The Safety of Cardiopulmonary Exercise Testing in a ... - Circulation

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DOI: 10.1161/CIRCULATIONAHA.112.110460

The Safety of Cardiopulmonary Exercise Testing in a Population with High-Risk Cardiovascular Diseases

Running title: Skalski et al.; Cardiopulmonary exercise testing Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Joseph Skalski, MD; Thomas G. Allison, PhD, MPH; Todd D. Miller, MD, FAHA

Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic, Rochester, Roc o hester, MN

Address for Correspondence: Todd D. Miller, MD, FAHA Mayo Clinic, Gonda 5 200 First Street SW Rochester, MN 55905 Tel: 507-284-4072 Fax: 507-266-0228 E-mail: [email protected]

Journal Subject Codes: [26] Exercise/exercise testing/rehabilitation; [125] Exercise testing 1

DOI: 10.1161/CIRCULATIONAHA.112.110460

Abstract:

Background—Cardiopulmonary exercise testing (CPX) with measurement of peak oxygen uptake (VO2) is a powerful test for assessment and quantification of functional impairment due to cardiovascular disease. The safety of CPX has been established in patients with coronary artery disease and congestive heart failure, but clinical use of CPX in other cardiac diseases has been limited, in part due to a paucity of safety data. This study investigates the safety of CPX in Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

a heterogeneous cohort of patients with a wide variety of underlying high-risk cardiac diagnoses. Methods and Results—This single-center retrospective review examined 5060 CPX studies performed in 4250 unique patients, including 1748 (35%) female subjects and 686 686 86 (14%) (144%) subjects ubjects of age 75 or older. The primary endpoint was major adverse event during stress testing. The Th he study stud st udyy population ud p pula po laati tion o included patients with a variety var arieety of high-riskk cardiac ar carrdi diaac ac diseases including congestive heart co ongestive ng heaart failure faailu lurre (n=1289, (n= n 12 12889, 89 25.5%) 25.5 25 .5% %) hypertrophic hyype ypertro ophicc ccardiomyopathy arddioomy ar omyopa yopath th hy (n=5 ((n=598, n=5 =5998, 98 11 111.8%), .8% .8 %), pulmonary pulm pu lmon lm onar on aryy hypertension hype hy perrteensi ension on n (n=194, (n= n=19 1944, 3.8%), 19 3.8 8%), %) and and aortic aort ao rtiic stenosis steenoosi siss (n=212, (n n=2 =2122, 4.2%). 4.2% 4. 2%). 2% ). This This patient patie at ent functional 1192 (24%) patients population ggenerally en ner e al ally ly y hhad ad ssevere ever ev e e fu func nction nc onal on al iimpairment mpai mp airrme ai ment n iincluding nclu nc ludi lu diing 119 1922 (2 19 (24% 4%)) pa 4% pati tien ti ents en t with peak ts k VO2 < 14mL/kg/min. Eight adverse events occurred during CPX for an adverse event rate of 0.16%. The most common adverse event (n=6) was sustained ventricular tachycardia. There were no fatal events. Conclusions—CPX is generally a safe procedure, even in a population with underlying high-risk cardiovascular diagnoses.

Key words: complications; exercise; heart diseases; stress test

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Introduction Exercise stress testing has been widely used for decades to aid in the diagnosis and prognosis of coronary artery disease (CAD). The complication rate during standard exercise testing in populations undergoing evaluation of CAD is well described. The 2002 American Heart Association exercise testing guidelines cite an adverse event rate of up to 0.04% or 1 per 2500 tests.1 This figure is drawn from reports of myocardial infarction or death in a 1980 multi-center study in which over 500,000 exercise stress tests were considered.2 Other studies have reported Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

similarly low adverse event rates.3-7 Exercise stress test safety depends on the baseline risk of the population. Many of the patients included in these studies were asymptomatic or had atypical chest pain and were low risk or did not have established CAD. Cardiopulmonary exercise testing (CPX) with ventilatory gas analysis is an appropriate test estt ffor or ddetermining eter et e mini er niing ng functional capacity in a broa broader ade d r population ooff pati patients tiien entts than only those with possible poss ssib si le or established esta tabblisshe hedd CAD. CAD. Peak Peak oxygen oxygen uptake upptak ke (VO2) (VO2 O2)) is O2 is generally gen nerral ally ly considered coonsi onsiide dere redd the th he most most accurate functional VO2 powerful acccu cura rate ra t ddeterminant te eteermi et ermina naant ooff fu func ncti t on ti nal ccapacity. ap paccit ity. y. Pe Peak ak kV O2 iiss a po O2 pow werf rful rf u ppredictor ul reedi dicctor ctor ooff prog pprognosis rog gno osi siss in n 8 10 11-14 14 CAD8-10 andd congestive con onge gest ge s iv st ve heart heear artt failure faail ilur uree (CHF), ur (C CHF HF), ),11 iss useful use sefu full for fu for selecting sele se l ct ctin ingg patients in pati pa tien ti en nts for for cardiac car a diac

transplantation,15-16 and represents a non-invasive surrogate for cardiac output.17-18 Measurement of carbon dioxide production (VCO2) in relationship to VO2 can provide information on exercise limitation. National guidelines cite both of the following as Class I indications for CPX: 1) Evaluation of exercise capacity and response to therapy in patients with CHF who are being considered for heart transplantation.2) Assistance in the differentiation of cardiac versus pulmonary limitations as a cause of exercise-induced dyspnea or impaired exercise capacity when the cause is uncertain.1 Emerging applications of CPX were recently addressed in an American Heart Association Scientific Statement.19 The application of CPX for

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these indications can involve testing high-risk patient subsets, including patients with valvular heart disease, hypertrophic cardiomyopathy (HCM), congenital heart disease, and pulmonary hypertension.20-24 Many of these conditions are considered relative contraindications to exercise testing. As such there is limited published data addressing the safety of CPX in these patient subsets.25-27 The purpose of this study was to examine the safety of CPX in a large, heterogeneous cohort of high-risk patients with a wide variety of underlying high-risk cardiovascular diagnoses. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Methods Study population. All patients who were referred for CPX at the Mayo Clinic in Rochester, Minnesota from Novvemb No vemb mber err 22007 0077 th thro rough March 2010 were retros osppectively identif os fie i d th hro roug u h a computer November through retrospectively identified through ddatabase. data a aba b se. This Th his time tim me period peri riod ri od was was as selected sel elec e tedd to reflect ec reeflecct tthe he ex expanded xpaanded d uuse see ooff CPX CPX to to iinclude nclu nclu lude de a hete he tero te ro oge gene neeou ouss popu ppopulation opu pula lattioon on off pa ppatients tien ti entts en ts w itth high hhigh-risk ighh-r -riiskk ca ardi diov di ovas ov asscu c la larr co cconditions. ndit nd i io it ons n. T he da ataabas abasee heterogeneous with cardiovascular The database contains dem mog ogra r ph ra phic icc data, dat a a, cardiovascular car a di diov ovas ov a cu as cula laar me medi d ca di call hi hhistory, sttor ory, y m y, edic ed i at atiion ons, s, aand n sstress nd trres esss te test results. demographic medical medications, Cardiovascular diagnoses for each patient are identified at the time of testing by reviewing the electronic medical record to determine diagnoses issued by the referring clinician. Initial interrogation of the database yielded 6136 cardiopulmonary exercise tests, which represents the total number of tests performed during the study period. CPX performed on subjects with no established cardiovascular disease were excluded from the analysis (n=1079), excluding patients with only pulmonary or other non-cardiovascular disease (n=805) or athletes undergoing a fitness assessment (n=274). All other patients who underwent CPX during this time period were included. A total of 5060 cardiopulmonary exercise tests were identified. For patients who

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underwent CPX multiple times during the study period (n=810), all tests are included. The data are reported per each unique stress test rather than per each unique patient because patient characteristics such as cardiac diagnoses, medications, and cardiac device status were all subject to change over the 29 month study period. Furthermore, each individual test presented an additional potential for an adverse event. To further characterize severity of cardiovascular disease in the study population, echocardiogram data for patients with diagnoses of congestive heart failure, pulmonary Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

hypertension, aortic stenosis, and HCM were reviewed. Echocardiograms performed from twelve months prior to the CPX date through one week after the CPX date were identified. If multiple echocardiograms were performed during that period, the echocardiogram echocardiograam closest c osest cl esst to the the CPX date was selected. If no echocardiogram was identified within this period, the patient was recorded eco ord rded ed as as having h viing no ha no recent echocardiogram. Patients Patiients with aortic Pa aortticc stenosis sten en nosis os were categorized as mild, m ild d, moderate, moderate te, orr severe sev ev verre based base ba sedd onn echocardiogram se ech hocarddioograam results: res essults ults:: severe, sev ever ere, e, aortic aortic valve valve val lve area areea ea ((AVA) AV VA) A < 1.0 1. .0 cm m2 and/or andd/o /orr mean mean a aortic aorrti ticc valve valv va lv ve gradient grad gr adie i nt (MVG) ie (MV MVG) G) > 40 40 mmHg; mmHg mm Hg;; moderate, Hg mode mo d rate de ratee, AVA AVA • 11.0 .0 an and nd ” 1.5 nd .5 G • 225 5 and and ” 40 40 mmHg; mmHg mm H ; mi Hg mild, ild l , AV AVA A > 1. 1.5 .5 an and nd < 3. 3.0 .0 cm2 oorr MV MVG G • 5 and and < 25 cm2 or MVG mmHg.28 Patients with hypertrophic cardiomyopathy were categorized as having basal obstruction, labile obstruction, or no obstruction based upon their resting and provoked gradients measured by the left ventricular outflow tract peak instantaneous Doppler gradient. Physiologically provoked gradient refers to the gradient measured during exercise, Valsalva maneuver, or amyl nitrite administration. Patients with resting gradient • 30 mmHg were categorized as having baseline obstruction; patients with resting gradient < 30 mmHg but provoked gradient • 30 mmHg were categorized as having labile obstruction; patients with resting and provoked gradients < 30 mmHg were categorized as having no obstruction.29

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Performance of CPX In the Mayo CPX laboratory both standard and CPX are performed in the same corridor in 7 separate rooms. The testing environment is supervised by a PhD clinical exercise physiologist and a cardiologist. The exercise physiologist assists testing personnel with decisions about test protocol and interprets respiratory gas exchange data. All tests are conducted by a 2-person team consisting of an exercise specialist and an electrocardiogram (ECG) technician. All exercise specialists have the following qualifications: 1) certified exercise specialist by the American Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

College of Sports Medicine or a registered nurse with coronary care certification; 2) advanced cardiac life support certification; and 3) successful completion of a 3-month internal training exercise program. Each exercise specialist typically performs 2-5 cardiopulmonary exerci ciisee ttests essts eeach achh ac day. Some of the specialists have greater than 20 years of experience supervising CPX. Although individual directly Alth Al th hou ugh eeach a h in ac ndivi div dual cardiopulmonary exercise exerc rciisee test is not dir rc rec e tlyy ob observed by a cardiologist, cardiologist CPX the immediate ca ard dio i logist, a ca ard dio olo l gi gist st iiss assi aassigned ssign gned gn ed too thee C PX X llaboratory abooraato torry ry an andd is is aavailable vaillab able le iin n th he im imme medi me diaate di area evaluation and The ar rea ffor o ppre-test or ree-t -tes estt ev val alua uati tiion of of selected seele lect cted ct ed ppatients atie at ient ie ntss an nd to t aassist ssis ss istt in is n tthe he eevent he v nt ooff an ve an eemergency. merg me rgen rg ncy y. T hee presents with (such cardiologist is is notified n ti no tifi fied fi ed d before beffor o e testing teest stin ingg iff a patient in pati pa t en ti entt pr pres essen ents ts w ithh a ne it nnew w fi ffinding ndin nd ingg (s in (suc uchh as uc accelerating symptoms, uncontrolled blood pressure, new ECG changes) that has developed since his or her clinical appointment. The majority of patients (n=4307, 85%) underwent exercise on a motor-driven treadmill (Quinton, Seattle, WA).

The remaining patients underwent cycle ergometry. A 3-lead ECG

was recorded continuously and a 12-lead ECG was recorded every minute using a General Electric CASE 8000 (Milwaukee, WI) system. Expired gas collection was performed on a Medical Graphics Corporation (MGC) system (St. Paul, MN). O2 saturation was monitored via forehead oximetry using a Nellcor N-595 (Pleasonton, CA). In selected patients a resting forced

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vital capacity (FVC) was performed on the MGC system pre- and 15 minutes post-exercise. Most patients (n=4116, 81%) exercised using an accelerated Naughton protocol consisting of 2minute duration stages beginning at approximately 2.5 metabolic equivalents (METs) and increasing by 2 METs per stage as previously described.30 The remaining patients exercised using a standard Naughton protocol or Naughton 1.5 protocol (treadmill speed 1.5 mph instead of 2.0 mph). Patients were asked about symptoms at each stage of the test; severity of responses were recorded on a 1-10 scale employed throughout Mayo Clinic. Patients were encouraged to Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

perform a symptom-limited maximal test (rating of perceived exertion t 17/20 Borg scale)31 unless they met another indication for test termination, including development of significant angina, hypotensive blood pressure response (defined as a drop in systolic bloodd pr pre essu sure su re m ore ore pressure more han 10 mmHg below resting blood pressure), horizontal or down-sloping ST depression of > 2.0 than mm m, or or ven en ntr t icul ullar tachycardia tachycardia of more than 5 beats beat be atss in duration. mm, ventricular nteerp r retation on ooff CP CPX. X.. Interpretation Alll test Al test results res esul ults ul ts were werre reviewed revi re viiew e ed d by by the the supervising suupe perv rviisiing cardiologist rv car ardi diiollog ogiistt and andd exercise an exer ex errcisse se pphysiologist. hysi hy siol si oloogis ol ogisst. Th The he cardiologistt interpreted int nter erpr er pret pr eted et ed the thee exercise exe x rci cise see ECG, ECG CG,, wh whil while ilee th il thee ex eexercise erci er cise ci se ph phys physiologist y io olo logi gist gi st iinterpreted n er nt erpr pret pr eted et ed the gas exchange data. The exercise ECG was considered ischemic if there was t1.0 mm horizontal or downsloping ST-segment depression 0.08 seconds after the J-point in the absence of significant resting ST-T abnormalities, pre-excitation, ventricular pacing, digitalis, or left bundle branch block. Heart rate recovery (HRR) was calculated by subtracting heart rate at one minute after peak exercise during active recovery (1.7 mph / 0% grade) from heart rate at peak exercise. HRR of 40 mmHg. Among HCM patients, 150 (3.0% of total, 25.1% of HCM patients) had basal obstruction. Among these patients, 142

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had a resting or provoked gradient of • 50 mmHg indicating severe obstruction. An additional 89 HCM patients (1.8% of total, 14.9% of HCM patients) had labile obstruction. CPX Results Table 4 and Figure 1 describe the stress test results. The vast majority of patients (n=4783, 94.5%) completed symptom-limited CPX with termination of the test due to symptoms of fatigue, dyspnea, or chest pain. In the remaining 5.5% of patients, the test was terminated due to ECG changes, abnormal blood pressure response, patient request, or major adverse event. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Almost one quarter of patients (24%) had peak VO2 < 14 mL/kg/min, consistent with severe functional impairment. Effort was generally good with a mean peak RER 1.18 ± 0.11. patients (2.5%) Nearly half of patients were observed to have abnormal HRR. Only 129 patient ts (2 2.5%) %) hhad ad aan n exercise ECG positive for ischemia. Due to a large number of patients with abnormal resting ECG, stress non-diagnostic. Resting EC CG, 338% 8% ooff st tre resss ss ECGs were reported as non n-d -diaagnostic. Rest tin i g EC ECG G abnormalities included nclluded 285 (5.6 (5. 5.66 %) patients pat atie ient ie ntss with nt with h LBBB LBBB and an nd 5622 (11.1%) (11..1%) patients pati tieents ents with wit i h paced paaceed rhythm. rh hytthm hm. Adverse Ad dve vers rsee Events rs Eveents Ev entss displays rate Figure 2 dis spl play ayss adverse ay adve ad vers ve r e events. even ev e ts en ts.. Eight Eig ight ht aadverse dver dv erse er s eevents se ven e tss ooccurred, ccur cc urre ur red, re d yyielding ield ie ldin ld ingg a ra in ate ooff 0. 00.16%. 16%. Table 5 contains a narrative description of the adverse events. Six of the 8 events resulted in hospitalization. There were no fatal events. Although approximately 10% of patients had an ICD at the time of their study, no ICD discharges occurred during stress testing. No patient experienced syncope. Six of the events (n=6) were sustained ventricular tachycardia. All terminated spontaneously without defibrillation or advanced cardiac life support medications. Four of the 6 episodes of ventricular tachycardia led to hospital admission, and the other 2 episodes were managed with close outpatient follow-up. One patient with known CAD developed severe and persistent dyspnea and was admitted for observation without objective

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evidence for a new cardiac event. The single myocardial infarction occurred in a 53-year-old man who had received cardiac transplant 6 years prior and was undergoing surveillance CPX as part of routine post-transplant follow-up. He had not been experiencing chest pain, dyspnea, or other concerning symptoms in the outpatient setting prior to his stress test. During the stress test he abruptly developed severe anginal pain and ST segment elevation on the cardiac monitor after 10.4 minutes of exercise. He was taken emergently to the cardiac catheterization laboratory where a new 90% stenosis was Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

noted in his first obtuse marginal coronary artery. A drug eluting stent placement was performed. He was discharged from the hospital in stable condition.

Discussion Earlier the safety of exercise ttesting performed in patient Ea arl rlie ierr studies ie stud st tud udie ies examining ie ex xamining am e ting were perf es for o meed primarily pr 1-7 -7 -7 populations undergoing possible CAD. pop pu pulations un nde derg goiing eevaluation vaalu luaati tion onn ooff po ossib blee CAD AD. 1AD Many M anny ny ppatients attie ient ntss iin n tthese hese he se sstudies t di tu dies ess w were eree er

as asymptomatic sym ympt ptom pt omat atic at ic or or had had atypical atyypic ypi al symptoms sym ympt ptom pt om ms and and likely likkelly did li d d not di not have haave v CAD, CAD AD,, diluting diluti dilu ting ti ng the the ddenominator en nom min nat ator o or and leading to o vvery erry lo llow w repo reported port po r ed rt d co comp complication mpli mp lica li cati ca tiion rrates ates at e ffor es or sstandard tand ta ndar nd ardd ex ar exercise xer erci cise ci se ttesting. e tiing es ng.. C Conversely, o versely, inn on the present study nearly all patients had known structural heart disease. The most important finding of this study is the very low adverse event rate of only 0.16% in a much higher risk population undergoing CPX. There were no fatal complications. A strength of this data set is the heterogeneity of the study population, which included a wide variety of underlying cardiac diagnoses. Many of these disorders are considered relative contraindications to exercise testing.1,17 In this study 19% of the population had HCM, pulmonary hypertension, or aortic stenosis. None of the adverse events occurred in patients with any of these conditions. The mean peak VO2 across all patients was only two-thirds of predicted, reflective of

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significant impairment in functional capacity for this population. Almost one quarter (23.5%) were found to have severely limited functional capacity as indicated by peak VO2 < 14 mL/kg/min. This value is the threshold that is often used to determine which CHF patients are eligible for heart transplantion.15 The majority of the patients (n=3210, 64%) exercised to an RER > 1.15 suggesting maximal exertion. Due to their severe functional impairment, some patients in this study would likely be candidates for disability due to cardiac disease. According to an Institute of Medicine panel Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

recently convened to advise the Social Security Administration on cardiovascular disability, CPX should be the procedure of choice for assessing cardiovascular disability.32 CPX provides the he most accurate means of quantifying functional impairment.19 Measurement of of tthe he R RER ER represents epresents the most objective method of assessing effort exerted during an exercise test, thereby providing pr rovvid idin ingg a means in mean an ns to t detect individuals who aree intentionally i tentionally underperforming in unde derper de errfo form r ing in an attempt to ““game” game” am m the system. sys yste teem. However, How owev ever ev er, stress er stre st r ss re ss testing tesstingg is is not no ot widely wide dely de ly applied appli pplied ed for for disability disab bili ility ity as asse assessment, seess ssme meent nt,, in n part concerns pa rt due due u to to co conc nceernns ns about abo out safety saafet afet etyy of testing tesstiing in in high-risk hig ghh-ri r sk sk populations. pop opul ullat a io ons ns.. The Thee results res esul ults ul ts of of this thiis study th stu tuddy will hopefully ly encourage enccou oura raage g iincreased ncre nc r as re ased e us ed uusee of C CPX PX ffor or tthis h s pu hi purp purpose. rpos rp ose. os e. Another notable finding from this study is that only 129 (3%) patients had a positive exercise ECG. The relatively low number of positive stress ECGs was due in part to the substantial number of patients with an abnormal resting ECG that precluded interpretation of the exercise ECG. Accounting for overlap of patients with multiple rhythm disorders, a total of 830 (16.4%) patients had an ECG demonstrating LBBB, paced rhythm, or WPW (Wolff-ParkinsonWhite) at rest. In 38% of patients the stress ECG was reported as non-diagnostic. Other reasons for the low number of positive stress ECGs include the average low functional capacity of the study population and referral generally for quantification of cardiopulmonary functional

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impairment rather than detection of ischemia. The low yield of positive exercise ECGs in this population should not undermine the value of the exercise ECG for detecting ischemia in patients undergoing stress testing for evaluation of chest pain. Other authors have reported on the safety of CPX in high-risk populations. In the HFACTION study (Heart Failure: A Controlled Trial Investigating Outcomes of exercise traiNing), Keteyian et al. examined 2037 subjects with left ventricular dysfunction (median left ventricular ejection fraction 25%) who underwent CPX on multiple occasions.25 There were no fatal events Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

and only 2 episodes of ventricular arrhythmia among 4411 exercise tests. Scardovi et al. examined 227 elderly patients with CHF who underwent 395 cardiopulmonary exercise tests.26 No adverse events were observed. Sun et al. also noted no adverse events in 53 patients pattie i nt ntss with with primary pulmonary hypertension who underwent CPX.27 The unique aspects of the present tud dy include incl in clud cl udee the ud th he larger larger size of the study population lar populaati tion onn and the heter rog o en nei eitty ty of cardiovascular study heterogeneity ddisorders diso i ord r ers pres present. sen entt. This Th is study stu tuddy dy has has limitations. lim im mit i attio ions ns. This ns Thiis data data set set iincludes nclu nc l des des st stre stress ress ss ttests ests es ts pperformed erfform form med at at a single sinngl ngle le academic tertiary terrtiiar aryy ca care re m medical ed dic ical a ccenter, ente en teer, r w which hich hi ch llimits im mit i s th the ex exte extent tent te n tto o wh which hic ichh ou ourr ob obse observed serv se rved rv ed ssafety afety data can be generalized. However, it is reassuring that these results are consistent with CPX safety data reported from other institutions. Nearly all patients were first assessed by a cardiologist and felt to be stable enough to be referred for CPX. There are limitations with the database to extensively characterize the study population. Some patients did not undergo additional diagnostic testing such as echocardiography in close proximity to CPX. Thus, additional data to quantify the severity of left ventricular systolic dysfunction, pulmonary hypertension, or valvular dysfunction (such as severity of aortic stenosis) cannot be reported for the entire study population.

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This study was not designed to determine if any underlying attribute or cardiovascular disease confers a higher risk of adverse event during CPX than others. Interestingly, all 8 of the adverse events occurred in males. Most (6 of 8) adverse events noted in our study were ventricular arrhythmia. Some observational studies do suggest that there is a higher rate of sudden cardiac death and ventricular arrhythmia in men compared to women.33,34 However, the conclusion that men are at greater risk than women of adverse event during CPX cannot be drawn from this study. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

The major value of this manuscript is the demonstration that CPX is a reasonably safe procedure in a population of patients with a spectrum of established cardiovascular diseases, many of which represent high-risk conditions and are considered relative contra ain ndiica cati tiion onss to t contraindications tress testing.1 It is important to recognize that all of the patients in this study had their stress ca ard dio iovvasc vasccul ulaar diagnoses dia iaggnoses gn PX aand nd that testin ng wa as carefully ca performed in an cardiovascular established prior to CPX testing was experienced ex xpe perienced la laboratory abo boraato ory aatt a te ter tertiary rtiary rtia ry ccare arre cen center. nter. T There heree aare re ssubsets ubse setts off ppatients atiien entts ts w with ithh th it thee mo most st extreme ex xtr trem em me va variants ari riaants ants ooff th thes these esee cconditions onndit ndit itio ions io ns iin n wh whom om sstress t esss te tr testing est stin ingg re in represents epr p esen esen ents ts aan n ab absolute bso s lu l tee contraindication, contraindica atiion on,, su such ch aass a pa pati patient t en entt wi w with th h ssevere ever ev e e sy er symp symptomatic mpto mp t ma to mati tiic ao aort aortic rtic rt i sstenosis. ic teno te nosi no sis. si s. Ho Howe However, weve we ver, ve r for other patients with these disorders, CPX appears to be reasonably safe and can serve as a helpful aid in the management of these patients. Given the low event rate in this study, a larger population would be necessary to determine which of these patients are at highest risk of experiencing a complication during during CPX.

Conflict of Interest Disclosures: Dr. Todd Miller has consulting arrangements with Astellas Pharma and Lantheus Medical Imaging and receives research funding from Forest Laboratories.

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References: 1. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, Mark DB, McCallister BD, Mooss AN, O'Reilly MG, Winters WL Jr. ACC/AHA 2002 guideline update for exercise testing: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). 2002. American College of Cardiology Web site. Available at: www.acc.org/clinical/guidelines/exercise/dirIndex.htm. 2. Stuart RJ Jr, Ellestad MH. National survey of exercise stress testing facilities. Chest. 1980;77:94-97. 3. Myers J, Voodi L, Umann T, Froelicher VF. A Survey of Exercise Testing: Methods, Utilization, Interpretation, and Safety in the VAHCS. J Cardiopulm Rehabil. 2000;20:251-258. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

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16. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. Ciirc rcul ulat atio ion. n. 2009;119:e391-479. 17. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003;167:211-277. 2003;1 ; 67:211-277 77. 18. Slazchic Massie B,, Kr Kramer B,, To Topic Tubau Correlates 188. Slazch S l hic JJ,, Ma Mass ssie ie B K am mer B Topi p c N,, T pi ubbau J. Co Corr r elat rr attes es aand nd pprognostic rogno nost stic st ic iimplication mp pliica c tiion ooff exercise capacity congestive Cardiol. ex xerci errc se capac cit ityy iin n cchronic h on hr oniic co cong nges e ti es t ve hheart earrt ffailure. ailu uree. Am J C ardiol. 1985;55:1037-1042. ard 198 9 5;55 55 5:1 103 0377 10 71042 4 . 42 19. Balady GJ, Arena R,, Si Sietsema K,, My Myers Coke L,, F Fletcher Forman D,, Fra Franklin 19 9. Ba Bala l dy G la J, A reena R S ettse sema ma K Myer erss J, C er oke L oke letc le tche herr GF he GF,, For F orman nD F rankklin kl n B, B, Guazzi Guaz azzi zi M, M, Gulati Gula Gu lati M, M, Keteyian K te Ke teyi y an SJ, SJ, Lavie Laviee CJ, CJ, Macko Mack Ma c o R, R Mancini Man anci cini n D, D, Milani Mila Mi l ni RV, RV, V Council Counc ncil on on Epidemiology Vascular Disease Interdisciplinary gy and andd Prevention, Preeve venttio ion, n Council Cou o nc n ill on on Peripheral Peri Pe r ph ri pher erral V ascu as cula cu larr Di la D seeas asee an andd In nte terd rdis rd issci c pl p inary Council Research. Clinician’s guide cardiopulmonary Coun Co unci cill on Quality Qua uali lity ty ooff Care Care and and Outcomes Out utco come mess Re Res sea earc rchh Cl Clin inic icia ian’ n s gu gui ide tto o ca card rdio iopu pulm lmon onar aryy exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010;122:191-225. 20. Arena R, Sietsema K. Cardiopulmonary exercise testing in the clinical evaluation of patients with heart and lung disease. Circulation. 2011;123:668-680. 21. Yasunobu Y, Oudiz RJ, Sun XG, Hansen JE, Wasserman K. End-tidal PCO2 abnormality and exercise limitation in patients with primary pulmonary hypertension. Chest. 2005;127;16371646. 22. Arena R, Owens DS, Arevalo J, Smith K, Mohiddin SA, McAreavey D, Ulisney KL, Tripodi D, Fananapazir L, Plehn JF. Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy. Med Sci Sports Exerc. 2008;40:799-805. 23. Giardini A, Donti A, Specchia S, Formigari R, Oppido G, Picchio FM. Long-term impact of transcatheter atrial septal defect closure in adults on cardiac function and exercise capacity. Int J

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Cardiol. 2008;124:179-182. 24. Fredriksen PM, Veldtman G, Hechter S, Therrien J, Chen A, Warsi MA, Freeman M, Liu P, Siu S, Thaulow E, Webb G. Aerobic capacity in adults with various congenital heart diseases. Am J Cardiol. 2001;87:310-314. 25. Keteyian SJ, Isaac D, Thadani U, Roy BA, Bensimhon DR, McKelvie R, Russel SD, Hellkamp AS, Kraus WE. Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction. Am Heart J. 2009;158:S72-S77. 26. Scardovi AB, Coletta C, Maria RD, Perna S, Aspromonte N, Feola M, Rosso G, Greggi M, Ceci V. The cardiopulmonary exercise test is safe and reliable in elderly patients with chronic heart failure. J Cardiovasc Med. 2007;8:608-612. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

27. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise Pathophysiology in Patients With Primary Pulmonary Hypertension. Circulation. 2001;104:429-435. MD, Gaasch WH, 28. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed M D, G aasc aa schh W sc H, Shanewise Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shane newi wisse wi se JJS. S. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of Cardiology/American Heart Association Task Force on Practice of the American College Co Guidelines Guid Gu idel id elin el ines in es ((Writing W ittin Wr ingg Committee to Develop Guidelines Guiideli de ines for the Management Maana n geement me of Patients With Valvular Heart Disease). Circulation. Valv Va vullar H eaart D isea is ease see). Ci C rcul rc ullat atio i n. 22006;114:e84-e231. io 006; 00 6;;11 114: 4:ee84-e2 231 31.. 29. Naidu SS, Nishimura 29 9. Gersh Gersh BJ, BJ, Maron Maron BJ, BJ Bonow Boonoow RO, RO O, Dearani Deearaanii JA, JA A, Fifer Fifeer MA, Fife MA Link Linnk nk MS,, N aiiduu S S, N ishhim is muraa RA, Rakowski H,, Se Seidman Towbin Udelson Yancy CW. 2011 RA A, Ommen Omme Om meen SR SR,, Rak R akowski wsk H Seid idma id maan CE CE, To Tow wbin wbin i JJA, A U A, deels l on on JJE, E Y E, ancy ancy yC W. 20 W. 201 11 11 ACCF/AHA hypertrophic cardiomyopathy: AC CCF CF/A /AHA HA gguideline u deeli ui line ne forr the he ddiagnosis iagn ia g osis aand nd ttreatment reeat atment nt ooff hy hype pertro roph phic ic car rdi d om omyo y paath thy: a rreport epor ep ort of the American Ameriica cann College Coll Co l eg ll e e off Cardiology Carrdi diol olog ol o y Foundation/American og Foun Fo unda un dati da tion on/A on /Ame /A meri me rica ri cann Heart ca Hearrt Association He Asso As soci so ciat ci atio ionn Task io Task s Force on Practice Guidelines. Circulation. Prac Pr acti tice ce G uide ui deli line ness Ci Circ rcul ulat atio ionn 22011;124:e783-e831. 011; 01 1;12 124: 4:e7 e783 83-e83 e8311 30. Daida H, Allison TG, Johnson BD, Squires RW, Gau GT. Comparison of peak exercise oxygen uptake in men versus women in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997;80:85-88. 31. Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabi Med. 1970;2:92-98. 32. IOM (Institute of Medicine). 2010. Cardiovascular disability: Updating the Social Security listings. Washington, DC: The National Academies Press. 33. Lampert R, McPherson CA, Clancy JF, Caulin-Glaser TL, Rosenfeld LE, Batsford WP. Gender Differences in Ventricular Arrhythmia Recurrence in Patients With Coronary Artery Disease and Implantable Cardioverter-Defibrillators. J Am Coll Cardiol. 2004;43:2293-2299. 34. Kannel WB, Wilson PWF, D’Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J. 1998;136:205-212. 17

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Table 1. Patient Characteristics: Demographics (n = 5060 tests, 4250 patients).

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Age Female BMI (kg/m2) Tobacco Smoking -Current -Former -Never Comorbid Conditions -Hyperlipidemia -Hypertension -Diabetes mellitus Medications -Beta Blocker -Aspirin -Statin -ACE-I -A ACE CE-I or or ARB* ARB -Diuretic -Diu -D iureeti ticc -Anti-Coagulant -Anti-Cooag -A agul ulaant ul -Calcium - alcium Ch -C Channel hannell B Blocker lock ck ker -Anti-Platelet -A Ant nti--Pllat atel eleet et ((other othher ot her than th n aspirin) aspiiri rin) in) -Digoxin -Di Digoxin in -Long-Acting Nitrate Lon ongg Ac Acti ting ng N itra it rate te -None of these Medications

(n) 57.0 ± 15.9 1748 29.0 ± 6.1

(%) 34.5

270 2113 2677

5.3 41.8 52.9

2608 2273 702

51.5 44.9 13.9

3119 2731 2582 2423 24423 1982 19 982 8 11151 11 51 51 74 743 43 721 72

61.6 54.0 51.0 47.9 47 39 39.2 222.7 2.77 14 14.7 4.77 14.2 144.22

5573 73 2677 26 442

11.3 11.33 55.3 3 8.7

Continuous variables are reported as mean ± standard deviation *Angiotensin Converting Enzyme Inhibitor (ACE-I) or Angiotensin II Receptor Blocker (ARB)

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Table 2. Patient Characteristics: Cardiovascular Disease.

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Cardiac Diagnosis Coronary Artery Disease -Prior Coronary Artery Angioplasty or Stent -Prior Coronary Artery Bypass Grafting (CABG) Surgery Valvular Heart Disease (Some subjects had multiple valvular disorders) -Aortic Stenosis -Aortic Regurgitation -History of aortic valve replacement or repair -Mitral Stenosis -Mitral Regurgitation -History of mitral valve replacement or repair -Tricuspid valve regurgitation -Pulmonary valve regurgitation or stenosis Congestive Heart Failure -No CAD -CAD Congenital Heart Disease -History of at least 1 open heart surgery Hypertrophic Cardiomyopathy Hype pert rtro oph p ic Car ardi diom o yopathy History Cardiac Transplantation Hist Hi stor st oryy of C or ardiiac T ransplantation Pulmonary Hypertension Pu ulm monary Hy H pert pe rten rt ensi sion si on Postural Orthostatic Tachycardia Syndrome Posstur u al Ortho ost stat atiic T acchyca hycaard rdia ia S yndroomee ynd Amyloid Heart Disease Amyloid Amy yl He ear art Dis D iseasse Cardiac Card Ca rdia rd iacc Sarcoidosis ia Sarc Sa rcoi rc oido dosi do siis Carcinoid Heart Disease Carc rcin inoidd He H a t Di ar Dise seas ae Ventricular Assist Assi As sist si st Device Dev vic icee Heart Rhythm Disorders H eartt Rh yth thm D isord ders Atrial Fibrillation or Flutter -Paroxysmal -Permanent Paroxysmal Supraventricular Tachycardia History of Cardiac Arrest Wolff-Parkinson-White Syndrome Congenital Long QT Syndrome History of Catheter Ablation Procedure Implanted Cardiac Device (Pacemaker and/or Implantable Cardioverter-Defibrillator) -Paced Rhythm on resting ECG Bundle Branch Block on resting ECG -Right -Left Note: Total of 5060 studies; some subjects had multiple diagnoses.

19

(n) 1787 934 688 1388

(%) 35.3 18.5 13.6 27.4

212 219 269 21 538 254 308 79 1289 839 450 688 463 598 59 3688 36 1944 19 955 744 222 11 8 ((n) n)) 1010 557 453 157 60 16 7 255 1012

4.2 4.3 5.3 0.4 10.6 5.0 6.1 1.6 25.5 16.6 16.66 8.9 8.9 13.6 13 .66 9.2 11.8 7.3 3.88 3. 1.9 1.9 11.5 .5 0.4 0.4 00.2 0. 2 0.2 (%) (%) 20.0 11.0 9.0 3.1 1.2 0.3 0.1 5.0 20.0

562

11.1

462 285

9.1 5.6

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Table 3. Patient Characteristics: Echocardiogram Data.

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(n) 1289 286 235 224 300 244 212 90 58 30 34 194 18 27 86 28 81 662 2 335 5 5988 59 64 89 150 295

Congestive Heart Failure LV Ejection Fraction ” 25% LV Ejection Fraction 26-35% LV Ejection Fraction 36-50% LV Ejection Fraction • 51% No recent echocardiogram Aortic Stenosis† Severe Moderate Mild No recent echocardiogram Pulmonaryy Hypertension yp RV Systolic Pressure ” 30 mmHg RV Systolic Pressure 31-40 mmHg RV Systolic Pressure 41-70 mmHg RV V Systolic Sys ysto toli to l c Pressure P esssu Pr sure r • 71 mmHg Right Ri igh ghtt ventricular v nt ve ntri riccula ri cu ar enlargement enlarg en gement Decreased D eccreased cr RV systolic sys y to toli licc fu li func function ncti nc tiion No N o rrecent e ent ec ec echocardiogram cho h caardioggraam Hypertrophic Hy ype pert rtro rt roph phiic ph ic Cardiomyopathy Carrdi diom omyo om y paath yo hy * No obstruction obs bstr truc ucti tion on Labile obstr obstruction ruc ucti tion ti on Basal obstruction No recent echocardiogram with measurement of LV outflow tract gradient

* The % refers to the percentage of patients within each disease category † See text for definitions

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(%)* 22.2 18.2 17.4 23.3 18.9 42.5 27.4 14.2 16.0 9.33 9. 13.99 13.9 44.3 14.4 41.8 32.0 32 .0 0 118.0 8.0 .0 10.7 10. 0.77 114.9 49 4. 25.1 49.3

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Table 4. CPX Results Value

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Peak VO2 (mL/kg/min) -Male

19.3 ± 7.0 20.4 ± 7.4

-Female Percent of Predicted Peak VO2 (%) -Male

17.2 ± 5.8 67.9 ± 21.3 67.9 ± 21.6

-Female Heart Rate: Resting (bpm)

67.7 ± 20.6 73.8 ± 15.0

Heart Rate: Peak Exercise (bpm) Heart Rate: Cooldown 1 min Post-Exercise (bpm) Resting Systolic Blood Pressure (mmHg)

132.9 ± 29.1 119.2 ± 25.9 117.7 ± 19.7

Peak Exercise Systolic Blood Pressure (mmHg) Peak Double Product (mmHg * bpm)

149.3 ± 32.8 20184 ± 7123 23 3

Peak RER End-tidal CO2 at Peak Exercise (mmHg) Ve / V VCO2 CO22 at CO a Pea Peak eakk Exercise ea

1.18 ± 0.11 35.4 ± 6.0 34 34.1 4.1 ± 6.9

Hypotensive Exercise Hyppotensive po e BP rresponse espo pons po nsse to E xerc xe rcis rc ie is Abnormal Abnormal no Hea Heart e rt R Rate ate Re Reco Recovery over very

(8.2%) 4155 (8.2 41 .2 2%) 247 2473 73 (4 73 (48.9%) 48.9%) %

Cont Continuous Cont ntin in nuo uous us vvariables ariiabl ar iablees aare re rreported epor ep o te or ted aass mean mea eann ± standard st nda stan darrd rd ddeviation. e iaatioon. Ca ev Cate Categorical tego te goriica go call va vvariables riab ri a lees are ab are re repo reported po ort rted ed aass nu number umber mber (percent). perrce cent nt)).

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Table 5. Narrative Description of Adverse Events. Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Subject

Peak VO2 (mL/kg/min)

Peak RER

Peak HR (bpm)

Adverse Event

Management

35 year-old male with restrictive cardiomyopathy

21.9

0.99

146

Sustained ventricular tachycardia

Hospital admission during which an ICD was implanted. Discharged in stable condition.

48 year-old male with dilated cardiomyopathy and history of recurrent ventricular tachycardia (VT). Had ICD / biventricular ricular pacemaker in place at the time off the study.

18.1

1.09

104

Sustained ventricular tachycardia

Hospital admission during which VT ablation was performed. Discharged in stable condition.

57 year-old r-old male with dilated cardiomyopathy. myopathy. Congenital heart disease istory of repaired ventricular septal with history defect. On homegoing IV milrinone infusion the on at th he time of CPX. CP

5.6

0.81

88

Sustained ventricular tachycardia

admission Hospital adm mis issi s on for si for o VT VT an andd severe seve se vere ve r re congestive decompensatedd conges tive i hheart eartt ffailure. ail ilure Discharged in stable condition.

45 year-old man aortic r-ol rold ol d ma m n with h ssevere e er ev e e ao aort rtic ic regurgitation setting bicuspid itat ta ion on in the setti ingg off bi bicu cusp cu spid id valve

26.3

1.05

151 15 51

Sustained ventricular ventricu cu ular a tachycardia tach ach hyc ycar ardi ar da di

ablation Ho Hospital admission during which VT ab wass pe performed. Discharged w wa erf rfor orrme med. d Di d. Disc scha harg rged rg e in ed in stable stab st able condition. condit o tio on. n

77 year-old exercise r old rd man with history ooff exerci x se se induced d VT T

11.5

11.00 .00

900

Sustained S ussta usta taiined ine ventricular ventric i ular a tachycardia tach ta chyc hycar ardia r a

Resolved Re R esolv ved d by rest. rest. t Close Clo l se se outpatient out u patien ie t follow-up, follo hospital Patient bbut ut no o hos o pi pital ad aadmission. m ssio mi ion.. Patien e t has subsequently well. subs ubseq eque qu nt n ly ddone o e well on ll.

77 year-old artery r-olld ma mann wi with ith ccoronary oronnarry ar rte tery ry e, history his isto tory to ry of of CABG, CABG CA BG, atrial BG atri at rial ri al disease, fibrillation, tricuspid ation, and severe tri ricu cu usp spid id regurgitation itation

11.0 111.0 0

11.04 .04 .0 04

120 20

Sustained Su Sust stai aine nedd ventricular vent ve n ricula ular tachycardia tach ta chyc ch ycar yc ardi ar diaa di

Resolved Re Reso solv ved by by rest. rest re s . Close Clo lose outpatient out utpa pati tient follow-up foll fo lo admission. Patient butt no hhospital bu ospi os pita pi tall ad ta admi miss mi ssio ss ionn. Pa io Pati tien ti entt ha en hass subsequently subs su bseq bs eque eq uent ntly nt ly y ddone onee we on well.

53 year-old man with history of cardiac transplant six years prior to the study

28.1

1.13

152

STEMI

Hospital admission. Successful angioplasty and stent placement. Discharged in stable condition.

72 year-old man with coronary artery disease

22.2

1.21

142

Hospital admission

Severe non-resolving dyspnea. Hospital admission out of concern for acute coronary syndrome. Further investigation ruled out myocardial infarction. Discharged in stable condition.

Abbreviations: CPX = cardiopulmonary exercise testing; CABG = coronary artery bypass grafting; ICD = implantable cardioverter defibrillator; STEMI = ST segment elevation myocardial infarction; VT = ventricular tachycardia

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Figure Legends:

Figure 1. CPX Characteristics.

Figure 2. Adverse event rate during CPX.

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The Safety of Cardiopulmonary Exercise Testing in a Population with High-Risk Cardiovascular Diseases Joseph Skalski, Thomas G. Allison and Todd D. Miller Circulation. published online October 22, 2012; Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2012 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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