Predictive Ability of Cardiopulmonary Exercise Test Parameters in Heart Failure Patients with Cardiac Resynchronization Therapy

Reis, João Ferreira; Gonçalves, António Valentim; Brás, Pedro Garcia; Moreira, Rita Ilhão; Rio, Pedro; Timóteo, Ana Teresa; Soares, Rui M.; Ferreira, Rui Cruz

doi:10.36660/abc.20210620

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Original Article • Arq. Bras. Cardiol. 119 (3) • Sept 2022 • https://doi.org/10.36660/abc.20210620 linkcopy

Predictive Ability of Cardiopulmonary Exercise Test Parameters in Heart Failure Patients with Cardiac Resynchronization Therapy

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background There is evidence suggesting that a peak oxygen uptake (pVO₂) cut-off of 10ml/kg/min provides a more precise risk stratification in cardiac resynchronization therapy (CRT) patients.

Objective To compare the prognostic power of several cardiopulmonary exercise testing (CPET) parameters in this population and assess the discriminative ability of the guideline-recommended pVO₂cut-off values.

Methods Prospective evaluation of consecutive heart failure (HF) patients with left ventricular ejection fraction ≤40%. The primary endpoint was a composite of cardiac death and urgent heart transplantation (HT) in the first 24 follow-up months, and was analysed by several CPET parameters for the highest area under the curve (AUC) in the CRT group. A survival analysis was performed to evaluate the risk stratification provided by several different cut-offs. p values <0.05 were considered significant.

Results A total of 450 HF patients, of which 114 had a CRT device. These patients had a higher baseline risk profile, but there was no difference regarding the primary outcome (13.2% vs 11.6%, p =0.660). End-tidal carbon dioxide pressure at anaerobic threshold (P_ETCO_2AT)had the highest AUC value, which was significantly higher than that of pVO₂in the CRT group (0.951 vs 0.778, p =0.046). The currently recommended pVO₂cut-off provided accurate risk stratification in this setting (p <0.001), and the suggested cut-off value of 10 ml/min/kg did not improve risk discrimination in device patients (p =0.772).

Conclusion P_ETCO_2ATmay outperform pVO₂’s prognostic power for adverse events in CRT patients. The current guideline-recommended pVO2 cut-off can precisely risk-stratify this population.

Heart Failure; Cardiac Resynchronization Therapy/methods; Exercise Test/methods; Oxygen Consumption; Heart Transplantation

	Overall n 450	CRT n 114	no CRT n 336	p value
	CLINICAL DATA – CHARACTERISTICS
Age	56.2 ± 12.5	62.3 ± 11.5	54.2 ± 12.2	< 0.001
Male (%)	354 (78.7%)	85 (74.6%)	269 (80.1%)	0.216
BMI (kg/m₂)	27.2 ± 4.3	27.2 ± 4.1	27.1 ± 4.4	0.829
Ischemic aetiology (%)	211 (46.9%)	42 (36.8%)	169 (50.6%)	0.011
ACEi/ARB/ARNI (%)	423 (94.0%)	104 (96.3%)	319 (96.1%)	1.000
BB (%)	388 (86.2%)	93 (85.3%)	295 (88.9%)	0.325
MRA (%)	340 (75.6%)	93 (84.5%)	247 (74.2%)	0.026
Diabetes (%)	98 (21.8%)	23 (22.3%)	75 (23.4%)	0.817
CKD (%)	140 (31.1%)	48 (46.6%)	92 (32.1%)	0.008
AF (%)	112 (24.9%)	43 (38.1%)	69 (20.6%)	< 0.001
ICD (%)	271 (60.2%)	112 (98.2%)	159 (47.3%)	< 0.001
NYHA Functional Class	2.2 ± 0.6	2.5 ± 0.5	2.1 ± 0.6	0.001
HFSS*	8.5 ± 1.0	8.14 ± 0.86	8.65 ± 1.04	< 0.001
	LABORATORIAL DATA
Creatinine (mg/dL)	1.4 ± 0.7	1.6 ± 0.4	1.0 ± 0.3	0.041
Sodium (mEq/L)	137.9 ± 3.1	137.5 ± 3.4	138.5 ± 2.9	0.138
NT-proBNP (pg/ml)	2224.2 ± 2764.0	2769.7 ± 2575.4	2034.3 ± 2808.1	0.045
	ECHOCARDIOGRAPHIC DATA
LVEDD (mm/m ² )*	35.5 ± 5.9	37.9 ± 5.5	34.7 ± 5.9	0.032
LVEF (%)	28.6 ± 6.9	26.2 ± 7.2	29.6 ± 6.6	< 0.001
MR III-IV (%)	65 (14.7%)	16 (14.0%)	49 (14.5%)	0.935
	CPET DATA
CPET duration (min)	9.6 ± 4.4	7.4 ± 4.1	10.3 ± 4.3	< 0.001
Peak RER	1.07 ± 0.11	1.05 ± 0.11	1.08 ± 0.10	0.139
pVO ₂ (ml/kg/min)	17.9 ± 6.1	15.2 ± 5.1	18.8 ± 6.1	< 0.001
VE/VCO ₂ slope	33.8 ± 9.5	35.8 ± 10.9	33.2 ± 8.9	0.026
OUES	2.1 ± 1.8	2.2 ± 2.2	2.0 ± 1.6	0.645
pVO ₂ (ml/kg/min) at AT	13.1 ± 4.5	10.3 ± 3.4	13.8 ± 4.5	0.001
O ₂ Pulse (mL/kg/beat)	0.14 ± 0.06	0.12 ± 0.04	0.14 ± 0.07	0.028
Circulatory Power (mmHg.ml.kg-1 min-1)	2786.9 ± 1578.8	2262.3 ± 965.4	2963 ± 1702.4	< 0.001
Ventilatory Power (mmHg)	4.8 ± 1.7	4.4 ± 1.7	4.9 ± 1.7	0.020
Cardiorespiratory Optimal Point	29.6 ± 7.4	30.7 ± 7.5	29.3 ± 7.4	0.274
P_ETCO₂at rest (mmHg)	33.4 ± 4.7	32.9 ± 4.8	33.6 ± 4.7	0.241
P _ET CO _2AT (mmHg)	36.7 ± 5.9	35.3 ± 5.9	37.1 ± 5.9	0.010
P _ET CO _2DIF (mmHg)	3.3 ± 3.7	2.3 ± 3.2	3.6 ± 3.8	0.004

Adverse events at 24 months follow-up	Overal n (%)	CRT Group n (%)	No CRT n (%)	p value
Combined primary endpoint	54 (12.0%)	15 (13.2%)	39 (11.6%)	0.660
Total mortality	38 (8.4%)	11 (9.6%)	27 (8.0%)	0.592
Cardiac mortality	37 (8.2%)	11 (9.6%)	26 (7.7%)	0.521
Sudden cardiac death	14 (3.1%)	3 (2.6%)	11 (3.3%)	0.977
Death for worsening HF	23 (5.1%)	8 (7.0%)	15 (4.5%)	0.285
Urgent HT	16 (3.6%)	4 (3.5%)	12 (3.6%)	0.991

Total Cohort	Univariate, OR (CI 95%)	p value		p value
pVO₂(ml/kg/min)	0.851 (0.799-0.906)	<0.001	0.867 (0.812-0.921)	0.004
VE/VCO₂slope	1.092 (1.061-1.124)	0.005	1.104 (1.020-1.196)	0.015
Cardiorespiratory Optimal Point	1.128 (1.050-1.212)	0.010		0.250
OUES	0.357 (0.179-0.713)	<0.001		0.284
Circulatory Power (mmHg.ml.kg-1 min-1)	0.996 (0.994-0.999)	0.040		0.540
Ventilatory Power (mmHg)	0.471(0.367-0.605)	0.017		0.287
Peak O₂Pulse (mL/kg/beat)	0.769 (0.573-1.031)	0.079		0.357
P_ETCO₂at rest (mmHg)	0.871 (0.814-0.931)	0.012		0.135
P_ETCO_2AT(mmHg)	0.814 (0.763-0.868)	<0.001	0.713 (0.577-0.880)	0.002
P_ETCO_2DIF(mmHg)	0.734 (0.660-0.815)	<0.001		0.110
CRT Group	Univariate, OR (CI 95%)	p value	Multivariate analysis, OR (CI 95%)	p value
pVO₂(ml/kg/min)	0.794 (0.688-0.916)	0.002	0.821 (0.647-0.905)	0.005
VE/VCO₂slope	1.162 (1.077-1.253)	<0.001	1.109 (1.053-1.165)	0.008
Cardiorespiratory Optimal Point	1.101 (0.982-1.235)	0.090		0.319
OUES	0.974 (0.702-1.353)	0.470		0.657
Circulatory Power (mmHg.ml.kg-1 min-1)	0.997 (0.998-0.999)	0.047		0.470
Ventilatory Power (mmHg)	0.313 (0.157-0.624)	0.001		0.314
Peak O₂Pulse (mL/kg/beat)	0.751 (0.371-1.063)	0.097		0.490
P_ETCO₂at rest (mmHg)	0.779 (0.668-0.910)	0.002		0.197
P_ETCO_2AT(mmHg)	0.564 (0.413-0.771)	<0.001	0.527 (0.309-0.898)	0.001
P_ETCO_2DIF(mmHg)	0.595 (0.451-0.786)	<0.001		0.097
No CRT Group
pVO₂(ml/kg/min)	0.860 (0.801-0.924)	<0.001	0.819 (0.668-0.930)	0.007
VE/VCO₂slope	1.075 (1.040-1.110)	<0.001	1.109 (1.015-1.210)	0.012
Cardiorespiratory Optimal Point	1.143 (1.040-1.257)	0.005		0.154
OUES	0.088 (0.030-0.253)	<0.001		0.454
Circulatory Power (mmHg.ml.kg-1 min-1)	0.095 (0.091-0.097)	0.039		0.564
Ventilatory Power (mmHg)	0.513 (0.391-0.674)	<0.001		0.309
Peak O₂Pulse (mL/kg/beat)	0.783 (0.453-1.021)	0.070		0.410
P_ETCO₂at rest (mmHg)	0.900 (0.834-0.972)	0.007		0.229
P_ETCO_2AT(mmHg)	0.849 (0.794-0.907)	0.001		0.080
P_ETCO_2DIF(mmHg)	0.765 (0.682-0.858)	<0.001	0.689 (0.532-0.893)	0.005

Characteristics	CRT Group		No CRT Group		Hanley and McNeil for ROC curve comparison between groups (p value)
Characteristics	AUC	CI 95%	AUC	CI 95%
pVO₂(ml/kg/min)	0.778	0.683-0.873	0.723	0.643-0.804	0.531
VE/VCO₂slope	0.868	0.782-0.954	0.757	0.693-0.822	0.159
Cardiorespiratory Optimal Point	0.668	0.355-0.980	0.739	0.487-0.991	0.699
OUES	0.775	0.591-0.960	0.800	0.710-0.890	0.808
Circulatory Power (mmHg.ml.kg-1 min-1)	0.777	0.679-0.876	0.743	0.668-0.819	0.697
Ventilatory Power (mmHg)	0.830	0.729-0.930	0.759	0.687-0.830	0.398
Peak O₂Pulse (mL/kg/beat)	0.659	0.486-0.831	0.716	0.642-0.761	0.546
P_ETCO₂at rest (mmHg)	0.797	0.518-0.713	0.615	0.518-0.713	0.042
P_ETCO_2AT(mmHg)	0.951	0.900-0.980	0.741	0.662-0.8220	0.002
P_ETCO_2DIF(mmHg)	0.889	0.819-0.960	0.776	0.712-0.841	0.121

Characteristics	CRT Group	No CRT Group
VE/VCO₂slope	0.353	0.613
Cardiorespiratory Optimal Point	0.487	0.900
OUES	0.979	0.261
Circulatory Power (mmHg.ml.kg-1 min-1)	0.992	0.766
Ventilatory Power (mmHg)	0.607	0.592
Peak O₂Pulse (mL/kg/beat)	0.277	0.918
P_ETCO₂at rest (mmHg)	0.855	0.123
P_ETCO_2AT(mmHg)	0.046	0.794
P_ETCO_2DIF(mmHg)	0.213	0.431

Characteristics	CRT Group		No CRT Group
Characteristics	NPV	PPV	NPV	PPV
pVO₂≤ 10 ml/kg/min	89.0%	30.8%	89.1%	26.7%
pVO₂≤ 12 ml/kg/min¹	98.4%	27.5%	93.3%	27.2%
VE/VCO₂slope ≥ 35	96.4%	26.1%	93.1%	21.7%
P_ETCO_2AT≤ 33 mmHg	98.4%	35.7%	91.9%	27.4%

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[TFN1001] Values are mean ± standard deviation or median (interquartile range);p values are calculated by Student´s T-test for independent samples or Mann-Whitney U test as appropriate; chi square test or Fisher exact test were used to compare categorical variables. *Variables with normal distribution. AT: anaerobic threshold; ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; ARNI: angiotensin receptor-neprilysin inhibitors; AF: Atrial fibrillation; BB: Beta-blockers; BMI: body mass index; CPET: cardiopulmonary exercise test; CKD: chronic kidney disease; HFSS: Heart Failure Survival Score; ICD: implantable cardioverter defibrillator; LVEF: left ventricular ejection fraction; LVEDD: left ventricular end-diastolic diameter; MRA: mineralocorticoid receptor antagonists; MR: Mitral regurgitation; NYHA: New York Heart Association; OUES: oxygen uptake efficiency slope; P_ETCO₂: partial pressure of end-tidal carbon dioxide; P_ETCO_2AT: P_ETCO₂at AT; P_ETCO_2DIF: P_ETCO₂increase until the AT is achieved; pVO₂: peak oxygen uptake; RER: respiratory exchange ratio; CRT: cardiac resynchronization therapy.