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Original Clinical Science—General

Impaired Exercise Tolerance Early After Heart Transplantation Is Associated With Development of Cardiac Allograft Vasculopathy

Yu, Mingxi D. MD1; Liebo, Max J. MD1; Lundgren, Scott MD2; Salim, Ahmed M. MD2; Joyce, Cara PhD1; Zolty, Ronald MD, PhD2; Moulton, Michael J. MD2; Um, John Y. MD2; Lowes, Brian D. MD, PhD2; Raichlin, Eugenia MD1,2

Author Information
doi: 10.1097/TP.0000000000003110
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Abstract

INTRODUCTION

Heart transplantation (HTx) is an established therapeutic option for patients with end-stage heart failure (HF) resulting in improvement of survival and symptoms. Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in HTx patients accounting for 30% mortality at 5 years.1 Early CAV is clinically silent, and ischemia is usually not evident until the disease is far advanced.2-6 Cardiac allograft failure tends to develop as a late manifestation of the disease. Therefore, identification of asymptomatic patients at early stages of the disease is an important strategy for the prevention of irreversible detrimental effects on the graft. Noninvasive screening tests have shown insufficient sensitivity and specificity for reliable detection of CAV,7 so coronary angiography is the accepted standard in diagnosing CAV. However, despite its high specificity of 97.8% for CAV, coronary angiography has only moderate sensitivity of 79.3% and underestimates the presence of early coronary atherosclerosis in transplant recipients.8,9

The intimal changes in CAV are best detected by intravascular ultrasound and optical coherence tomography,7 and assessment of endothelial dysfunction and microvascular disease is also useful in early CAV detection10-13; however, these methods are expensive, invasive, and are not routinely performed by many heart transplant programs. Therefore, it is important to identify the cardiac allograft recipients who are most likely to develop CAV to direct more advanced screening by these techniques.

Exercise performance is a marker of quality of life and is an important tool in the assessment of the HF population.14 Of the variables obtained from cardiopulmonary exercise test (CPET), peak oxygen consumption (VO2) and ventilatory equivalent for CO2 (min ventilation [VE]/carbon dioxide production [VCO2] slope) have been demonstrated to be the most prognostic in patients with HF.15,16

After HTx, despite restoration of left ventricular ejection fraction (LVEF), exercise capacity is reported to be 50%– 60% of age-matched healthy controls,17,18 and cardiac limitation may not be different from medically stable HF patients.19 The factors affecting exercise performance after HTx have been studied extensively,20-25 but the prognostic utility of exercise limitation in HTx patients is unknown.

The purpose of this study was to evaluate the prognostic applications of CPET performed 1 year after HTx, and specifically, to identify the ability of peak VO2 and VE/VCO2 to predict the development of angiographic CAV.

MATERIALS AND METHODS

Study

The study was performed at University of Nebraska Medical Center and approved by the institutional review board. A total of 304 consecutive patients who underwent HTx between 2006 and 2017 and had at least 2-year follow-up were considered for analysis. Patients with a history of International Society of Heart and Lung Transplantation (ISHLT) grade ≥ 2R acute cellular rejection (ACR) or grade ≥ 2 pathologic antibody-mediated rejection (AMR) (n = 15) and significant valvular disease (n = 19) during first year after HTx were excluded. Of the rest (n = 270), 243 HTx recipients had performed CPET at 1 year after HTx and comprised the study population.

Patient demographics and clinical data were obtained from the medical records. Donor data were obtained from UNOS DonorNet files. As part of a standard posttransplant protocol, all patients received induction therapy with basiliximab after HTx and were on a triple-drug immunosuppression regimen with tacrolimus, mycophenolate mofetil, and prednisone. Prednisone was tapered from an initial dose of 60 mg daily to 0.2 mg/kg within 3 weeks after HTx and was then weaned gradually by 6 months after HTx. All patients completed a phase II cardiac rehabilitation program during first 6 months after HTx.

Routine endomyocardial biopsies and C4D staining were performed according to the ISHLT recommendations.26,27 The ACR score was calculated at 12 months post-HTx based on the revised ISHLT grading of ACR (ACR: 1R = 1, 2R = 2; 3R = 3) and was normalized to the number of biopsies taken during this period in the individual patient.28 Beginning in 2012, allomap testing replaced biopsies at 6 months post-HTx in stable patients with no prior history of significant rejection. AMR was diagnosed based on positive C4D staining.29

CPET was performed during the first annual post-HTx evaluation. Symptom-limited treadmill exercise testing with respiratory gas exchange analysis using a modified Naughton protocol (2-min workloads, 2 metabolic equivalents/workload increments in work) was performed. Electrocardiograms were continuously monitored, and blood pressure was assessed the last 30 seconds of each 2-minute workload. Exercise duration was expressed in minutes and as a percentage of age and gender-predicted values. Breath-by-breath VE, VCO2, ventilatory equivalent for CO2 (VE/VCO2), and VO2 were measured using a Medical Graphics metabolic cart (St. Paul, MN). Calibration used gravimetric quality gases before each test, and physiologic calibration was performed for weekly quality control. Peak VO2 was the highest averaged 30-second VO2 during exercise and was expressed as absolute peak VO2 or normalized peak VO2 (percentage of age, gender, and weight predicted). Quality of exercise effort was assessed by respiratory exchange ratio (RER). Chronotropic incompetence was defined when heart rate fails to reach an arbitrary 85% of predicted maximal heart rate.30 The original reports were prospectively extracted directly from the medical record and recorded in a research database.

Echocardiography and right heart catheterization (RHC) were performed at 1 year after HTx and within 24 hours of CPET in the majority of patients. All echocardiograms were performed at University of Nebraska Medical Center using a standardized protocol. Left ventricular end-diastolic dimension (LVDD) and left ventricular end-systolic dimension (LVSD), end-diastolic posterior wall thickness, and end-diastolic interventricular septum thickness were measured by 2-dimensional echocardiography. Left ventricular mass was calculated according to the formula 0.8 (1.04 [LVDD + end-diastolic posterior wall thickness + end-diastolic interventricular septum thickness]3 − LVDD)3 + 0.6 g. Stroke volume was determined by Doppler method. LVEF was calculated from the end-systolic and end-diastolic volumetric data using the biplane Simpson rule calculation from the apical 4-chamber and apical 2-chamber views. Diastolic characteristics, assessed by pulse and tissue Doppler, were assessed for each subject.

RHC studies were performed in the supine position through the internal jugular vein. Right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure were assessed at end expiration. Arterial–venous oxygen content difference (A-VO2diff) was measured directly as the difference between systemic and pulmonary arterial O2 contents (Δ saturation × hemoglobin × 1.34). Cardiac output (CO) was determined by the direct Fick method (¼VO2/A–VO2diff), and cardiac index (CI) was determined by CO normalized to body surface area. Stroke volume was determined by CO/heart rate. Restrictive cardiac allograft physiology was defined as symptomatic HF with echocardiographic E to A velocity ratio ≥2, shortened isovolumetric relaxation time (≤60 ms), shortened deceleration time (≤150 ms), or restrictive hemodynamic values (right atrial pressure ≥12 mm Hg, pulmonary capillary wedge pressure ≥ 25 mm Hg, CI ≤2 L/min/m2).31

Coronary angiograms were performed and interpreted yearly during the first 2 annual evaluations and then annually in patients with CAV or every 2 years alternating with noninvasive stress tests as a screening method, and angiography was performed upon detection of clinically significant ischemia. Additional angiograms were obtained if clinically justified. The patients’ charts were reviewed to assess for the development and timing of CAV onset. The diagnosis of CAV was made in accordance with current guidelines,31 and patients with CAV2 or CAV3 comprised the CAV group.

Statistical Analysis

Descriptive analysis was performed by presenting the mean ± SD for normally distributed continuous data or with the median with 25th and 75th percentile interquartile range (IQR). For categorical variables, data were summarized as counts and percentages. To examine differences between groups, Wilcoxon rank sum tests were conducted to compare continuous variables. Pearson’s chi-square tests were conducted for categorical variables. Receiver operating characteristic (ROC) curves were constructed for normalized peak VO2 and VE/VCO2 slope separately for the prediction of CAV, and the optimal threshold values were estimated to maximize sensitivity and specificity. Univariable Cox proportional hazards models were used to estimate hazard ratios for CPET-derived predictors of CAV. An additional Cox proportional hazards model tested for normalized peak VO2 and VE/VCO2 slope with adjustments for other explanatory variables associated with development of CAV. Kaplan–Meier estimates and a log-rank test were used to describe the time to development of CAV. All significance tests were 2 sided, and P values < 0.05 were considered statistically significant.

RESULTS

Among the 243 HTx recipients included in the study, 18 (7%) patients were diagnosed with CAV1 and no patients had signs of more advanced CAV2-3 during first post-HTx angiographic study at 1 year. During a median follow-up time of 31 (IQR 19;61) months, 78 (32%) patients developed CAV2 or CAV3 and comprised the future CAV group.

Patient demographic and pre-HTx clinical characteristics dichotomized by presence or absence of future CAV are illustrated in Table 1. CAV group patients had older donors (32.8 ± 11.2 versus 29.2 ± 10.3 y, P = 0.02). The remainder of demographic and pretransplant clinical characteristics did not differ between the CAV and non-CAV groups.

TABLE 1. - Pretransplant donor and recipient characteristics
Future CAV
N = 78
No future CAV
N = 165
P
Donor
Donor age (y) 32.8 ± 11.2 29.2 ± 10.3 0.02
CIT (min) 168 ± 65 180 ± 58 0.22
Female gender, n (%) 16 (21) 40 (24) 0.62
Duration of CPR (min) 18.3 ± 7.4 23.6 ± 9.3 0.45
Donor history of diabetes, n (%) 5 (6) 7 (4) 0.31
Donor heavy alcohol use, n (%) 10 (13) 30 (18) 0.3
Donor cigarette use, n (%) 10 (13) 23 (14) 0.8
Donor history of hypertension, n (%) 13 (17) 18 (11) 0.3
Donor IV drug use, n (%) 7 (9) 13 (8) 0.9
Donor/recipient BMI 1.0 ± 0.27 1.0 ± 0.32 0.7
Recipient
Age at transplantation (y) 52.6 ± 13.8 50.3 ± 15.0 0.26
LVAD before transplantation, n (%) 27 (35) 71 (43) 0.27
Female gender, n (%) 13 (17) 38 (23) 0.15
White race, n (%) 73 (93) 150 (91) 0.57
Etiology for HTx
 Ischemic cardiomyopathy, n (%)
 Nonischemic cardiomyopathy, n (%)
 Other, n (%)
37 (48)
38 (49)
2 (3)
74 (45)
87 (53)
3 (2)
0.71
Pretransplant diabetes, n (%) 33 (42) 69 (42) 0.91
Pretransplant smoking, n (%) 49 (63) 94 (57) 0.38
Pre-HTx hyperlipidemia, n (%) 51 (65) 87 (53) 0.10
Pre-HTx BMI (kg/m2) 28.7 ± 5.6 28.9 ± 5.8 0.84
PRA class 1, n 4.8 ± 14.6 4.0 ± 14.2 0.71
PRA class 2, n 7.9 ± 22.3 5.7 ± 18.4 0.53
FEV1, % of predicted 74 ± 19 69 ± 16 0.12
DLCO, % of predicted 69 ± 18 67 ± 19 0.42
Time of follow-up (mo) 36 (13;41) 42 (17;63) 0.004
BMI, body mass index; CAV, cardiac allograft vasculopathy; CIT, cold ischemic time; CPR, cardiopulmonary resuscitation; DLCO, diffuse lung capacity for carbon monoxide; FEV, forced respiratory volume; HTx, heart transplantation; LVAD, left ventricular assist device; PRA, panel reactive antibodies.

Clinical characteristics and findings at 1 year post-HTx are illustrated in Table 2. Maintenance immunosuppression was based on tacrolimus and mycophenolate mofetil in both groups, and prednisone was weaned by 1 year post- HTx in 63 (81%) and 143 (87%) HTx recipients in the CAV and non-CAV groups, respectively (P = 0.76). There was no difference in ACR score or incidence of AMR. A larger number of HTx recipients in the CAV group were treated with angiotensin-converting enzyme inhibitors (ACEi) (39[50%] versus 53[32%], P = 0.03) and mineralocorticoid receptor antagonists (11[14%] versus 8[5%], P = 0.04). No difference in laboratory tests at 1 year were identified.

TABLE 2. - Clinical data and laboratory findings 1 y post-HTx stratified by future CAV diagnosis
Future CAV
N = 78
No future CAV
N = 165
P
Hypertension, n (%) 57 (73) 115 (70) 0.57
Diabetes, n (%) 47 (61) 96 (58) 0.68
History of CMV viremia, n (%) 18 (24) 28 (17) 0.11
BMI (kg/m2) 27.5 ± 6.2 26.9 ± 5.1 0.34
AMR, n (%) 12 (15) 16 (16) 0.93
Rejection score 0.35 ± 0.25 0.40 ± 0.24 0.35
Medications
Aspirin, n (%) 66 (85) 135 (82) 0.66
Statin, n (%) 72 (92) 147 (89) 0.43
Diltiazem, n (%) 22 (28) 59 (36) 0.24
Hydralazine, n (%) 6 (8) 18 (11) 0.52
ACE inhibitor, n (%) 39 (50) 53 (32) 0.03
Spironolactone, n (%) 11 (14) 8 (5) 0.04
Tacrolimus, n (%) 78 (100) 165 (100) 1.0
Mycophenolate, n (%) 65 (83) 138 (84) 0.86
Azathioprine, n (%) 7 (6) 10 (6) 0.83
Prednisone, n (%) 15 (19) 22 (13) 0.76
Prednisone dose (mg) 5.3 ± 3.1 3.6 ± 3.0 0.10
Laboratories
WBC (K/μL) 7.4 ± 3.9 6.3 ± 2.4 0.08
Hemoglobin (g/dL) 13.3 ± 1.7 13.0 ± 1.9 0.41
Platelet count (K/μL) 211 ± 73 185 ± 58 0.14
BUN (mg/dL) 23 ± 9 23 ± 13 0.67
Creatinine (mg/dL) 1.3 ± 0.5 1.2 ± 0.4 0.28
GFR (mL/min/m2) 67.7 ± 28.6 71.8 ± 31.3 0.41
Bilirubin (mg/dL) 1.0 ± 3.5 1.0 ± 2.8 0.90
Albumin (g/dL) 3.9 ± 0.4 3.8 ± 0.5 0.47
TSH (μIU/mL) 2.1 ± 1.2 2.0 ± 1.7 0.91
LDL cholesterol (mg/dL) 87.3 ± 33 78.6 ± 27 0.15
HDL cholesterol (mg/dL) 42.5 ± 12.8 46.8 ± 17.7 0.13
Triglycerides (mg/dL) 206 ± 95 185 ± 73 0.19
Echocardiographic findings
LVDD (cm) 4.3 ± 0.5 4.3 ± 0.4 0.81
LVM (g) 179 ± 47 168 ± 48 0.12
LVEF (%) 57 ± 11 60 ± 10 0.19
E′ (m/s) 9.7 ± 2.3 10.8 ± 2.6 0.02
E/E 10.0 ± 4.7 8.2 ± 3.0 0.03
RVDD (cm) 3.4 ± 0.6 3.5 ± 0.5 0.76
TR ≤ grade 2, n (%) 10 (8) 7 (4) 0.30
RHC
RAP mean (mm Hg) 8.3 ± 6.0 7.1 ± 4.7 0.14
PAP mean (mm Hg) 22.8 ± 7.9 20.9 ± 5.3 0.12
PCWP mean (mm Hg) 13.1 ± 6.9 11.4 ± 5.0 0.12
PCWP >25 mm Hg, n (%) 2 (3) 5 (3) 0.99
CI (L/min/m2 Fick) 2.9 ± 0.5 3.2 ± 0.7 0.0008
PA sat (%) 67.1 ± 8.3 70.5 ± 5.8 0.008
Angiographic CAV1, n (%) 8 (10) 10 (6) 0.09
ACE, angiotensin-converting enzyme; AMR, antibody-mediated rejection; BMI, body mass index; BUN, blood urea nitrogen; CAV, cardiac allograft vasculopathy; CI, cardiac index; GFR, glomerular filtration rate; HDL, high-density lipoprotein; HTx, heart transplantation; LDL, low-density lipoprotein; LVDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVM, left ventricular mass; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RHC, right heart catheterization; TSH, thyroid-stimulating hormone; WBC, white blood cells.

On echocardiography 1 year after HTx, cardiac allograft size, left ventricular mass, and LVEF did not differ between the CAV and non-CAV groups. E′ was smaller (9.7 ± 2.3 versus 10.8 ± 2.6, P = 0.02) and E/E′ was higher (10.0 ± 4.7 versus 8.2 ± 3.0, P = 0.03) in the CAV group. There was no difference between the groups in right ventricular function or size and tricuspid valve function.

For invasive RHC hemodynamics 1 year post-HTx, there was no significant difference in intracardiac and pulmonary artery pressures; however, pulmonary artery oxygen saturation (67.1% ± 8.3% versus 70.5% ± 5.8%, P = 0.008) and CI (2.9 ± 0.5 versus 3.2 ± 0.7 L/min, P = 0.0008) were lower in the CAV group.

CPET findings 1 year post-HTx dichotomized by future CAV are illustrated in Table 3. There were no ECG changes consistent with ischemia during CPET. Resting heart rate during CPET was similar between groups; however, normalized heart rate (77% ± 11% versus 82% ± 13%; P = 0.03) was lower in the CAV patients. The resting and peak stress blood pressures did not differ between the groups. Mean exercise duration (9.6 ± 3.5 versus 11.4 ± 4.8 min; P = 0.008) and exercise capacity (5.2 ± 1.9 versus 6.5 ± 2.2 metabolic equivalents; P = 0.001) were significantly reduced in the CAV group compared to the non-CAV group. RER was similar (1.13 ± 0.08 versus 1.12 ± 0.08; P = 0.78) and indicated good exercise effort in both groups.

TABLE 3. - CPET results 1 y after HTx stratified by future CAV diagnosis
Future CAV
N = 78
No future CAV
N = 165
P
Exercise duration (min) 9.6 ± 3.5 11.4 ± 4.8 0.008
Rest HR at CPET (bpm) 96 ± 10 99 ± 11 0.17
Peak HR at CPET (bpm) 128 ± 17 141 ± 18 <0.0001
Normalized HR (%) 77 ± 11 82 ± 13 0.03
Systolic BP rest (mm Hg) 122 ± 15 121 ± 12 0.61
Diastolic BP rest (mm Hg) 73 ± 11 74 ± 8 0.55
Systolic BP stress (mm Hg) 144 ± 23 147 ± 20 0.44
Diastolic BP stress (mm Hg) 78 ± 10 77 ± 9 0.81
METs (kcal/kg/h) 5.2 ± 1.9 6.5 ± 2.2 0.001
Peak VO2 (mL/kg/min) 18.4 ± 5.4 21.4 ± 6.1 0.0005
Peak VO2 ≤14, mL/kg/min, n (%) 20 (25) 18 (11) 0.01
Normalized VO2 (%) 63 ± 18 71 ± 19 0.007
Normalized VO2 ≤60%, n (%) 37 (47) 36 (22) 0.001
RER 1.13 ± 0.08 1.12 ± 0.08 0.78
VE/VCO2 34 ± 5 32 ± 5 0.04
VE/VCO ≥34, n (%) 40 (51) 38 (23) 0.005
Norm peak VO2% ≤60 and VE/VCO2 ≥34, n (%) 27 (35) 13 (8) 0.0001
Breathing reserve (%) 50 ± 12 49 ± 13 0.75
BP, blood pressure; CAV, cardiac allograft vasculopathy; CPET, cardiopulmonary exercise test; HR, heart rate; HTx, heart transplantation; METs, metabolic equivalents; RER, respiratory exchange ratio; VCO2, carbon dioxide production; VE, minute ventilation; VO2, oxygen consumption.

Absolute peak VO2 (18.4 ± 5.4 versus 21.4 ± 6.1 mL/kg/min; P = 0.0005) was lower, and the proportion of patients with peak VO2 ≤14 mL/kg/min was higher (18[25%] versus 16 [11%], P = 0.01) in the CAV group as compared to the non-CAV group. The CAV group patients also had a lower normalized peak VO2 (63% ± 18% versus 71% ± 19%; P = 0.007) and higher VE/VCO2 (34 ± 5 versus 32 ± 5, P = 0.04). In the CAV and non-CAV groups, respectively, 37 (47%) versus 36 (22%) patients had normalized peak VO2 ≤60% (P = 0.001); 40 (51%) versus 38 (23%) had VE/VCO2 ≥34 (P = 0.005); and 27 (35%) versus 13 (8%) had combined normalized peak VO2 ≤60% and VE/VCO2 ≥34.

ROC curve analysis demonstrated that normalized peak VO2 (area under the curve, 0.69; 95% CI 0.61-0.72; P = 0.03) and VE/VCO2 slope (area under the curve 0.75; 95% CI 0.68-0.79; P = 0.001) prognostic classification schemes were both statistically significant. Optimal prognostic threshold values for normalized peak VO2 and VE/VCO2 were 60% (sensitivity 73%; specificity 52%) and 34% (sensitivity 85%; specificity 57%), respectively.

We divided the study cohort into 4 subgroups on the basis of the presence or absence of normalized peak VO2 ≤60% and the presence or absence of VE/VCO2 ≥34. On Kaplan–Meier analysis, freedom from CAV at 5 years after HTx was 77% for patients with normalized VO2 >60% and VE/VCO2 <34, 68% for patients with normalized VO2 ≤60% and VE/VCO2 <34, 45% for patients with normalized VO2 >60 and VE/VCO2 ≥34, and 13% in patients with normalized VO2 ≤60% and VE/VCO2 ≥34 (Figure 1; P < 0.0001). Curve separation starts approximately 2 years after HTx and continues during the entire follow-up period.

FIGURE 1.
FIGURE 1.:
Angiographic CAV-free survival stratified for normalized peak VO2 and VE/VCO2 levels. A, VO2% >60 and VE/VCO2 <34. B, VO2% ≤ 60 and VE/VCO2 <34. C, VO2% >60 and VE/VCO2 ≥ 34. D, VO2% ≤ 60 and VE/VCO2 ≥ 34. Freedom from CAV at 5 y after HTx was 77%, 68%, 45%, and 13% in the different groups, respectively (P < 0.0001). CAV, cardiac allograft vasculopathy; HTx, heart transplantation; VCO2, carbon dioxide production; VE, minute ventilation; VO2, oxygen consumption.

On Cox proportional hazards regression analysis, normalized peak VO2 ≤60% and VE/VCO2 ≥34 were the strongest predictors of angiographic CAV among CPET indices. There was a significant increased risk of CAV compared to the normalized peak VO2 >60% and VE/VCO2 <34 referent subgroup, with an HR of 1.5 (95% CI 1.08-3.31, P = 0.05) for the normalized peak VO2 ≤60% and VE/VCO2 <34 subgroup, an HR of 2.0 (95% CI 1.14-4.47, P = 0.04) for normalized peak VO2 >60% and VE/VCO2 ≥34 subgroup, and an HR of 3.7 (95% CI 1.90-7.19, P = 0.001) for VO2 ≤60% and VE/VCO2 ≥34 subgroup (Table 4).

TABLE 4. - CPET-derived predictors of CAV (Cox proportional hazards regression analysis)
Variable Hazard ratio 95% CI P
Time exercised 1.5 0.41-6.09 0.68
% predicted HR 0.6 0.38-3.89 0.56
% norm peak VO2 >60 and VE/VCO2 <34 1 (reference)
% norm peak VO2 ≤60 and VE/VCO2 <34 1.5 1.08-3.31 0.05
% norm peak VO2 >60 and VE/VCO2 ≥34 2.0 1.14-4.47 0.04
% norm peak VO2 ≤60 and VE/VCO2 ≥34 3.7 1.90-7.19 0.001
CAV, cardiac allograft vasculopathy; CPET, cardiopulmonary exercise test; VCO2, carbon dioxide production; VE, minute ventilation; VO2, oxygen consumption.

After adjustment for clinical variables, hemodynamic variables, and the presence of 1-year angiographic CAV, normalized peak VO2 ≤60% and VE/VCO2 ≥34 independently predicted a 1.8 (95% CI 1.10-4.53, P = 0.03) and 2.5 (95% CI 1.01-8.81, P = 0.04) hazard ratio for future CAV, respectively. A combination of normalized peak VO2 ≤60% and VE/VCO2 ≥34 identified a subgroup of patients with the highest risk for development of CAV (HR = 5.2, 95% CI 2.27-15.17, P = 0.001). Older donor age (HR 1.04, 95% CI 0.81-1.17, P = 0.05) and the presence of CAV1 on 1-year angiogram (HR 2.1, 95% CI 0.95-5.50, P = 0.03) were associated with progression to CAV2-3 (Table 5).

TABLE 5. - Predictors of angiographic CAV adjusted for clinical variables (Cox proportional hazards regression analysis)
Variable Hazard ratio 95% CI P
Donor age 1.04 0.81-1.17 0.05
Spironolactone 0.71 0.24-1.22 0.14
ACEi 0.8 0.27-1.34 0.24
CAV1, 1 y 2.1 0.95-5.50 0.03
E/E 0.34 0.18-1.74 0.52
CI (Fick), 1 y 1.4 0.98-5.50 0.06
Mean RAP, 1 y 2.1 0.85-3.30 0.80
% norm peak VO2 ≤60 and VE/VCO2 <34 1.8 1.10-4.53 0.03
% norm peak VO2 >60 and VE/VCO2 ≥34 2.5 1.01-8.81 0.04
% norm peak VO2 ≤60 and VE/VCO2 ≥34 5.2 2.27-15.17 0.001
ACEi, angiotensin-converting enzyme inhibitors; CAV, cardiac allograft vasculopathy; RAP, right atrial pressure; VE, minute ventilation; VCO2, carbon dioxide production; VO2, oxygen consumption.

There was no association of 1-year CAV and donor age with peak VO2 or VE/VCO2.

There was no association of CPET measurements with survival.

DISCUSSION

Using a longitudinal analysis, the current study demonstrates that exercise intolerance on CPET performed at 1 year after HTx is associated with increased risk of future CAV. The reduction in peak VO2 and increased ventilatory equivalent for CO2 independently identified patients at higher risk for subsequent advanced angiographic CAV. Furthermore, decreased peak VO2 ≤60% and elevated VE/VCO2 ≥34 had an additive effect in the prediction of risk for future CAV2-3. The associations remained significant after taking into account other hemodynamic, echocardiographic, and clinical characteristics, including the presence of CAV1 at 1 year post-HTx. In this manner, CPET performed 1 year after HTx may contribute to better identification of patients at increased risk for the development of advanced CAV, a leading cause of late morbidity and mortality in HTx recipients.1 Early clinical identification of these patients is important for choosing invasive diagnostics strategies and medical treatment for the prevention or attenuation of progressive irreversible detrimental effects on the graft.32-35

Exercise capacity is severely limited in advanced HF patients.16 It improves early after HTx with a peak at 1 year36; however, despite restoration of left ventricular systolic function after HTx, exercise performance continues to be subnormal in a significant proportion of HTx recipients.37-41 In the present study, CPET 1 year after HTx was significantly abnormal in about half of the HTx recipients who in the long run developed angiographic CAV. Among all measurements performed during CPET, normalized peak VO2 consumption and VE/VCO2 were the strongest predictors of future CAV.

Peak VO2, a noninvasive surrogate for CO during exercise, was significantly reduced in our HTx population: 25% of CAV patients had absolute peak VO2 ≤14 mL/kg/min. Normalized peak VO2, a more reliable exercise parameter,42 was also associated with increased risk. In our study, a normalized peak VO2 ≤60% was associated with a hazard ratio of 1.8 (95% CI 1.10-4.53, P = 0.03) for future CAV. Exercise effort assessed by RER was good in both groups; however, it is possible that peak VO2 was not accurately obtained in individual patients because of decrease in cardiac effort and/or limitations in peripheral muscle metabolic capacity in the setting of immunosuppressive medications.

VE/VCO2 is generally independent from subject effort, and a VE/VCO2 slope ≥34 has been suggested to be a useful prognostic marker of HF outcomes.40,41,43,44 In line with previous studies,45 51% of post-HTx our study patients had VE/VCO2 ≥34 which was also associated with a hazard ratio of 2.5 (95% CI 1.01-8.81, P = 0.04) for CAV.

Our study also provided evidence that the combination of normalized peak VO2 ≤60% and VE/VCO2 ≥34, which was found in 35% of CAV group patients, identified a subgroup having a 5.2-fold (95% CI 2.27-15.17, P = 0.001) increased hazard ratio for CAV. The freedom from CAV at 5 years after HTx in this patient subgroup was only 13%.

The combination of reduced normalized peak VO2 and increased VE/VCO2 in HTx recipients may provide possible mechanistic insight into the cardiopulmonary limitations to exercise in the patients with subclinical CAV. Elevated VE/VCO2 ratio is indicative of pulmonary congestion and, in the setting of preserved LVEF, may imply a decrease in diastolic compliance during exercise. In our study, the future CAV group also had lower E′ and higher E/E′ values on echocardiography, supporting this mechanism. The detrimental effect of exaggerated increased LV filling pressure during exercise on exercise capacity after HTx has been previously described.19,25,36 Additionally, there is a growing body of evidence that elevated LV filling pressure is associated with subclinical CAV in pediatric46,47 and adult48 HTx recipients.

Although simultaneous invasive and noninvasive exercise hemodynamics were not obtained in this study, RHC and echocardiograms were performed within 24 hours from CPET in the majority of patients. Among the various echocardiographic parameters, E/E′ was the only univariate predictor of CAV progression. Invasively measured resting cardiac filling pressures did not differ between the groups; however, the patients who ultimately developed CAV had lower CIs at 1 year after HTx. In multivariable analysis, none of the resting hemodynamic parameters had any predictive value, whereas the CPET indices were the strongest predictors of CAV.

Similar to other studies,20,49,50 exercise capacity after HTx in our study was limited by chronotropic incompetence of the cardiac allograft. Chronotropic incompetence has previously been suggested as a poor predictor of clinical outcomes in heart transplant patients.20 The association between sinus node dysfunction or chronotropic incompetence and CAV was shown in a small study previosuly.51

ACEi are used as a first-line therapy for hypertension in patients after HTx. Although they stabilize levels of endothelial progenitor cells and improve microvascular function, these effects do not appear to translate into amelioration or prevention of CAV.52 In our study, a larger proportion of patients in the CAV group were treated with ACEi and mineralocorticoid receptor antagonist during first year after transplantation, but no effect on CAV progression was found with multivariate analysis.

Clinical Implications

An optimal screening method for early detection of CAV has not been established. Coronary angiography, while highly specific for CAV, lacks sensitivity and is associated with significant risk including contrast-induced nephropathy making it a suboptimal initial screening tool for many patients.53,54 Similarly, intravascular ultrasound and optical coherence tomography, the gold standard for the detection of increased intimal thickness and early CAV,55-58 can be time-consuming and expensive and associated with additional increased risk of complications. Herein, our study suggests exercise intolerance with reduced normalized peak VO2 and elevated VE/VCO2 on noninvasive CPET during first annual post-HTx screening can be used to identify patients who would most benefit from more sensitive intravascular diagnostic imaging techniques. Since only early changes in immunosuppression from calcineurin inhibitors to proliferation signal inhibitors have been associated with attenuation of CAV progression, the use of CPET early after HTx to facilitate the diagnosis of subclinical CAV could be cost-effective and improve outcomes after HTx.

Limitations

This is a single-center retrospective analysis of a prospectively created database. High-risk patients, those who died during the first 2 years after HTx, patients with significant rejection and valvular disease, and patients who were not able to perform CPET at 1 year after HTx 27 (10%), were excluded from the study. Therefore, no patient had advanced CAV at first-year angiographic study. Because of this selection bias, overall mortality was low in our study (16 patients) and may explain why we did not observe any association between CPET performance and mortality. Furthermore, the median follow-up time was only 31 (IQR 19;61) months. A larger study with longer follow-up would be needed to assess the role of CPET and mortality after HTx.

The intimal changes of CAV were not assessed with intravascular technologies, and as such, some cases may have been underdiagnosed. Moreover, the association of poor exercise performance and ventilatory response with later development of angiographic CAV does not prove causality, and the potential benefit of therapies that retard the progression of CAV in patients with poor exercise performance will require further investigation.

The ROC curve analysis in our study demonstrated that normalized peak VO2 and VE/VCO2 slope prognostic classification schemes were both statistically significant, and our optimal cut-points for peak VO2 and VE/VCO2 were consistent with clinical practice; however, the sensitivities and specificities of the ROC curves analysis were suboptimal. Future prospective studies are necessary to validate our findings.

CONCLUSIONS

This study suggests that CPET performed during the first annual screening of HTx recipients can identify patients at high risk of developing advanced CAV. CPET should be performed before coronary angiogram, and patients with normalized peak VO2 ≤60% and VE/VCO2 ≥34 should be targeted for more sensitive intravascular diagnostic interventions. Further studies are needed to validate these findings and to determine whether early diagnostic and pharmacologic intervention based on CPET results can improve outcome after HTx.

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