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Prognostic Role of Hypertensive Response to Exercise in Patients With Repaired Coarctation of Aorta
Canadian Journal of Cardiology 34 (2018) 676e682
Clinical Research
Prognostic Role of Hypertensive Response to Exercise in Patients With Repaired Coarctation of Aorta Vidhushei Yogeswaran, BS,a Heidi M. Connolly, MD,b Mohamad Al-Otaibi, MBBS,b Naser M. Ammash, MD,b Carole A. Warnes, MD,b Sameh M. Said, MD,c and Alexander C. Egbe, MD, MPHb a b
Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA c
Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA
See editorial by Millar and Oechslin, pages 536-539 of this issue. ABSTRACT
RESUM E
Background: This study aimed to determine the prevalence of hypertensive response to exercise (HRE) and its association with cardiovascular adverse events (CAEs) in patients with repaired coarctation of aorta (rCOA). Methods: We retrospectively reviewed records of adult patients with rCOA who had cardiopulmonary exercise tests (CPETs) and follow-up from 1994 to 2014 at Mayo Clinic. Patients with residual COA, defined as aortic isthmus peak velocity >2.5 m/s, were excluded. HRE was defined as peak systolic blood pressure >200 mm Hg; CAEs were defined as cardiovascular death, stroke, acute coronary syndrome, heart failure hospitalization, and left ventricular ejection fraction (LVEF) < 35%. Results: One hundred thirty-eight patients (82 men [59%]) underwent 213 CPETs, with follow-up of 85 13 months. Age at initial COA repair was 9 3 years; age at initial CPET was 40 13 years. HRE occurred in 26 (19%) patients, and 24 (92%) of the patients with HRE had normal resting blood pressure. There were no differences in age, blood pressure at rest, and CPET findings between patients with HRE and those with normotensive response to exercise. There were 28 CAEs in
tude visait à de terminer la pre valence de la re ponse Contexte : Cette e ponse hypertensive à l’effort (RHE) ainsi que l’association entre cette re ve nements inde sirables cardiovasculaires (EIC) chez des paet les e paration d’une coarctation de l’isthme aortique tients ayant subi une re (rCOA). thodologie : Nous avons effectue un examen re trospectif des Me te dossiers de patients adultes ayant subi une rCOA, qui avaient e preuves d’effort cardiopulmonaire (EECP) et à un suivi soumis à des e sentant une entre 1994 et 2014 à la clinique Mayo. Les patients pre siduelle (de finie par une vitesse maximale du flux sur l’isthme COA re te exclus. La RHE e tait de finie par une aortique > 2,5 m/s) ont e rielle systolique maximale > 200 mm Hg; la de finition pression arte ve nements suivants : mortalite cardiovascudes EIC comprenait les e laire, AVC, syndrome coronarien aigu, hospitalisation pour insuffisance jection ventriculaire gauche (FEVG) < 35 %. cardiaque et fraction d’e sultats : Un total de 138 patients (82 hommes [59 %]) ont subi 213 Re 85 13 mois. L’âge des patients au moment EECP, et leur suivi a dure paration initiale de la COA e tait de 9 3 ans; au moment des de la re tait de 40 13 ans. La RHE est apparue chez EECP initiaux, leur âge e
Coarctation of the aorta (COA) is a congenital anomaly characterized by a narrowed aortic segment near the ligamentum arteriosum, and it accounts for 5% to 8% of congenital heart diseases.1-3 The timing of presentation is variable, ranging from newborn to adulthood, and the timing is often related to the severity of the obstruction and the presence of other associated structural heart diseases.1,2
Several studies have shown that patients with repaired coarctation of aorta (rCOA) remain at risk for cardiovascular morbidity and mortality even after successful surgical repair.2,4,5 Mortality is mainly due to the consequences of hypertension and coronary artery disease.2,4,5 Meticulous blood pressure control has become the standard of care in the management of patients with rCOA because of the central role of systemic hypertension in the pathogenesis of cardiovascular adverse events (CAEs) in this population.6 The criterion for initiation and titration of antihypertension therapy is based primarily on blood pressure measurement obtained at rest.6 Patients with COA have abnormal vascular compliance and endothelial dysfunction, and this can result in hypertensive response to exercise (HRE) even in the setting of normal
Received for publication December 13, 2017. Accepted February 5, 2018. Corresponding author: Dr Alexander C. Egbe, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. Tel.: þ1507-284-2520; fax: 507-266-0103. E-mail: [email protected] See page 681 for disclosure information.
https://doi.org/10.1016/j.cjca.2018.02.004 0828-282X/Ó 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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24 patients (17%), and HRE was an independent risk factor for CAE (hazard ratio [HR], 1.46 [1.13e2.52]; P ¼ 0.04). Conclusions: HRE can occur even in the setting of normal blood pressure at rest, and it is a risk factor for CAE. We speculate that patients with HRE represent a high-risk group of patients who, presumably, have occult, advanced vascular dysfunction. CPET can identify these patients. The benefit of intensive antihypertension therapy needs to be confirmed.
taient normotendus au 26 (19 %) patients; 24 (92 %) de ces patients e rence n’a e te observe e quant à l’âge, à la pression repos. Aucune diffe rielle au repos et aux re sultats des EECP entre les patients arte sentant une RHE et ceux dont la re ponse hypertensive e tait norpre male à l’effort. Il s’est produit 28 EIC chez 24 patients (17 %), et la tait un facteur de risque inde pendant d’EIC (rapport des risques RHE e s [RRI]: 1,46 [1,13-2,52]; p ¼ 0,04). instantane Conclusion : La RHE peut apparaître même chez les sujets normotendus au repos, et constitue un facteur de risque d’EIC. Selon notre sentent un groupe à hypothèse, les patients obtenant une RHE repre leve qui, vraisemblablement, sont atteints d’une dysfonction risque e e occulte. Les EECP pourraient permettre de reconvasculaire avance naître ces patients. L’avantage du traitement antihypertensif nergique reste à confirmer. e
blood pressure at rest.6,7 The concept of HRE after rCOA is well known, and it is sometimes used as an indicator of clinically significant residual or recurrent obstruction.8,9 However, the prevalence and the clinical implications of HRE in the absence of clinically significant residual or recurrent COA have not been studied in adults with rCOA. Therefore, the purpose of this study was to (1) determine the prevalence of HRE in patients without clinically significant residual or recurrent COA; (2) determine the association between HRE and the occurrence of CAE; and (3) determine the risk of procedure-related complications during cardiopulmonary exercise tests (CPETs).
peak oxygen consumption (VO2), and minute ventilation were measured with a computerized breath-by-breath analyzer. Blood pressure was measured manually every 2 minutes, and the 12-lead ECG and transcutaneous oxygen saturation were monitored continuously. Resting heart rate was measured with the patient in a seated position after at least 2 minutes of complete rest. The peak heart rate was defined as the maximal heart rate during exercise monitoring.11 Chronotropic index and heart rate reserve were calculated as previously described.11 Peak exercise parameters were generated using standard equations, as previously described.12 Peak VO2 was expressed as percent of predicted value because of the inherent differences by age in mL/kg/min for normal peak VO2.
Methods
Study hypothesis and end points
Patient selection
The study hypothesis was that HRE would be prognostic of CAEs in patients with rCOA. HRE was defined as systolic blood pressure at peak exercise of more than 200 mm Hg, and normotensive response to exercise (NRE) was defined as systolic blood pressure at peak exercise of equal to or less than 200 mm Hg.13 We decided to use this cut-point for HRE instead of the gender-specific cut-point of >210 mm Hg for men and >190 mm Hg for women,14 so that our study design will be comparable with previously published studies. A CAE was defined as cardiovascular death, stroke, acute coronary syndrome, heart failure hospitalization, and severe left ventricular systolic dysfunction (ejection fraction [EF] <35%). The definitions of these CAE end points have been previously published.15,16 Only 1 CAE was counted per patient, and the time of the first CAE was used as the occurrence of a CAE end point for that patient; the time of the first CPET within the study period was considered as time zero. Procedural complications during CPET were defined as exercise-induced atrial or ventricular arrhythmia, exercise-induced ischemia on ECG, sudden cardiac death, or mechanical injury during exercise.
This is a retrospective review of electronic health records for adults (age >18 years) with a history of rCOA followed up in the Mayo Clinic Adult Congenital Heart Disease clinic from January 1, 1994, through December 31, 2014. The inclusion criteria were (1) history of rCOA; (2) at least 1 CPET using a treadmill ergometer; and (3) at least 1 year of follow-up after CPET. The exclusion criteria were (1) incomplete documentation of blood pressure at peak exercise and (2) clinically significant residual or recurrent COA, defined as the presence of 1 of the following: uncorrected peak velocity >2.5 m/s at the aortic isthmus; abnormal Doppler profile of the abdominal aorta, with a blunted upstroke suggestive of COA; and a difference in blood pressure gradient for the upper and lower extremity of more than 20 mm Hg. The Mayo Clinic Institutional Review Board approved this study and waived written informed consent for those who provided research authorization. Acquisition of exercise and clinical data Electronic health records were reviewed in detail, including clinical notes, echocardiograms, electrocardiograms (ECGs), CPET results, and surgical notes. CPET was performed using a treadmill ergometer with an incremental protocol (Naughton protocol or the modified Bruce protocol), and CPET protocol used in this study has been previously described.10 CPET is the standard of care for all adult congenital heart disease patients at Mayo Clinic. Carbon dioxide elimination,
Statistical analysis Continuous variables were reported as mean standard deviation or median (range) for skewed data. KolmogorovSmirnov was used as goodness-of-fit test to determine the distribution of continuous variables. Categorical variables were reported as percentages. Continuous variables were compared with a 2-sided, unpaired Student t test or a Wilcoxon rank sum test, and categorical variables were compared
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using the c2 test or the Fisher exact test, as appropriate. Analyses were done with JMP software, version 10.0 (SAS Institute Inc., Cary, North Carolina). CPET, echocardiographic, and clinical data obtained at baseline (at the time of first evaluation within the study period) were reviewed, and the association between these variables and the occurrence of a CAE was analyzed using a Cox proportional hazards model. The variables included in the univariate model were chosen a priori on the basis of clinical variables that have been shown to affect outcomes in patients with congenital and acquired heart disease.10,13,16 The single conditional imputation method was used to correct for missing data. Schoenfeld residuals method was used to test proportional hazard model assumptions. Variables that reached statistical significance on univariate analysis were used to construct an incremental model to assess the impact of HRE on the occurrence of a CAE. Model 1 was created to adjust for the presence of HRE. Model 2 included all variables in Model 1 plus adjustments for hypertension diagnosis. Model 3 included all variables in Model 2 plus adjustment for age at COA repair. Model 4 included all variables in Model 3 plus adjustment for age at CPET. Model 5 included all variables in Model 4 plus adjustment for relative wall thickness. The risk for each variable was expressed as a hazard ratio (HR) and 95% confidence interval (CI). The freedom from CAE was assessed using the Kaplan-Meier method and compared using the log-rank test. For all statistical analyses, P < 0.05 was considered significant. Results Baseline characteristics Of 483 adult patients with rCOA, 138 met the inclusion criteria for this study. The mean age at the time of baseline CPET was 40 13 years, and 82 (59%) patients were men. Of the 138 patients, 109 (79%) had hypertension, and 11 (8%) had coronary artery disease (CAD). The most common associated left heart lesions were bicuspid aortic valve in 126 (91%) patients and subaortic stenosis in 13 (9%) patients. Patients had an average of 2 (range: 1e3) surgical or transcatheter interventions; the most common procedures were resection and end-to-end anastomosis (98 [41%] patients) and aortic valve replacement (31 [13%] patients). The baseline clinical data are shown in Table 1, and the baseline CPET and echocardiographic data are shown in Table 2. The 138 patients underwent 213 CPET, and there were 21 (10%) procedural complications (exercise-induced atrial arrhythmia, 19 patients; exercise-induced ischemia on ECG, 2 patients). All cases of arrhythmia and ischemia resolved within 5 minutes after termination of exercise. There were no mechanical injuries or sudden cardiac deaths during exercise. Hypertensive response to exercise HRE occurred in 26 (19%) patients. Table 3 compares the baseline characteristics of the patients with HRE and those with NRE. The groups were similar in age at the time of COA repair and CPET, sex, blood pressure at rest, and exercise capacity. However, the patients with HRE had a higher left ventricular filling pressure based on assessment by Doppler echocardiography, a higher relative wall thickness, and were less likely to be on
Canadian Journal of Cardiology Volume 34 2018 Table 1. Baseline clinical characteristics at time of first CPET (N ¼ 138) Age, mean SD, years Male sex Body mass index, kg/m2 Comorbidities Coronary artery disease Hypertension Diabetes mellitus Hyperlipidemia Smoking Sleep apnea Creatinine clearance <60 mL/min Atrial fibrillation Atrial flutter NYHA class III/IV Associated left-sided heart lesions Bicuspid aortic valve Subaortic stenosis Mitral valve stenosis Parachute mitral valve Supravalvular mitral ring Procedural data (240 total interventions) Interventions per patient, No. (range) Resection and end-to-end anastomosis Subclavian flap repair Patch aortoplasty Ascending to descending aorta jump graft Balloon dilatation/stenting Aortic valve replacement Mitral valve repair/replacement Resection of subaortic stenosis Other Therapies Antihypertension therapy* Antiplatelet therapy Anticoagulation therapy
40 13 82 (59%) 28 8 11 109 10 56 20 14 13 20 10 4
(8%) (79%) (7%) (41%) (14%) (10%) (9%) (14%) (7%) (3%)
126 13 4 9 1
(91%) (9%) (3%) (7%) (0.7%)
2 (1-3) 98 (41%) 12 (5%) 8 (3%) 26 (11%) 15 31 15 18 17
(6%) (13%) (6%) (8%) (7%)
79 (57%) 60 (43%) 34 (25%)
CPET, cardiopulmonary exercise test; NYHA, New York Heart Association. * Calcium channel blocker, beta blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, thiazide diuretic, hydralazine.
antihypertension therapy. Among the 26 patients with HRE, 21 had their antihypertension therapy changed in response to the abnormal CPET result: initiation of antihypertension agent, 11 patients; dosage increase, 6 patients; addition of a second antihypertension agent, 2 patients; and change to a different antihypertension agent, 2 patients. Ambulatory blood pressure recording was available in 43 patients (31%); 14 and 29 patients had HRE and NRE, respectively. Median systolic blood pressure > 140 mm Hg was present in 7 of 14 patients (50%) in the HRE group vs 4 of 29 patients (14%) in the NRE group, P ¼ 0.01, even though both groups had similar resting blood pressures. When we re-analyzed our data using the gender-based cut-point that defined HRE as >210 mm Hg for men and > 190 mm Hg for women, HRE was still present in 26 patients (19%), but the gender distribution changed slightly (14 male patients and 12 female patients instead of 15 men and 11 women using the cutpoint of > 200 mm Hg for both genders. Cardiovascular adverse events A total of 28 CAEs occurred in 24 (17%) patients during a follow-up period of 85 13 months. These CAEs were
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Table 2. CPET and echocardiography data (N ¼ 138)
Table 4. Predictors of cardiovascular adverse events
CPET Peak VO2, mL/kg/min Peak VO2, % predicted VE/VCO2 nadir Metabolic equivalent Functional aerobic capacity Resting systolic BP, mm Hg Resting diastolic BP, mm Hg Resting heart rate, bpm Peak systolic BP, mm Hg Peak diastolic BP, mm Hg Peak heart rate, bpm Peak heart rate, % predicted Sinus rhythm Echocardiographic parameters LV ejection fraction, % LV E/e0 ratio LV mass index, g/m2 Tricuspid regurgitation velocity, m/s Mean aortic valve gradient, mm Hg Mean mitral valve gradient, mm Hg COA peak velocity, m/s Corrected COA peak velocity, m/s Relative wall thickness
25 13 67 20 31 3 94 77 20 122 18 73 14 72 18 171 25 69 21 149 32 83 15 128 (93%) 62 13 108 2.7 11 3 2.2 1.9 0.46
8 2 35 0.6 4 2 0.6 0.2 0.05
BP, blood pressure; bpm, beats per minute; COA, coarctation of aorta; CPET, cardiopulmonary exercise test; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; LV, left ventricular; peak VO2, peak oxygen consumption; VE/VCO2, ventilatory equivalent for carbon dioxide.
Table 3. Hypertensive response to exercise Variable Age, year Age at first COA repair, year Male sex Ever smoker Body mass index, kg/m2 Resting systolic BP, mm Hg Resting diastolic BP, mm Hg Resting systolic BP <140 mm Hg Peak diastolic BP, mm Hg Prior diagnosis of hypertension Peak heart rate, bpm Peak VO2, mL/kg/min Metabolic equivalent Peak VO2, % predicted Mean aortic valve gradient, mm Hg COA peak velocity, m/s Corrected COA peak velocity, m/s LV ejection fraction, % LV E/e0 ratio LV mass index, g/m2 Relative wall thickness Antihypertension therapy Beta blocker Calcium channel blocker ACEi/ARB Hydralazine Thiazide diuretic agent
HRE (n ¼ 26)
NRE (n ¼ 112)
P value
41 8 10 4 15 (58%) 4 (25%) 29 6 129 6 81 5 24 (92%)
40 11 92 67 (60%) 16 (14%) 28 9 121 14 71 11 106 (95%)
0.21 0.33 0.34 0.72 0.18 0.17 0.09 0.43
89 3 12 (46%)
82 10 76 (68%)
0.22 0.07
28 8 2 14 5
0.41 0.11 0.16 0.08 0.49
2.4 0.4 1.9 0.3
2.2 0.5 1.9 0.2
0.13 0.38
66 5 15 2 116 24 0.47 0.02 4 (15%) 2 (8%) 5 (20%) 0 1 (4%) 4 (15%)
61 8 12 2 104 36 0.44 0.02 39 (35%) 20 (18%) 36 (32%) 5 (5%) 20 (18%) 39 (35%)
0.33 0.04 0.17 0.01 0.03 0.05 0.49 0.26 0.99 0.85
151 24 8 63 9
17 11 5 16 4
147 26 9 71 12
ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blockers; BP, blood pressure; bpm, beats per minute; COA, coarctation of aorta; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; HRE, hypertensive response to exercise; LV, left ventricle; NRE, normotensive response to exercise; peak VO2, peak oxygen consumption.
Univariate HR (95% CI)
P value
1.87 (1.12e2.67)
0.03
2.14 0.97 1.74 1.15 1.32 1.36 1.02 2.41 1.29 1.17 0.83 1.12 0.91 1.76 2.05
(1.36e3.77) (0.38e2.16) (1.13e3.12) (0.78e1.98) (0.81e3.11) (0.88e2.85) (0.15e6.32) (1.36e4.12) (0.76e3.15) (0.82e2.97) (0.55e5.14) (0.77e2.39) (0.03e4.18) (0.94e3.11) (1.24e3.97)
0.02 0.18 0.03 0.31 0.19 0.09 0.33 0.01 0.17 0.31 0.46 0.16 0.32 0.08 0.01
1.76 (0.93e2.88)
0.07
Variable Age at COA repair, per 5 year increment Age at CPET, per 5 year increment Male sex Diagnosis of hypertension Antihypertension therapy Ever smoker Peak VO2, < 50% predicted VE/VCO2 nadir > 32 HRE (peak systolic BP > 200 mm Hg) Resting systolic BP > 140 mm Hg Peak diastolic BP > 90 mm Hg Exercise-induced arrhythmia Exercise-induced ischemia on ECG LV ejection fraction < 50% LV E/e0 ratio > 14 Relative wall thickness, per 0.2-point increment COA peak velocity > 2.0 m/s
BP, blood pressure; CI, confidence interval; COA, coarctation of aorta; CPET, cardiopulmonary exercise test; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; ECG, electrocardiogram; HR, hazard ratio; LV, left ventricular; peak VO2, peak oxygen consumption; VE/VCO2, ventilatory equivalent for carbon dioxide.
cardiovascular death (n ¼ 4), stroke (n ¼ 9), acute coronary syndrome (n ¼ 2), heart failure hospitalization (n ¼ 8), and severe left ventricular systolic dysfunction (n ¼ 5). Tables 4 and 5 show the univariate and multivariate risk factors for CAEs. HRE was an independent risk factor for CAE (HR, 1.46; 95% CI: 1.13e2.52; P ¼ 0.04). The freedom from CAEs was significantly lower in the patients with HRE than in those with NRE (67% vs 88% at 60 months, P ¼ 0.03) (Fig. 1). Discussion Patients with rCOA are at a higher risk for cardiovascular morbidity and mortality than age-matched controls from the general population.1,2,5 For this study, we reviewed records for 138 adult patients with rCOA and without clinically significant residual or recurrent COA. The study showed that HRE
Table 5. Incrementally adjusted risk for cardiovascular adverse events Model Model Model Model Model Model
HR (95% CI) 1* 2y 3z 4x 5{
2.41 1.78 1.69 1.53 1.46
(1.36e4.12) (1.31e2.54) (1.33e2.69) (1.22e2.14) (1.13e2.52)
P value 0.01 0.02 0.02 0.04 0.04
CI, confidence interval; HR, hazard ratio. * Model 1: included adjustments for hypertensive response to exercise. y Model 2: included all variables in Model 1 plus adjustments for hypertension diagnosis. z Model 3: included all variables in Model 2 plus adjustment for age at coarctation repair. x Model 4: included all variables in Model 3 plus adjustment for age at cardiopulmonary exercise testing. { Model 5: included all variables in Model 4 plus adjustment for relative wall thickness.
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Figure 1. Freedom for cardiovascular adverse events (CAEs) for patients with hypertensive response to exercise (HRE) and normotensive response to exercise (NRE); a significant difference existed between groups (P ¼ 0.03).
can occur in patients with normal resting blood pressure and that HRE was associated with a higher risk of CAEs during follow-up. Hypertensive response to exercise HRE occurred in 26 (19%) of the patients; of these 26 patients, 24 (92%) had normal blood pressure at rest, and 10 (29%) were on antihypertension therapy. Hypertension is present in 5% to 45% of patients with rCOA, and the prevalence is associated with older age at the time of initial repair, duration of follow-up, male sex, and higher body mass index.17-19 Hypertension has important prognostic value in patients with rCOA because it is postulated to be the underlying factor that drives the pathogenesis of cardiovascular morbidity and mortality.17,18 The definition of hypertension and the outcome data for hypertension in this population is based on blood pressure obtained at rest.1,2,17 The concept of HRE in patients with rCOA was described more than 4 decades ago.9 Since that time, studies have reported the prevalence and clinical implications (or absence) of HRE in patients with rCOA.9,20,21 In a retrospective study by Correia et al.,20 of 65 adult patients with rCOA (49 had CPET), HRE occurred in 11 (22%) patients. The authors reported that baseline hypertension treated with an angiotensin-converting enzyme inhibitor and a higher gradient at the aortic isthmus were risk factors for HRE. In our study, the patients’ demographic characteristics, such as age at the time of COA repair and age at CPET, were similar to those in the study by Correia et al.20 However, our study excluded patients with clinically significant residual or recurrent COA. As a result, the HRE in our study patients was more likely a true reflection of vascular dysfunction than fixed obstruction due to re-coarctation. Unlike the study by Correia et al., which focused on the incidence and risk factors for HRE, our study reported an association between HRE and CAEs in this population. This is novel and may perhaps become a potentially important risk-stratification tool. In a prospective study of 74 patients with rCOA, 36% of the patients were hypertensive at rest, 15% had HRE, and 49% had normal blood pressure at rest and during exercise.21
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More than half the patients with HRE developed hypertension at rest during a follow-up period of 6 years. The authors postulated that HRE was a marker for preclinical hypertension. In our study, both the patients with HRE and NRE had similar blood pressure at rest despite a difference in the response of blood pressure to exercise. During aerobic exercise, cardiac output increases because of a sympathetically mediated increase in heart rate and stroke volume. The blood pressure response to an exercise-induced increase in cardiac output is moderated, in part, by a decrease in peripheral vascular resistance via endothelium-dependent vasodilation and microcirculatory reserve.22,23 This mechanism prevents an exaggerated increase in systolic blood pressure (peak systolic pressure > 200 mm Hg) during exercise.22,23 Patients with COA, in contrast, have diffuse arteriopathy characterized by impaired vascular compliance and endothelial dysfunction, and as a result, an exercise-induced increase in cardiac output can result in spikes in systolic blood pressure and, hence, HRE.6,7,19 Another potential mechanism involves alteration in autonomic function. The known vascular dysfunction could impair arterial baroreflex sensitivity.24 The current study suggests that this abnormality in vascular function can be unmasked during exercise even in patients with normal blood pressure at rest. Cardiovascular adverse events There were 28 CAEs among the 24 (17%) patients followed up for 85 months. In addition to the previously described risk factors for CAE, such as age and hypertension at rest, the current study identified HRE as a risk factor for CAE. Previous studies have described HRE as a marker for preclinical hypertension, and some studies have used HRE as an indicator for hemodynamically significant re-coarctation.20-23 According to guidelines from the American College of Cardiology/American Heart Association and the European Society of Cardiology, the importance of isolated HRE is a matter of debate and is not considered a definite indication for the initiation of antihypertension therapy.25,26 The current study showed that HRE was an independent risk factor for CAEs in patients without significant re-coarctation, even after correction for the traditional risk factors such as age and blood pressure at rest. Furthermore, the current study also showed that CPET was safe in patients with COA. Clinical implications and future directions There are 2 important clinical observations from this study: (1) A different blood-pressure response to exercise was noted for rCOA patients with NRE and HRE despite similar blood pressure at rest, and (2) rCOA patients with HRE were less likely to have a formal diagnosis of hypertension and less likely to be taking antihypertension therapy. These observations highlight the limitations of using systolic blood pressure obtained at rest in the office as the benchmark for determining adequate blood pressure control in this population. We speculated that if the occurrence of HRE were incorporated as one of the criteria for initiation and titration of antihypertension therapy in this population, more patients with HRE would be taking antihypertension medications. Antihypertension therapy could potentially decrease the risk for CAEs.
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In addition, the results of the current study have another important clinical implication: Blood pressure at rest may not be reflective of day-to-day blood pressure for patients with rCOA because of spikes during physical activity that are caused by reduced aortic compliance. Unfortunately, ambulatory blood pressure was not routinely monitored in our practice, and, as a result, the data were not analyzed. However, the observations from this study provide preliminary data for future studies to evaluate the association between HRE, changes in ambulatory blood pressure, and direct measures of vascular and endothelial function. Such studies will provide more robust mechanistic data about the dissociation between blood pressure during rest and exercise observed in the current study. In addition, a prospective study could compare clinical outcomes for patients on conventional antihypertension regimens, using the benchmark of resting blood pressure less than 140 mm Hg, with patients on intensive antihypertension regimens titrated on the basis of blood-pressure response during exercise. Limitations This is a single-center, retrospective study of outcomes in a small cohort of patients with rCOA who underwent CPET. We did not analyze the occurrence of CAE in the rest of the COA cohort who did not undergo CPET, and this may affect generalizability of our results. Another important limitation of the current study is the absence of data for ambulatory bloodpressure monitoring; as a result, we do not know the average blood pressure of the patients during their day-to-day activities and its potential impact on CAEs. Furthermore, we did not directly assess vascular function, thus making it difficult to infer a direct association between HRE and vascular dysfunction. All these factors limit the inferences that can be drawn from the current study. Conclusions Based on a review of 138 patients with rCOA who underwent to 213 CPETs and were followed for 85 months, the current study showed that HRE was present in 19% of patients with rCOA and was associated with an increased risk of CAE on short-term follow-up. Also, CPETs can be performed safely in this population without serious procedure-related complications. We speculate that rCOA patients with HRE represent a high-risk group of patients who, presumably, have more advanced vascular dysfunction, and cardiopulmonary exercise testing can identify these patients to allow for more intensive antihypertension therapy. Disclosures The authors have no conflicts of interest to disclose. References 1. Rosenthal E. Coarctation of the aorta from fetus to adult: curable condition or life long disease process? Heart 2005;91:1495-502. 2. Krieger EV, Stout K. The adult with repaired coarctation of the aorta. Heart 2010;96:1676-81. 3. Egbe A, Uppu S, Stroustrup A, Lee S, Ho D, Srivastava S. Incidences and sociodemographics of specific congenital heart diseases in the United
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States of America: an evaluation of hospital discharge diagnoses. Pediatr Cardiol 2014;35:975-82. 4. Brown ML, Burkhart HM, Connolly HM, Dearani JA, Hagler DJ, Schaff HV. Late outcomes of reintervention on the descending aorta after repair of aortic coarctation. Circulation 2010;122:S81-4. 5. Brown ML, Burkhart HM, Connolly HM, et al. Coarctation of the aorta: lifelong surveillance is mandatory following surgical repair. J Am Coll Cardiol 2013;62:1020-5. 6. de Divitiis M, Pilla C, Kattenhorn M, et al. Ambulatory blood pressure, left ventricular mass, and conduit artery function late after successful repair of coarctation of the aorta. J Am Coll Cardiol 2003;41:2259-65. 7. de Divitiis M, Pilla C, Kattenhorn M, et al. Vascular dysfunction after repair of coarctation of the aorta: impact of early surgery. Circulation 2001;104(12 suppl 1):I165-70. 8. Daniels SR, James FW, Loggie JM, Kaplan S. Correlates of resting and maximal exercise systolic blood pressure after repair of coarctation of the aorta: a multivariable analysis. Am Heart J 1987;113:349-53. 9. James FW, Kaplan S. Systolic hypertension during submaximal exercise after correction of coarctation of aorta. Circulation 1974;50:II27-34. 10. Egbe AC, Driscoll DJ, Khan AR, et al. Cardiopulmonary exercise test in adults with prior Fontan operation: the prognostic value of serial testing. Int J Cardiol 2017;235:6-10. 11. Diller GP, Dimopoulos K, Okonko D, et al. Heart rate response during exercise predicts survival in adults with congenital heart disease. J Am Coll Cardiol 2006;48:1250-6. 12. Astrand I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand Suppl 1960;49:1-92. 13. Lauer MS, Levy D, Anderson KM, Plehn JF. Is there a relationship between exercise systolic blood pressure response and left ventricular mass? The Framingham Heart Study. Ann Intern Med 1992;116: 203-10. 14. Fletcher GF, Ades PA, Kligfield P, et al; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology, Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular and Stroke Nursing, and Council on Epidemiology and Prevention. Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation 2013;128:873-934. 15. Egbe AC, Connolly HM, Niaz T, et al. Prevalence and outcome of thrombotic and embolic complications in adults after Fontan operation. Am Heart J 2017;183:10-7. 16. Egbe AC, Warnes CA. Cardiovascular adverse events after aortic valve replacement in mixed aortic valve disease: beyond ejection fraction. J Am Coll Cardiol 2016;68:2591-3. 17. Rinnstrom D, Dellborg M, Thilen U, et al. Hypertension in adults with repaired coarctation of the aorta. Am Heart J 2016;181:10-5. 18. Wu MH, Chen HC, Kao FY, Huang SK. Risk of systemic hypertension and cerebrovascular accident in patients with aortic coarctation aged <60 years (from a National Database Study). Am J Cardiol 2015;116:779-84. 19. de Divitiis M, Rubba P, Calabro R. Arterial hypertension and cardiovascular prognosis after successful repair of aortic coarctation: a clinical model for the study of vascular function. Nutr, Metab. Cardiovasc Dis 2005;15:382-94. 20. Correia AS, Goncalves A, Paiva M, et al. Long-term follow-up after aortic coarctation repair: the unsolved issue of exercise-induced hypertension. Rev Port Cardiol 2013;32:879-83.
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21. Luijendijk P, Bouma BJ, Vriend JW, Vliegen HW, Groenink M, Mulder BJ. Usefulness of exercise-induced hypertension as predictor of chronic hypertension in adults after operative therapy for aortic isthmic coarctation in childhood. Am J Cardiol 2011;108:435-9. 22. Thanassoulis G, Lyass A, Benjamin EJ, et al. Relations of exercise blood pressure response to cardiovascular risk factors and vascular function in the Framingham Heart Study. Circulation 2012;125:2836-43. 23. Lim PO, MacFadyen RJ, Clarkson PB, MacDonald TM. Impaired exercise tolerance in hypertensive patients. Ann Intern Med 1996;124: 41-55. 24. Lee MGY, Hemmes RA, Mynard J, et al. Elevated sympathetic activity, endothelial dysfunction, and late hypertension after repair of coarctation of the aorta. Int J Cardiol 2017;243:185-90.
Canadian Journal of Cardiology Volume 34 2018 25. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e143-263. 26. Baumgartner H, Bonhoeffer P, De Groot NM, et al; Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC); Association for European Paediatric Cardiology (AEPC); ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31:2915-57.
Clinical Research
Prognostic Role of Hypertensive Response to Exercise in Patients With Repaired Coarctation of Aorta Vidhushei Yogeswaran, BS,a Heidi M. Connolly, MD,b Mohamad Al-Otaibi, MBBS,b Naser M. Ammash, MD,b Carole A. Warnes, MD,b Sameh M. Said, MD,c and Alexander C. Egbe, MD, MPHb a b
Mayo Clinic School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA c
Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA
See editorial by Millar and Oechslin, pages 536-539 of this issue. ABSTRACT
RESUM E
Background: This study aimed to determine the prevalence of hypertensive response to exercise (HRE) and its association with cardiovascular adverse events (CAEs) in patients with repaired coarctation of aorta (rCOA). Methods: We retrospectively reviewed records of adult patients with rCOA who had cardiopulmonary exercise tests (CPETs) and follow-up from 1994 to 2014 at Mayo Clinic. Patients with residual COA, defined as aortic isthmus peak velocity >2.5 m/s, were excluded. HRE was defined as peak systolic blood pressure >200 mm Hg; CAEs were defined as cardiovascular death, stroke, acute coronary syndrome, heart failure hospitalization, and left ventricular ejection fraction (LVEF) < 35%. Results: One hundred thirty-eight patients (82 men [59%]) underwent 213 CPETs, with follow-up of 85 13 months. Age at initial COA repair was 9 3 years; age at initial CPET was 40 13 years. HRE occurred in 26 (19%) patients, and 24 (92%) of the patients with HRE had normal resting blood pressure. There were no differences in age, blood pressure at rest, and CPET findings between patients with HRE and those with normotensive response to exercise. There were 28 CAEs in
tude visait à de terminer la pre valence de la re ponse Contexte : Cette e ponse hypertensive à l’effort (RHE) ainsi que l’association entre cette re ve nements inde sirables cardiovasculaires (EIC) chez des paet les e paration d’une coarctation de l’isthme aortique tients ayant subi une re (rCOA). thodologie : Nous avons effectue un examen re trospectif des Me te dossiers de patients adultes ayant subi une rCOA, qui avaient e preuves d’effort cardiopulmonaire (EECP) et à un suivi soumis à des e sentant une entre 1994 et 2014 à la clinique Mayo. Les patients pre siduelle (de finie par une vitesse maximale du flux sur l’isthme COA re te exclus. La RHE e tait de finie par une aortique > 2,5 m/s) ont e rielle systolique maximale > 200 mm Hg; la de finition pression arte ve nements suivants : mortalite cardiovascudes EIC comprenait les e laire, AVC, syndrome coronarien aigu, hospitalisation pour insuffisance jection ventriculaire gauche (FEVG) < 35 %. cardiaque et fraction d’e sultats : Un total de 138 patients (82 hommes [59 %]) ont subi 213 Re 85 13 mois. L’âge des patients au moment EECP, et leur suivi a dure paration initiale de la COA e tait de 9 3 ans; au moment des de la re tait de 40 13 ans. La RHE est apparue chez EECP initiaux, leur âge e
Coarctation of the aorta (COA) is a congenital anomaly characterized by a narrowed aortic segment near the ligamentum arteriosum, and it accounts for 5% to 8% of congenital heart diseases.1-3 The timing of presentation is variable, ranging from newborn to adulthood, and the timing is often related to the severity of the obstruction and the presence of other associated structural heart diseases.1,2
Several studies have shown that patients with repaired coarctation of aorta (rCOA) remain at risk for cardiovascular morbidity and mortality even after successful surgical repair.2,4,5 Mortality is mainly due to the consequences of hypertension and coronary artery disease.2,4,5 Meticulous blood pressure control has become the standard of care in the management of patients with rCOA because of the central role of systemic hypertension in the pathogenesis of cardiovascular adverse events (CAEs) in this population.6 The criterion for initiation and titration of antihypertension therapy is based primarily on blood pressure measurement obtained at rest.6 Patients with COA have abnormal vascular compliance and endothelial dysfunction, and this can result in hypertensive response to exercise (HRE) even in the setting of normal
Received for publication December 13, 2017. Accepted February 5, 2018. Corresponding author: Dr Alexander C. Egbe, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. Tel.: þ1507-284-2520; fax: 507-266-0103. E-mail: [email protected] See page 681 for disclosure information.
https://doi.org/10.1016/j.cjca.2018.02.004 0828-282X/Ó 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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24 patients (17%), and HRE was an independent risk factor for CAE (hazard ratio [HR], 1.46 [1.13e2.52]; P ¼ 0.04). Conclusions: HRE can occur even in the setting of normal blood pressure at rest, and it is a risk factor for CAE. We speculate that patients with HRE represent a high-risk group of patients who, presumably, have occult, advanced vascular dysfunction. CPET can identify these patients. The benefit of intensive antihypertension therapy needs to be confirmed.
taient normotendus au 26 (19 %) patients; 24 (92 %) de ces patients e rence n’a e te observe e quant à l’âge, à la pression repos. Aucune diffe rielle au repos et aux re sultats des EECP entre les patients arte sentant une RHE et ceux dont la re ponse hypertensive e tait norpre male à l’effort. Il s’est produit 28 EIC chez 24 patients (17 %), et la tait un facteur de risque inde pendant d’EIC (rapport des risques RHE e s [RRI]: 1,46 [1,13-2,52]; p ¼ 0,04). instantane Conclusion : La RHE peut apparaître même chez les sujets normotendus au repos, et constitue un facteur de risque d’EIC. Selon notre sentent un groupe à hypothèse, les patients obtenant une RHE repre leve qui, vraisemblablement, sont atteints d’une dysfonction risque e e occulte. Les EECP pourraient permettre de reconvasculaire avance naître ces patients. L’avantage du traitement antihypertensif nergique reste à confirmer. e
blood pressure at rest.6,7 The concept of HRE after rCOA is well known, and it is sometimes used as an indicator of clinically significant residual or recurrent obstruction.8,9 However, the prevalence and the clinical implications of HRE in the absence of clinically significant residual or recurrent COA have not been studied in adults with rCOA. Therefore, the purpose of this study was to (1) determine the prevalence of HRE in patients without clinically significant residual or recurrent COA; (2) determine the association between HRE and the occurrence of CAE; and (3) determine the risk of procedure-related complications during cardiopulmonary exercise tests (CPETs).
peak oxygen consumption (VO2), and minute ventilation were measured with a computerized breath-by-breath analyzer. Blood pressure was measured manually every 2 minutes, and the 12-lead ECG and transcutaneous oxygen saturation were monitored continuously. Resting heart rate was measured with the patient in a seated position after at least 2 minutes of complete rest. The peak heart rate was defined as the maximal heart rate during exercise monitoring.11 Chronotropic index and heart rate reserve were calculated as previously described.11 Peak exercise parameters were generated using standard equations, as previously described.12 Peak VO2 was expressed as percent of predicted value because of the inherent differences by age in mL/kg/min for normal peak VO2.
Methods
Study hypothesis and end points
Patient selection
The study hypothesis was that HRE would be prognostic of CAEs in patients with rCOA. HRE was defined as systolic blood pressure at peak exercise of more than 200 mm Hg, and normotensive response to exercise (NRE) was defined as systolic blood pressure at peak exercise of equal to or less than 200 mm Hg.13 We decided to use this cut-point for HRE instead of the gender-specific cut-point of >210 mm Hg for men and >190 mm Hg for women,14 so that our study design will be comparable with previously published studies. A CAE was defined as cardiovascular death, stroke, acute coronary syndrome, heart failure hospitalization, and severe left ventricular systolic dysfunction (ejection fraction [EF] <35%). The definitions of these CAE end points have been previously published.15,16 Only 1 CAE was counted per patient, and the time of the first CAE was used as the occurrence of a CAE end point for that patient; the time of the first CPET within the study period was considered as time zero. Procedural complications during CPET were defined as exercise-induced atrial or ventricular arrhythmia, exercise-induced ischemia on ECG, sudden cardiac death, or mechanical injury during exercise.
This is a retrospective review of electronic health records for adults (age >18 years) with a history of rCOA followed up in the Mayo Clinic Adult Congenital Heart Disease clinic from January 1, 1994, through December 31, 2014. The inclusion criteria were (1) history of rCOA; (2) at least 1 CPET using a treadmill ergometer; and (3) at least 1 year of follow-up after CPET. The exclusion criteria were (1) incomplete documentation of blood pressure at peak exercise and (2) clinically significant residual or recurrent COA, defined as the presence of 1 of the following: uncorrected peak velocity >2.5 m/s at the aortic isthmus; abnormal Doppler profile of the abdominal aorta, with a blunted upstroke suggestive of COA; and a difference in blood pressure gradient for the upper and lower extremity of more than 20 mm Hg. The Mayo Clinic Institutional Review Board approved this study and waived written informed consent for those who provided research authorization. Acquisition of exercise and clinical data Electronic health records were reviewed in detail, including clinical notes, echocardiograms, electrocardiograms (ECGs), CPET results, and surgical notes. CPET was performed using a treadmill ergometer with an incremental protocol (Naughton protocol or the modified Bruce protocol), and CPET protocol used in this study has been previously described.10 CPET is the standard of care for all adult congenital heart disease patients at Mayo Clinic. Carbon dioxide elimination,
Statistical analysis Continuous variables were reported as mean standard deviation or median (range) for skewed data. KolmogorovSmirnov was used as goodness-of-fit test to determine the distribution of continuous variables. Categorical variables were reported as percentages. Continuous variables were compared with a 2-sided, unpaired Student t test or a Wilcoxon rank sum test, and categorical variables were compared
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using the c2 test or the Fisher exact test, as appropriate. Analyses were done with JMP software, version 10.0 (SAS Institute Inc., Cary, North Carolina). CPET, echocardiographic, and clinical data obtained at baseline (at the time of first evaluation within the study period) were reviewed, and the association between these variables and the occurrence of a CAE was analyzed using a Cox proportional hazards model. The variables included in the univariate model were chosen a priori on the basis of clinical variables that have been shown to affect outcomes in patients with congenital and acquired heart disease.10,13,16 The single conditional imputation method was used to correct for missing data. Schoenfeld residuals method was used to test proportional hazard model assumptions. Variables that reached statistical significance on univariate analysis were used to construct an incremental model to assess the impact of HRE on the occurrence of a CAE. Model 1 was created to adjust for the presence of HRE. Model 2 included all variables in Model 1 plus adjustments for hypertension diagnosis. Model 3 included all variables in Model 2 plus adjustment for age at COA repair. Model 4 included all variables in Model 3 plus adjustment for age at CPET. Model 5 included all variables in Model 4 plus adjustment for relative wall thickness. The risk for each variable was expressed as a hazard ratio (HR) and 95% confidence interval (CI). The freedom from CAE was assessed using the Kaplan-Meier method and compared using the log-rank test. For all statistical analyses, P < 0.05 was considered significant. Results Baseline characteristics Of 483 adult patients with rCOA, 138 met the inclusion criteria for this study. The mean age at the time of baseline CPET was 40 13 years, and 82 (59%) patients were men. Of the 138 patients, 109 (79%) had hypertension, and 11 (8%) had coronary artery disease (CAD). The most common associated left heart lesions were bicuspid aortic valve in 126 (91%) patients and subaortic stenosis in 13 (9%) patients. Patients had an average of 2 (range: 1e3) surgical or transcatheter interventions; the most common procedures were resection and end-to-end anastomosis (98 [41%] patients) and aortic valve replacement (31 [13%] patients). The baseline clinical data are shown in Table 1, and the baseline CPET and echocardiographic data are shown in Table 2. The 138 patients underwent 213 CPET, and there were 21 (10%) procedural complications (exercise-induced atrial arrhythmia, 19 patients; exercise-induced ischemia on ECG, 2 patients). All cases of arrhythmia and ischemia resolved within 5 minutes after termination of exercise. There were no mechanical injuries or sudden cardiac deaths during exercise. Hypertensive response to exercise HRE occurred in 26 (19%) patients. Table 3 compares the baseline characteristics of the patients with HRE and those with NRE. The groups were similar in age at the time of COA repair and CPET, sex, blood pressure at rest, and exercise capacity. However, the patients with HRE had a higher left ventricular filling pressure based on assessment by Doppler echocardiography, a higher relative wall thickness, and were less likely to be on
Canadian Journal of Cardiology Volume 34 2018 Table 1. Baseline clinical characteristics at time of first CPET (N ¼ 138) Age, mean SD, years Male sex Body mass index, kg/m2 Comorbidities Coronary artery disease Hypertension Diabetes mellitus Hyperlipidemia Smoking Sleep apnea Creatinine clearance <60 mL/min Atrial fibrillation Atrial flutter NYHA class III/IV Associated left-sided heart lesions Bicuspid aortic valve Subaortic stenosis Mitral valve stenosis Parachute mitral valve Supravalvular mitral ring Procedural data (240 total interventions) Interventions per patient, No. (range) Resection and end-to-end anastomosis Subclavian flap repair Patch aortoplasty Ascending to descending aorta jump graft Balloon dilatation/stenting Aortic valve replacement Mitral valve repair/replacement Resection of subaortic stenosis Other Therapies Antihypertension therapy* Antiplatelet therapy Anticoagulation therapy
40 13 82 (59%) 28 8 11 109 10 56 20 14 13 20 10 4
(8%) (79%) (7%) (41%) (14%) (10%) (9%) (14%) (7%) (3%)
126 13 4 9 1
(91%) (9%) (3%) (7%) (0.7%)
2 (1-3) 98 (41%) 12 (5%) 8 (3%) 26 (11%) 15 31 15 18 17
(6%) (13%) (6%) (8%) (7%)
79 (57%) 60 (43%) 34 (25%)
CPET, cardiopulmonary exercise test; NYHA, New York Heart Association. * Calcium channel blocker, beta blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, thiazide diuretic, hydralazine.
antihypertension therapy. Among the 26 patients with HRE, 21 had their antihypertension therapy changed in response to the abnormal CPET result: initiation of antihypertension agent, 11 patients; dosage increase, 6 patients; addition of a second antihypertension agent, 2 patients; and change to a different antihypertension agent, 2 patients. Ambulatory blood pressure recording was available in 43 patients (31%); 14 and 29 patients had HRE and NRE, respectively. Median systolic blood pressure > 140 mm Hg was present in 7 of 14 patients (50%) in the HRE group vs 4 of 29 patients (14%) in the NRE group, P ¼ 0.01, even though both groups had similar resting blood pressures. When we re-analyzed our data using the gender-based cut-point that defined HRE as >210 mm Hg for men and > 190 mm Hg for women, HRE was still present in 26 patients (19%), but the gender distribution changed slightly (14 male patients and 12 female patients instead of 15 men and 11 women using the cutpoint of > 200 mm Hg for both genders. Cardiovascular adverse events A total of 28 CAEs occurred in 24 (17%) patients during a follow-up period of 85 13 months. These CAEs were
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Table 2. CPET and echocardiography data (N ¼ 138)
Table 4. Predictors of cardiovascular adverse events
CPET Peak VO2, mL/kg/min Peak VO2, % predicted VE/VCO2 nadir Metabolic equivalent Functional aerobic capacity Resting systolic BP, mm Hg Resting diastolic BP, mm Hg Resting heart rate, bpm Peak systolic BP, mm Hg Peak diastolic BP, mm Hg Peak heart rate, bpm Peak heart rate, % predicted Sinus rhythm Echocardiographic parameters LV ejection fraction, % LV E/e0 ratio LV mass index, g/m2 Tricuspid regurgitation velocity, m/s Mean aortic valve gradient, mm Hg Mean mitral valve gradient, mm Hg COA peak velocity, m/s Corrected COA peak velocity, m/s Relative wall thickness
25 13 67 20 31 3 94 77 20 122 18 73 14 72 18 171 25 69 21 149 32 83 15 128 (93%) 62 13 108 2.7 11 3 2.2 1.9 0.46
8 2 35 0.6 4 2 0.6 0.2 0.05
BP, blood pressure; bpm, beats per minute; COA, coarctation of aorta; CPET, cardiopulmonary exercise test; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; LV, left ventricular; peak VO2, peak oxygen consumption; VE/VCO2, ventilatory equivalent for carbon dioxide.
Table 3. Hypertensive response to exercise Variable Age, year Age at first COA repair, year Male sex Ever smoker Body mass index, kg/m2 Resting systolic BP, mm Hg Resting diastolic BP, mm Hg Resting systolic BP <140 mm Hg Peak diastolic BP, mm Hg Prior diagnosis of hypertension Peak heart rate, bpm Peak VO2, mL/kg/min Metabolic equivalent Peak VO2, % predicted Mean aortic valve gradient, mm Hg COA peak velocity, m/s Corrected COA peak velocity, m/s LV ejection fraction, % LV E/e0 ratio LV mass index, g/m2 Relative wall thickness Antihypertension therapy Beta blocker Calcium channel blocker ACEi/ARB Hydralazine Thiazide diuretic agent
HRE (n ¼ 26)
NRE (n ¼ 112)
P value
41 8 10 4 15 (58%) 4 (25%) 29 6 129 6 81 5 24 (92%)
40 11 92 67 (60%) 16 (14%) 28 9 121 14 71 11 106 (95%)
0.21 0.33 0.34 0.72 0.18 0.17 0.09 0.43
89 3 12 (46%)
82 10 76 (68%)
0.22 0.07
28 8 2 14 5
0.41 0.11 0.16 0.08 0.49
2.4 0.4 1.9 0.3
2.2 0.5 1.9 0.2
0.13 0.38
66 5 15 2 116 24 0.47 0.02 4 (15%) 2 (8%) 5 (20%) 0 1 (4%) 4 (15%)
61 8 12 2 104 36 0.44 0.02 39 (35%) 20 (18%) 36 (32%) 5 (5%) 20 (18%) 39 (35%)
0.33 0.04 0.17 0.01 0.03 0.05 0.49 0.26 0.99 0.85
151 24 8 63 9
17 11 5 16 4
147 26 9 71 12
ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blockers; BP, blood pressure; bpm, beats per minute; COA, coarctation of aorta; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; HRE, hypertensive response to exercise; LV, left ventricle; NRE, normotensive response to exercise; peak VO2, peak oxygen consumption.
Univariate HR (95% CI)
P value
1.87 (1.12e2.67)
0.03
2.14 0.97 1.74 1.15 1.32 1.36 1.02 2.41 1.29 1.17 0.83 1.12 0.91 1.76 2.05
(1.36e3.77) (0.38e2.16) (1.13e3.12) (0.78e1.98) (0.81e3.11) (0.88e2.85) (0.15e6.32) (1.36e4.12) (0.76e3.15) (0.82e2.97) (0.55e5.14) (0.77e2.39) (0.03e4.18) (0.94e3.11) (1.24e3.97)
0.02 0.18 0.03 0.31 0.19 0.09 0.33 0.01 0.17 0.31 0.46 0.16 0.32 0.08 0.01
1.76 (0.93e2.88)
0.07
Variable Age at COA repair, per 5 year increment Age at CPET, per 5 year increment Male sex Diagnosis of hypertension Antihypertension therapy Ever smoker Peak VO2, < 50% predicted VE/VCO2 nadir > 32 HRE (peak systolic BP > 200 mm Hg) Resting systolic BP > 140 mm Hg Peak diastolic BP > 90 mm Hg Exercise-induced arrhythmia Exercise-induced ischemia on ECG LV ejection fraction < 50% LV E/e0 ratio > 14 Relative wall thickness, per 0.2-point increment COA peak velocity > 2.0 m/s
BP, blood pressure; CI, confidence interval; COA, coarctation of aorta; CPET, cardiopulmonary exercise test; E, mitral inflow early velocity; e0 , mitral annular tissue early velocity; ECG, electrocardiogram; HR, hazard ratio; LV, left ventricular; peak VO2, peak oxygen consumption; VE/VCO2, ventilatory equivalent for carbon dioxide.
cardiovascular death (n ¼ 4), stroke (n ¼ 9), acute coronary syndrome (n ¼ 2), heart failure hospitalization (n ¼ 8), and severe left ventricular systolic dysfunction (n ¼ 5). Tables 4 and 5 show the univariate and multivariate risk factors for CAEs. HRE was an independent risk factor for CAE (HR, 1.46; 95% CI: 1.13e2.52; P ¼ 0.04). The freedom from CAEs was significantly lower in the patients with HRE than in those with NRE (67% vs 88% at 60 months, P ¼ 0.03) (Fig. 1). Discussion Patients with rCOA are at a higher risk for cardiovascular morbidity and mortality than age-matched controls from the general population.1,2,5 For this study, we reviewed records for 138 adult patients with rCOA and without clinically significant residual or recurrent COA. The study showed that HRE
Table 5. Incrementally adjusted risk for cardiovascular adverse events Model Model Model Model Model Model
HR (95% CI) 1* 2y 3z 4x 5{
2.41 1.78 1.69 1.53 1.46
(1.36e4.12) (1.31e2.54) (1.33e2.69) (1.22e2.14) (1.13e2.52)
P value 0.01 0.02 0.02 0.04 0.04
CI, confidence interval; HR, hazard ratio. * Model 1: included adjustments for hypertensive response to exercise. y Model 2: included all variables in Model 1 plus adjustments for hypertension diagnosis. z Model 3: included all variables in Model 2 plus adjustment for age at coarctation repair. x Model 4: included all variables in Model 3 plus adjustment for age at cardiopulmonary exercise testing. { Model 5: included all variables in Model 4 plus adjustment for relative wall thickness.
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Figure 1. Freedom for cardiovascular adverse events (CAEs) for patients with hypertensive response to exercise (HRE) and normotensive response to exercise (NRE); a significant difference existed between groups (P ¼ 0.03).
can occur in patients with normal resting blood pressure and that HRE was associated with a higher risk of CAEs during follow-up. Hypertensive response to exercise HRE occurred in 26 (19%) of the patients; of these 26 patients, 24 (92%) had normal blood pressure at rest, and 10 (29%) were on antihypertension therapy. Hypertension is present in 5% to 45% of patients with rCOA, and the prevalence is associated with older age at the time of initial repair, duration of follow-up, male sex, and higher body mass index.17-19 Hypertension has important prognostic value in patients with rCOA because it is postulated to be the underlying factor that drives the pathogenesis of cardiovascular morbidity and mortality.17,18 The definition of hypertension and the outcome data for hypertension in this population is based on blood pressure obtained at rest.1,2,17 The concept of HRE in patients with rCOA was described more than 4 decades ago.9 Since that time, studies have reported the prevalence and clinical implications (or absence) of HRE in patients with rCOA.9,20,21 In a retrospective study by Correia et al.,20 of 65 adult patients with rCOA (49 had CPET), HRE occurred in 11 (22%) patients. The authors reported that baseline hypertension treated with an angiotensin-converting enzyme inhibitor and a higher gradient at the aortic isthmus were risk factors for HRE. In our study, the patients’ demographic characteristics, such as age at the time of COA repair and age at CPET, were similar to those in the study by Correia et al.20 However, our study excluded patients with clinically significant residual or recurrent COA. As a result, the HRE in our study patients was more likely a true reflection of vascular dysfunction than fixed obstruction due to re-coarctation. Unlike the study by Correia et al., which focused on the incidence and risk factors for HRE, our study reported an association between HRE and CAEs in this population. This is novel and may perhaps become a potentially important risk-stratification tool. In a prospective study of 74 patients with rCOA, 36% of the patients were hypertensive at rest, 15% had HRE, and 49% had normal blood pressure at rest and during exercise.21
Canadian Journal of Cardiology Volume 34 2018
More than half the patients with HRE developed hypertension at rest during a follow-up period of 6 years. The authors postulated that HRE was a marker for preclinical hypertension. In our study, both the patients with HRE and NRE had similar blood pressure at rest despite a difference in the response of blood pressure to exercise. During aerobic exercise, cardiac output increases because of a sympathetically mediated increase in heart rate and stroke volume. The blood pressure response to an exercise-induced increase in cardiac output is moderated, in part, by a decrease in peripheral vascular resistance via endothelium-dependent vasodilation and microcirculatory reserve.22,23 This mechanism prevents an exaggerated increase in systolic blood pressure (peak systolic pressure > 200 mm Hg) during exercise.22,23 Patients with COA, in contrast, have diffuse arteriopathy characterized by impaired vascular compliance and endothelial dysfunction, and as a result, an exercise-induced increase in cardiac output can result in spikes in systolic blood pressure and, hence, HRE.6,7,19 Another potential mechanism involves alteration in autonomic function. The known vascular dysfunction could impair arterial baroreflex sensitivity.24 The current study suggests that this abnormality in vascular function can be unmasked during exercise even in patients with normal blood pressure at rest. Cardiovascular adverse events There were 28 CAEs among the 24 (17%) patients followed up for 85 months. In addition to the previously described risk factors for CAE, such as age and hypertension at rest, the current study identified HRE as a risk factor for CAE. Previous studies have described HRE as a marker for preclinical hypertension, and some studies have used HRE as an indicator for hemodynamically significant re-coarctation.20-23 According to guidelines from the American College of Cardiology/American Heart Association and the European Society of Cardiology, the importance of isolated HRE is a matter of debate and is not considered a definite indication for the initiation of antihypertension therapy.25,26 The current study showed that HRE was an independent risk factor for CAEs in patients without significant re-coarctation, even after correction for the traditional risk factors such as age and blood pressure at rest. Furthermore, the current study also showed that CPET was safe in patients with COA. Clinical implications and future directions There are 2 important clinical observations from this study: (1) A different blood-pressure response to exercise was noted for rCOA patients with NRE and HRE despite similar blood pressure at rest, and (2) rCOA patients with HRE were less likely to have a formal diagnosis of hypertension and less likely to be taking antihypertension therapy. These observations highlight the limitations of using systolic blood pressure obtained at rest in the office as the benchmark for determining adequate blood pressure control in this population. We speculated that if the occurrence of HRE were incorporated as one of the criteria for initiation and titration of antihypertension therapy in this population, more patients with HRE would be taking antihypertension medications. Antihypertension therapy could potentially decrease the risk for CAEs.
Yogeswaran et al. Hypertensive Response in Coarctation of Aorta
In addition, the results of the current study have another important clinical implication: Blood pressure at rest may not be reflective of day-to-day blood pressure for patients with rCOA because of spikes during physical activity that are caused by reduced aortic compliance. Unfortunately, ambulatory blood pressure was not routinely monitored in our practice, and, as a result, the data were not analyzed. However, the observations from this study provide preliminary data for future studies to evaluate the association between HRE, changes in ambulatory blood pressure, and direct measures of vascular and endothelial function. Such studies will provide more robust mechanistic data about the dissociation between blood pressure during rest and exercise observed in the current study. In addition, a prospective study could compare clinical outcomes for patients on conventional antihypertension regimens, using the benchmark of resting blood pressure less than 140 mm Hg, with patients on intensive antihypertension regimens titrated on the basis of blood-pressure response during exercise. Limitations This is a single-center, retrospective study of outcomes in a small cohort of patients with rCOA who underwent CPET. We did not analyze the occurrence of CAE in the rest of the COA cohort who did not undergo CPET, and this may affect generalizability of our results. Another important limitation of the current study is the absence of data for ambulatory bloodpressure monitoring; as a result, we do not know the average blood pressure of the patients during their day-to-day activities and its potential impact on CAEs. Furthermore, we did not directly assess vascular function, thus making it difficult to infer a direct association between HRE and vascular dysfunction. All these factors limit the inferences that can be drawn from the current study. Conclusions Based on a review of 138 patients with rCOA who underwent to 213 CPETs and were followed for 85 months, the current study showed that HRE was present in 19% of patients with rCOA and was associated with an increased risk of CAE on short-term follow-up. Also, CPETs can be performed safely in this population without serious procedure-related complications. We speculate that rCOA patients with HRE represent a high-risk group of patients who, presumably, have more advanced vascular dysfunction, and cardiopulmonary exercise testing can identify these patients to allow for more intensive antihypertension therapy. Disclosures The authors have no conflicts of interest to disclose. References 1. Rosenthal E. Coarctation of the aorta from fetus to adult: curable condition or life long disease process? Heart 2005;91:1495-502. 2. Krieger EV, Stout K. The adult with repaired coarctation of the aorta. Heart 2010;96:1676-81. 3. Egbe A, Uppu S, Stroustrup A, Lee S, Ho D, Srivastava S. Incidences and sociodemographics of specific congenital heart diseases in the United
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