariate Analyses of V̇_E/V̇_CO2 Slope in Patients With NA-HFpEF/HFmrEF (n=51)

Variables	Univariate analysis				Multivariate analysis
Variables	Regression coefficient	95% CI	R²	P value	Regression coefficient	95% CI	P value
Age	0.300	−0.039, 0.639	0.059	0.0896	0.51	−0.676, 1.696	0.447
Sex	2.000	−0.221, 4.221	0.061	0.0840	−2.132	−8.267, 4.003	0.5337
BMI	−0.383	−0.932, 0.166	0.037	0.1788
LVEF	0.102	−0.061, 0.265	0.031	0.2241
LVIDd	−0.399	−0.660, −0.138	0.158	0.0043	−0.279	−0.783, 0.225	0.338
E/A ratio	7.047	−2.743, 16.837	0.047	0.1660
Deceleration time	0.036	0.009, 0.063	0.127	0.0131	−0.008	−0.086, 0.070	0.8547
E/E′ ratio	0.556	0.244, 0.868	0.206	0.0010	−0.154	−1.183, 0.875	0.7846
TAPSE	0.346	−0.577, 1.269	0.031	0.4718
RV s′	0.753	−1.258, 2.764	0.035	0.4739
TAPSE/PASP	−22.499	−36.429, −8.569	0.385	0.0060	−20.132	−50.532, 10.268	0.2641
RAP	0.310	−0.403, 1.023	0.020	0.4000
RVSP	0.112	−0.153, 0.377	0.014	0.4116
mPAP	0.150	−0.205, 0.505	0.014	0.4110
PAWP	0.172	−0.269, 0.613	0.012	0.4497
Cardiac index	−2.246	−6.648, 2.156	0.020	0.3223
SvO₂	−0.420	−0.834, −0.006	0.077	0.0516
PVR	2.510	−0.277, 5.297	0.061	0.0839
PAPi	0.863	0.057, 1.669	0.084	0.0412	1.664	−0.837, 4.165	0.2621
RVSWI	0.360	−0.457, 1.177	0.015	0.3930
RAP/PAWP ratio	−9.448	−17.531, −1.365	0.099	0.0264	−8.139	−31.169, 14.891	0.5266
SVR	0.401	0.033, 0.769	0.087	0.0375	0.649	−0.566, 1.864	0.3545
ACEi/ARB/ARNI	1.183	−1.249, 3.615	0.019	0.3451
β-blocker	−0.429	−2.785, 1.927	0.003	0.7225
MRA	−0.453	−2.809, 1.903	0.003	0.7077
SGLT2i	0.230	−2.534, 2.994	0.001	0.8713
Diuretics	0.119	−2.562, 2.800	0.000	0.9313

Abbreviations as in Tables 1–3.

Discussion

In the present study, we demonstrated impaired exercise capacity in patients with ATTR-CA, as evidenced by reduced peak V̇_O2 and AT, and elevated V̇_E/V̇_CO2 slope in the CPET. Most patients showed chronotropic incompetence during exercise stress, and the patients with chronotropic incompetence exhibited elevated V̇_E/V̇_CO2 and decreased peak V̇_O2. V̇_E/V̇_CO2, the most powerful predictive marker of prognosis in heart failure, was significantly correlated with age, LV GLS, E/A ratio, TAPSE, RV s′, TAPSE/PASP ratio, and SvO₂ in patients with ATTR-CA. Multivariate analysis revealed that only the TAPSE/PASP ratio is an independent predictor of V̇_E/V̇_CO2. The TAPSE/PASP ratio was correlated with peak V̇_O2 and peak O₂ pulse, as well as V̇_E/V̇_CO2. These results suggest a strong correlation between the TAPSE/PASP ratio (RV-PA coupling) and exercise capacity in patients with ATTR-CA. Decreased peak V̇_O2 and chronotropic incompetence are reported in patients with ATTR-CA,⁷ but determinants of impaired exercise capacity in ATTR-CA have not yet been established. This is the first study demonstrating that the TAPSE/PASP ratio is an independent predictor of exercise capacity in patients with ATTR-CA, including both HFpEF and HFrEF. We also investigated exercise capacity and its predictors in patients with NA-HFpEF/HFmrEF and found that the TAPSE/PASP ratio was not an independent predictor of V̇_E/V̇_CO2 slope in this cohort, in contrast to ATTR-CA patients.

Right-sided heart failure or RV dysfunction is caused by cardiomyopathies with RV involvement, RV infarction, congenital heart diseases, valvular diseases, and pulmonary hypertension.¹⁹ RV dysfunction has attracted interest because decreased RV ejection fraction (RVEF) is associated with reduced survival in patients with both heart failure with reduced ejection fraction (HFrEF) and HFpEF.²⁰^,²¹ Impaired RV function has also been reported in patients with ATTR-CA.²² RV systolic dysfunction was associated with low survival in patients with CA including both AL and ATTR.²³ RV dysfunction also predicts exercise intolerance in HFrEF and CA.²⁴^,²⁵

Because RV function is determined by venous return, RV afterload, pericardial compliance, and RV contractility, RV-PA coupling is thought to be the most accurate and reliable indicator of the performance of the right heart system. Each parameter reflects only one aspect of RV performance. The relationship between RV end-systolic elastance (Ees) and effective PA elastance (Ea) provides a ratio defining RV-PA coupling, which reflects contractility in the context of afterload.¹⁹ Although the Ees/Ea ratio is a reliable marker of RV-PA coupling, determinations of Ees and Ea require instantaneous measurements of RV pressure and volume to generate sequential pressure-volume loops obtained by a decrease in venous return via stepwise inflation of an inferior vena cava balloon or a Valsalva maneuver.¹⁹ Instead, the TAPSE/PASP ratio has been accepted as a marker of RV-PA coupling because TAPSE reflects RV contractility and PASP serves as a surrogate of afterload.¹⁹ The TAPSE/PASP ratio is associated with mortality in AL-CA.²⁶ An association between the TAPSE/PASP ratio or RV-PA coupling and exercise tolerance has been demonstrated in patients with heart failure, HFpEF, pulmonary arterial hypertension, and chronic thromboembolic pulmonary hypertension.²⁷^–³¹ We have added new evidence of the association between exercise capacity and the TAPSE/PASP ratio in patients with ATTR-CA. In our control cohort of NA-HFpEF/HFmrEF patients, the TAPSE/PASP ratio was not an independent predictor of the V̇_E/V̇_CO2 slope, unlike in a previous study.²⁷ HFpEF is a heterogeneous syndrome and it is possible therefore that our NA-HFpEF/HFmrEF cohort included patients with a different background from that in the previous study.²⁷ Because our HFpEF/HFmrEF cohort included only patients who were histopathologically proven not to have CA by endomyocardial biopsy, we believe that we successfully excluded ATTR-CA patients from the control cohort of HFpEF/HFmrEF with greater certainty than previous studies.

An elevated V̇_E/V̇_CO2 slope has been recognized as one of the greatest prognostic markers in heart failure.⁸^,¹⁸ V̇_E/V̇_CO2, slope is also raised and associated with outcome in pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and chronic thromboembolic pulmonary disease.³²^,³³ Elevated V̇_E/V̇_CO2 slope is associated with increased pulmonary vascular resistance and inversely associated with RVEF.¹⁸ V̇_E/V̇_CO2 slope obtained during submaximal exercise reflects cardiac output, pulmonary artery pressure, and pulmonary capillary wedge pressure.¹⁸ Thus, V̇_E/V̇_CO2 reflects LV dysfunction, RV dysfunction, and pulmonary circulation disturbance. The observation that only the TAPSE/PASP ratio is an independent predictor of the V̇_E/V̇_CO2 slope in the present study suggests that RV involvement of amyloidosis rather than elevated left atrial and LV filling pressures determines exercise intolerance in patients with ATTR-CA. There are 2 possible mechanisms to explain our observation that impaired exercise capacity is associated with RV dysfunction rather than LV dysfunction in ATTR-CA. First, amyloid deposition may occur in the RV prior to the LV, or occur predominantly in the RV in the early stage of disease. In fact, RV function parameters such as TAPSE and RV s′ were decreased even in patients with an early stage of AL-CA presenting normal LV wall thickness and normal E′.³⁴ It is possible that the same phenomenon occurs in ATTR-CA. Second, RV dysfunction-associated skeletal muscle congestion and subsequent microcirculatory disturbance rather than LV dysfunction-associated low cardiac output and pulmonary congestion may determine exercise capacity in the early stage of ATTR-CA. RV dysfunction secondary to pulmonary hypertension led to microcirculatory disturbances in the skeletal muscle in a rat model.³⁵ Patients with idiopathic pulmonary arterial hypertension presenting markedly elevated RAP and PAP with preserved cardiac output showed peripheral muscle dysfunction.³⁶ Future studies with quantitative magnetic resonance imaging assessment of the myocardium and skeletal muscles will investigate these hypotheses.

From a clinical perspective, the RV-PA uncoupling associated with ATTR-CA has been underappreciated. The present study highlights the importance of early therapeutic intervention against amyloidosis regardless of the presence of marked LV hypertrophy or overt left heart failure if patients show a reduced TAPSE/PASP ratio to prevent reductions in quality of life and a poor prognosis.

This study has several limitations. First, this was a retrospective and observational study with a small sample size from a single center. The CPET protocol was not strictly determined in advance and there may be selection bias. Thus, the results may not be applicable to all ATTR-CA patients. Considering that it is not always easy to recruit a number of participants with ATTR-CA to perform maximum exercise testing because of the rarity of ATTR-CA and comorbid multiple ligament disorders and frailty, we believe that the present study is valuable because it successfully demonstrated statistically significant results despite the disadvantage of disease rarity. Second, the present study included only Japanese patients with ATTR-CA. However, the characteristics of patients with ATTR-CA are thought to be relatively homogeneous beyond ethnicity because of the same pathophysiology of amyloidosis. Third, one may raise the possibility that the present analysis may represent the characteristics of relatively mild ATTR-CA population, because 72% of patients were in Stage 1 according to the NAC staging system.¹⁷ It is, however, practically difficult to perform CPET in patients with advanced-stage ATTR-CA. Because one-quarter of the patients in this study were in NAC Stage 2 or 3, we believe it acceptable to consider that our results reflect the characteristics of all stages of ATTR-CA to some extent.

In conclusion, RV-PA coupling estimated by the TAPSE/PASP ratio determines exercise capacity in patients with ATTR-CA. This observation highlights the early involvement of RV dysfunction in ATTR-CA and warrants early therapeutic intervention to improve quality of life and outcome in patients with ATTR-CA.

Acknowledgments

None.

Sources of Funding

This study did not receive any specific funding.

Disclosures

None.

IRB Information

This study was approved by the Kyushu University Hospital Review Board (No. 21113-01).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0402

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