clinical study end-systolic elastance and ventricular...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 235194 14 pageshttpdxdoiorg1011552013235194

Clinical StudyEnd-Systolic Elastance and Ventricular-ArterialCoupling Reserve Predict Cardiac Events inPatients with Negative Stress Echocardiography

Tonino Bombardini1 Marco Fabio Costantino2 Rosa Sicari1 Quirino Ciampi3

Lorenza Pratali1 and Eugenio Picano1

1 Institute of Clinical Physiology National Research Council Via Moruzzi 1 56124 Pisa Italy2 Cardiology Department San Carlo Hospital Via Potito Petrone 85100 Potenza Italy3 Division of Cardiology Fatebenefratelli Hospital Viale Principe di Napoli 12 82100 Benevento Italy

Correspondence should be addressed to Tonino Bombardini bombardiniifccnrit

Received 26 April 2013 Accepted 1 July 2013

Academic Editor Tong Tang

Copyright copy 2013 Tonino Bombardini et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Background Amaximal negative stress echo identifies a low-risk subset for coronary events However the potentially prognosticallyrelevant information on cardiovascular hemodynamics for heart-failure-related events is unsettled Aim of this study was to assessthe prognostic value of stress-induced variation in cardiovascular hemodynamics in patients with negative stress echocardiographyMethodsWe enrolled 891 patients (593malesmean age 63plusmn 12 ejection fraction 48plusmn 17) with negative (exercise 172 dipyridamole482 and dobutamine 237) stress echocardiography result During stress we assessed left ventricular end-systolic elastance index(119864LVI) ventricular arterial coupling (VAC) indexed by the ratio of the 119864LVI to arterial elastance index (119864aI) systemic vascularresistance (SVR) and pressure-volume area (PVA) Changes from rest to peak stress (reserve) were tested as predictors of mainoutcomemeasures combined death and heart failure hospitalizationResults During amedian followup of 19months (interquartilerange 8ndash36) 50 deaths and 84 hospitalization occurred Receiver-operating-characteristic curves identified as best predictors 119864LVIreserve for exercise (AUC = 0871) and dobutamine (AUC = 0848) and VAC reserve (AUC = 0696) for dipyridamole ConclusionsPatients with negative stress echocardiography may experience an adverse outcome which can be identified by assessment of 119864LVIreserve and VAC reserve during stress echo

1 Introduction

A maximal negative stress echo identifies a low-risk subsetfor coronary events However prognostically relevant infor-mation on cardiovascular hemodynamics for heart-failure-related events is still unsettled When a physiological (exer-cise) or pharmacological (dipyridamole dobutamine) stressecho is scheduled interest focuses on wall motion segmentalcontraction abnormalities to diagnose ischemic response tostress [1] and on left ventricular ejection fraction to assesscontractile reserve Echocardiographic evaluation of volumes(plus standard assessment of heart rate and blood pressure) isideally suited for the quantitative and accurate calculation ofa set of parameters allowing a complete characterization ofcardiovascular hemodynamics (including cardiac output and

systemic vascular resistance) left ventricular elastance (mir-roring left ventricular contractility theoretically independentof preload and afterload changes heavily affecting the ejectionfraction) arterial elastance ventricular arterial coupling (acentral determinant of net cardiovascular performance innormal and pathological conditions) and pressure-volumearea an index of LV oxygen consumption [2 3]

All these parameters at least in principle are availablein the stress echocardiography laboratory since all of themrequire the accurate estimation of left ventricular volumesand stroke volume Aim of the study was to assess theprognostic value of stress-induced variation in cardiovascularhemodynamics in patients with negative stress echocardiog-raphy

2 BioMed Research International

2 Methods21 Patients From January 2003 1174 patients underwentstress echocardiography in seven quality-controlled stressecho laboratories (Pisa Potenza Benevento Cesena Berg-amo and Belgrade) Informed consent was obtained fromall patients (or their guardians) before testing and thestudy protocol was approved by the institutional ethicscommittee Stress echo data were collected and analyzed bystress echocardiographers not involved in patient care Thedata of 258 of these patients have been already publishedregarding aspects related to feasibility [4 5] diagnostic results[6 7] and short-term outcome [8] Exclusion criteria weresignificant congenital heart disease unsatisfactory imagingof left ventricle at rest or during stress atrial fibrillationpositive stress echocardiography severe mitral regurgitationor no available followup data From the initial population of1174 patients 118 were excluded for stress echo positivity 11for congenital heart disease 18 for atrial fibrillation 41 forunsatisfactory echo imaging and 32 were lost at follow-up63 patients with severe stress mitral regurgitation underwentsurgical repair of 118 patients with positive stress 2 had hearttransplants 40 had percutaneous coronary interventions25 coronary artery bypass grafting (8 with left ventricularremodeling 4 with mitral valve repair) and 51 were followedon medical therapy Thus the study population included 891patients 593 (67) men 298 (33) women mean age 63(SD 12) years ejection fraction 47 plusmn 12 (Figure 1) withnegative stress echo by wall motion criteria and follow-updata Patients were categorized ex-post as normals 119899 = 91idiopathic dilated cardiomyopathy 119899 = 222 known coronaryartery disease 119899 = 331 (dilated ischemic cardiomyopathy 119899 =102 not dilated 119899 = 229) diagnostic tests 119899 = 162 hyper-tensive 119899 = 85 Diagnostic tests were stress tests in patientswith low pretest probability of CAD ECG abnormalities atrest or exercise electrocardiography and no LV dilation Thecharacteristics of the study patients are reported in Table 1Patients with normal rest and peak normal left ventricularfunction no drug therapy were the normals Diagnosis ofcoronary artery diseasewas based upon history ofmyocardialinfarction or coronary revascularization andor presence ofge1 angiographically documented coronary stenosis gt 50Thediagnosis of idiopathic dilated cardiomyopathywasmadeon the basis of echocardiography (left ventricular dilationand diffuse hypocontractility) and coronary angiography (nosignificant coronary artery stenosis)

Stress echocardiography was performed on anti-ischemicmedical therapy in 510 patients (57) (Table 1) The stressorused (exercise dipyridamole dobutamine) was chosen onthe basis of specific contraindications local facilities andphysicianrsquos preferences Dobutamine was the preferred stres-sor in case for viability assessment [1] Figure 1 shows leftventricular ejection fraction values in this patient population

22 Stress Protocol Two-dimensional echocardiography and12-lead electrocardiographic monitoring were performed incombination with semisupine bicycle exercise high-dose(up to 40 120583gkgmin) dobutamine or high-dose dipyri-damole (84mgkgmin over 6min) according to protocols

suggested by the European Association of Echocardiography[1] guidelines During the procedure blood pressure andthe electrocardiogram were recorded each minute The testwas stopped in cases of obvious severe inducible wallmotion abnormalities intolerable symptoms or limiting sideeffects including hypertension (systolic blood pressure gt220mmHg diastolic blood pressure gt 120mmHg) hypoten-sion (relative or absolute gt30mmHg decrease in bloodpressure) supraventricular arrhythmias (supraventriculartachycardia or atrial fibrillation) ventricular arrhythmias(ventricular tachycardia frequent polymorphous prematureventricular beats) and bradyarrhythmias Amaximal test wasdefined by the achievement of 85 of age-predicted maximalheart rate andmaximal drug dose in pharmacological studies

23 Echocardiographic Analysis Echocardiographic imageswere semiquantitatively assessed using a 17-segment four-point scale model of the left ventricle [1] A wall motionscore index was derived by dividing the sum of individualsegment scores by the number of interpretable segments Leftventricular ejection fraction was assessed using the biplaneSimpson method [9] Ischemia was defined as stress-inducednew wall motion abnormality or worsening of pre-existingwall motion abnormality or biphasic response (ie low-dose improvement followed by high-dose deterioration) Byselection all patients had negative stress echo by wall motioncriteria Improvement of wall motion score index betweenresting and peak of stress indicated myocardial viability [10]

24 Volume Analysis All patients underwent transthoracicechocardiography at baseline and at peak of stress Aftercompletion of the study echocardiographic images were readby one experienced cardiologist unaware of the identity ofthe patient Left ventricular end-diastolic and end-systolicvolumes were measured from apical four- and two-chamberviews using the biplane Simpson method [11] Only repre-sentative cycles with optimal endocardial visualization weremeasured and the average of three measurements was takenThe endocardial border was traced excluding the papillarymuscles The frame captured at the R wave of the ECG wasconsidered to be the end-diastolic frame and the frame withthe smallest left ventricular silhouette the end-systolic frameAll cardiac volumes were normalized to body surface areayielding their respective indexes end-systolic volume indexand stroke volume index

25 Blood Pressure Analysis One nurse recorded blood pres-sures at rest and during each individual study The bloodpressure recording was made using a sphygmomanometerand the diaphragm of a standard stethoscope Systolic bloodpressure and diastolic blood pressure was obtained in theright arm (with patient lying in a left rotated supine positionduring pharmacological stress) Patients were told to let theirright hand go limp when blood pressure was measuredEnd-systolic pressure was approximated as 09x brachialsystolic blood pressure a noninvasive estimate of end-systolicpressure that accurately predicts pressure-volume loop mea-surements of end-systolic pressure [12] Pulse pressure was

BioMed Research International 3

DCM

DC

CAD

HYP

Test

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20 40 60 80

Stre

ss E

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100

100

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30 plusmn 6

33plusmn 7

57 plusmn 9

53plusmn 11

59 plusmn 10

63 plusmn 5

LVEF

(a)

DCM

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

IP

300

30

030

030

030

0

28 plusmn 9

59plusmn 9

61 plusmn 5

61plusmn 7

59 plusmn 5

LVEF

(b)

DCM

DC

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

OB

150

150

150

150

150

150

30 plusmn 7

28plusmn 6

54 plusmn 8

55plusmn 9

57 plusmn 9

60 plusmn 7

LVEF

(c)

Figure 1 Histogram of ejection fractions in the patient population (a) Exercise stress patients (b) Dipyridamole stress patients (c)Dobutamine stress patients Next to each panel is the mean SD for the LVEF CAD coronary artery disease CI cardiac Index DC dilatedischemic cardiomyopathy DCM idiopathic dilated cardiomyopathy DIP dipyridamole DOB dobutamine 119864aI arterial elastance index119864LVI LV end-systolic elastance index 119864LVI119864aI ventricular-arterial coupling ratio EX exercise HYP hypertensives NL normals PVApressure-volume area SVR systemic vascular resistance and TEST diagnostic tests


Table 1 Demographics resting values and follow-up events

119899 () or mean plusmn SD NL TEST HYP CAD DC DCMPatients 91 162 85 229 102 222Age (years) 56 plusmn 15 62 plusmn 12 66 plusmn 11 66 plusmn 10 67 plusmn 9 61 plusmn 12lowast

Males 52 (57) 73 (45) 47 (55) 173 (76) 87 (85) 161 (73)120594

Body surface area (m2) 184 plusmn 019 181 plusmn 018 184 plusmn 020 187 plusmn 019 182 plusmn 0185 185 plusmn 20Previous myocardial infarction mdash (0) mdash (0) mdash (0) 111 (49) 102 (100) mdash (0)120594

Beta blockers on mdash (0) 53 (33) 42 (49) 119 (52) 54 (53) 133 (60)120594

Angiotensin converting enzyme inhibitor on mdash (0) 36 (22) 45 (53) 87 (38) 82 (80) 183 (82)Calcium blockers on mdash (0) 31 (19) 23 (27) 55 (24) 2 (2) 7 (3)120594

Wall motion score index 1 plusmn 0 103 plusmn 015 106 plusmn 023 117 plusmn 03 226 plusmn 037 223 plusmn 034lowast

LV ejection fraction () 60 plusmn 6 60 plusmn 8 58 plusmn 7 58 plusmn 9 28 plusmn 7 28 plusmn 9lowast

119864LVI119864aI (ratio) 16 plusmn 04 16 plusmn 06 15 plusmn 04 15 plusmn 06 04 plusmn 01 04 plusmn 02lowast

119864LVI (mmHg sdotmLminus1 sdotmminus2) 71 plusmn 24 7 plusmn 36 63 plusmn 28 62 plusmn 3 17 plusmn 07 19 plusmn 1lowast

119864aI (mmHg sdotmLminus1 sdotmminus2) 45 plusmn 13 44 plusmn 15 43 plusmn 15 43 plusmn 15 42 plusmn 14 54 plusmn 38lowast

SWI (mmHg sdotmL sdotmminus2) 3248 plusmn 1020 3626 plusmn 1187 4456 plusmn 1473 3819 plusmn 1254 2817 plusmn 942 2861 plusmn 1437lowast

PVA (mmHg sdotmL sdotmminus2) 4306 plusmn 1276 4845 plusmn 1483 6052 plusmn 1858 5275 plusmn 1722 6493 plusmn 2147 6414 plusmn 2737lowast

LV end-systolic volume index (mLm2) 18 plusmn 5 20 plusmn 8 24 plusmn 9 24 plusmn 10 71 plusmn 26 67 plusmn 30lowast

Stroke volume index (mLm2) 28 plusmn 7 30 plusmn 9 34 plusmn 10 31 plusmn 9 27 plusmn 8 27 plusmn 12lowast

LV end-diastolic volume index (mLm2) 46 plusmn 11 50 plusmn 14 58 plusmn 17 54 plusmn 16 99 plusmn 31 94 plusmn 38lowast

End-systolic pressure (mmHg) 117 plusmn 17 121 plusmn 19 133 plusmn 19 123 plusmn 18 104 plusmn 18 107 plusmn 19lowast

Heart rate at rest (bpm) 70 plusmn 13 70 plusmn 13 71 plusmn 14 69 plusmn 12 73 plusmn 14 76 plusmn 16lowast

Cardiac index (L sdotmin sdotmminus2) 1933 plusmn 560 2089 plusmn 624 2364 plusmn 735 2052 plusmn 659 1991 plusmn 743 1971 plusmn 989lowast

SVR (dyn sdot sminus1 sdot cmminus5) 2205 plusmn 698 2151 plusmn 816 2063 plusmn 712 2130 plusmn 750 2129 plusmn 825 2390 plusmn 1424Follow-up events 119899 () mdash (0) 7 (4) mdash (0) 12 (5) 30 (29) 85 (38)120594

Death mdash (0) 4 (3) mdash (0) 2 (1) 8 (8) 36 (16)120594

Heart failure mdash (0) 3 (2) mdash (0) 10 (4) 22 (22) 49 (22)120594lowast

119875 lt 001 between groups (ANOVA) 120594chi square 119875 lt 001 between groupsCAD coronary artery disease CI cardiac index DC dilated ischemic cardiomyopathy DCM idiopathic dilated cardiomyopathy 119864aI arterial elastanceindex ELVI LV end-systolic elastance index ELVI119864aI ventricular-arterial coupling ratio HYP hypertensives NLs normals PVA pressure-volume area SVRsystemic vascular resistance and TEST diagnostic tests

calculated as the difference between systolic and diastolicblood pressure and mean arterial pressure as (2 lowast diastolicblood pressure + systolic blood pressure)3 The indexes ofventricular and arterial elastance were calculated as (1) leftventricular end-systolic elastance index (119864LVI) = end-systolicpressureend-systolic volume index (2) arterial elastanceindex (119864aI) = end-systolic pressurestroke volume index and(3) ventricular-arterial coupling ratio (119864LVI119864aI) = strokevolume indexend-systolic volume index [13]

The noninvasive assessment of 119864LVI is based on theequation 119864LVI = (end-systolic pressureend-systolic volumeindex ndash 119881

0) and assumes that 119881

0(the theoretical volume

when no pressure is generated) is negligible compared withend-systolic volume The 119864aI can be calculated as end-systolic pressurestroke volume Stroke volume can be readilymeasured noninvasively (eg by echocardiography or gatedblood pool scans) [3 14] Chen et al [15] found that the cal-culation of end-systolic pressure from 09x brachial systolicblood pressure reasonably approximated end-systolic pres-sure measured invasively the correlation coefficient betweenthe two variables was 075 and the regression line had a slopeof 101 (119875 lt 00001) From these noninvasive determinationsof119864LVI and119864aI the119864LVI119864aI ratio can be calculatedThenon-invasively obtained values of 119864LVI119864aI closely approximatethose obtained invasively [16 17] The 119864LVI119864aI is directly

related to the ejection fraction [119864LVI119864aI asymp 1((1EF) minus 1)]The advantage of 119864LVI119864aI over ejection fraction is thatexamining the components of 119864LVI119864aI allows us to evaluatewhether alterations in 119864LVI119864aI are due to alterations in leftventricular properties arterial properties or both [18 19]Stroke work index (SWI) was calculated as stroke volumeindex times end-systolic pressure [20] Pressure-volume area(PVA) an index of left ventricular oxygen consumption [21]was calculated as SWI + potential energy (defined as end-systolic pressure times (end-systolic volume index minus119881

0)2) [13]

wherein 1198810 the volume-axis intercept of the end-systolic

pressure volume relationship was assumed to be zero aspreviously reported [22] Systemic vascular resistance (SVR)was calculated as mean arterial pressurecardiac output times80 The stroke volume (mL) was calculated as end-diastolicvolume minus end-systolic volume Stroke volume was indexedby dividing it by body surface area Stroke volume index(mLm2) = stroke volumebody surface area The Cardiacindex (Lminm2) was calculated as heart rate lowast strokevolume index Reserve was defined as the difference in thesevariables between rest and peak stress

26 Followup All-cause mortality was determined by reviewof death certificates Death was considered to be due tocardiovascular causes if the death certificate listed acute


myocardial infarction congestive heart failure or arrhythmiaas the primary cause of death Sudden death defined asdeath occurring unexpectedly within 1 h of the onset ofsymptoms was also considered cardiovascular In order toavoidmisclassification of the cause of death overall mortalitywas considered Hospitalization for heart failure was definedas a minimum 1-night hospital stay for a clinical syndromecomprising at least two of the following paroxysmal noc-turnal dyspnea orthopnea elevated jugular venous pressurepulmonary rales third heart sound and cardiomegaly orpulmonary edema on chest roentgenography These clinicalsigns and symptoms must have represented a clear changefrom the baseline clinical status of the participant and musthave been accompanied by either failing cardiac output asdetermined by peripheral hypoperfusion (in the absence ofother causes such as sepsis or dehydration) or peripheral orpulmonary edema requiring intravenous diuretics inotropesor vasodilators

27 Statistical Analysis SPSS 13 for Windows was used forstatistical analysis The statistical analyses included descrip-tive statistics (frequency and percentage of categorical vari-ables and mean and standard deviation of continuous vari-ables) Pearson chi-square with Fisherrsquos exact test for categor-ical variables and theMann-Whitney test for continuous vari-ables for intergroup comparisons were performed to confirmsignificance (using the Monte Carlo method for small sam-ple comparisons) One-way ANOVA was used to comparecontinuous variables between groups when homogeneity ofvariance was not present the Kruskal-Wallis test for nonpara-metric independent samples was used Our significance testswere two sided in the sense that sufficiently large departuresfrom the null hypothesis in either direction were judgedsignificant if 119875 lt 005 Predefined primary cardiovascularevents were defined as the composite of death and heartfailure hospitalization Only the first event was taken intoaccount Receiver-operator characteristic (ROC) curves wereconstructed to assess the accuracy of cardiovascular hemody-namic values changes (Δ = reserve) from rest to peak stress topredict primary cardiovascular events The ROC curve wasconsidered statistically significant if the AUC differed from05 as determined by the 119911-test The optimal cut point valuesfrom theROCcurveswere chosen by use of theYouden index

3 Results and Discussion

All studies have been performed by an experienced cardiolo-gist with documented experience in stress echocardiographyand who passed the quality-control procedures of stressechocardiography reading according to criteria adopted inthe EPIC (Echo Persantine International Cooperative) andin the EDIC (Echo Dobutamine International Cooperative)multicentre studies [10] By selection of 2D measurements ofLV volumes were feasible in all patients In sixty randomlyselected patients there was an excellent interobserver agree-ment with the Bland Altman method with mean plusmn SD for LVend-diastolic volume at rest (23 plusmn 18mL 95 CI minus38mLto 34mL) and at peak stress (58 plusmn 16mL 95 CI minus38mLto 26mL) LV end-systolic volume at rest (36 plusmn 23mL 95

CI minus48 to 41mL) and at peak stress (03 plusmn 13mL 95CI minus27 to 27mL) The variability was lower for LV end-diastolic and end-systolic volumes both for pharmacologicaland exercise echo at low heart rates (lt100 bpm) at peakstress In a subset of study patients (119899 = 17) the intra-observer variability was calculated The analyses of observer1 were compared with those previously calculated after aminimum interval of 8 weeks In this subgroup the agreementwas excellent with the Bland Altman method with a meanplusmn SD for LV end-diastolic volume at rest (47 plusmn 11mL95 CI minus27mL to 17mL) and at peak stress (5 plusmn 15mL95 CI minus34mL to 24mL) LV end-systolic volume at rest(34 plusmn 7mL 95 CI minus17 to 10mL) and at peak stress(12 plusmn 77mL 95 CI minus162 to 139mL) By selection notest was interrupted because of limiting side effects and notest was positive for regional wall motion abnormalities Themain clinical and echocardiographic findings of the studypopulation are shown in Table 1 Figure 1 shows histograms ofejection fractions in this patient population The mean LVEFincreased from 61 plusmn6 to 72 plusmn7 in normal subjects andfrom46plusmn17 to 54plusmn18 in patients Differences betweenresting and stress echocardiographic variables for differentstresses are shown in Table 2 Of 420 subjects with restingwall motion abnormalities 219 (52) showed improvementof wall motion abnormalities under stress (wall motion scoreindex rest = 223 plusmn 039 versus stress = 181 plusmn 046)

31 Arterial-Ventricular Coupling Ratio and Its Componentsat Rest A reduced end-systolic elastance index (119864LVI) andventricular-arterial coupling ratio (119864LVI119864aI) were foundin dilated ischemic and idiopathic dilated cardiomyopathypatients (Table 1) Arterial elastance index (119864aI) was signifi-cantly higher in idiopathic dilated cardiomyopathy patientsThe SVR was similar between patients at rest The pressure-volume area an index of oxygen consumption was higherin hypertensive dilated ischemic and idiopathic dilatedcardiomyopathy patients versus normals

32 Comparison of the Coupling Ratio Reserve and Its Com-ponents between Groups and Different Stresses The end-systolic elastance index (119864LVI) increased from 71 plusmn 24 to15 plusmn 66mmHgsdotmLminus1sdotmminus2 at peak stress in normal subjectsbut increased less in the patients (from 46 plusmn 34 to 66 plusmn57mmHgsdotmLminus1sdotmminus2 119875 lt 001 versus normals) althoughthe response was heterogeneous at the individual level andbetween stress types (Figure 2 and Table 2) Thus there wasa twofold difference in the peak stress LV inotropic state andan even greater difference in the stress induced increase in theinotropic state between normal subjects versus DC andDCMpatients (119875 lt 001) During stress arterial elastance mildlydecreased in the patients (minus02 plusmn 18mmHgsdotmLminus1sdotmminus2) andincreased in normal subjects (+11plusmn 2mmHgsdotmLminus1sdotmminus2)119875 lt001 between groups The 119864LVI119864aI reserve during stress wasblunted (119875 lt 005) in dilated ischemic and idiopathic dilatedcardiomyopathy patients compared with other groups withintermediate changes for coronary artery disease patients(Figures 2(a) 2(b) and 2(c)) In exercise and dobutaminetests this was almost entirely due to a blunted increase (119875 lt005) in 119864LVI from rest to peak stress interestingly despite


0

4

8

12

DCMDCCADHYPTestNL

ELV

I res

erve

(mm

Hgmiddot

mLminus

1middotm

minus2)

(a)

0

4

8

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DCMDCCADHYPTestNL

EaI

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(b)

00

05

10

15

DCMDCCADHYPTestNL

ELV

IEaI

rese

rve

(c)

0

minus500

minus1000

minus1500

EXDIPDOB

DCMDCCADHYPTestNL

SVR

rese

rve (

dynmiddot

sminus1middotcm

minus5)

(d)

0

minus1000

3000

1000

2000

EXDIPDOB

DCMDCCADHYPTestNL

PVA

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(e)

0

3

1

2

EXDIPDOB

DCMDCCADHYPTestNL

CI re

serv

e (Lmiddotminmiddotm

minus2)

(f)

Figure 2 Ventricular-arterial coupling reserve its components and hemodynamic changes during exercise dipyridamole and dobutaminestress echocardiographies Bars show changes form rest to peak stress (reserve) in the patients who underwent exercise (green bars)dipyridamole (yellow bars) and dobutamine (red bars) stress echocardiography CAD coronary artery disease CI cardiac Index DC dilatedischemic cardiomyopathy DCM idiopathic dilated cardiomyopathy 119864aI arterial elastance index 119864LVI LV end-systolic elastance index119864LVI119864aI ventricular-arterial coupling ratio HYP hypertensive NL normals PVA pressure-volume area SVR systemic vascular resistanceand TEST diagnostic tests

a blunted increase in end-systolic elastance index (119864LVI) inall dipyridamole tests still coupling (119864LVI119864aI) reserve waspresent in normals for a negative arterial elastance (119864aI)reserve in this vasodilator test The pressure-volume area(PVA) reserve an index of left ventricular oxygen con-sumption [3 18 21 23] was negative in dipyridamole testswhile it increased in exercise and dobutamine tests this isaccording to the heart rate times systolic blood pressure productwhich increasedmuchmore in exercise and dobutamine testsversus dipyridamole (Table 2) In accord with their knownpharmacological effects dobutamine and dipyridamole testsinduced a greater reduction in SVR from rest to peak exercisethan exercise tests (Figures 2(d) 2(e) and 2(f)) [1 24]Obviously there was a complete fit between ventricular-arterial coupling ratio (119864LVI119864aI) and left ventricular ejectionfraction at rest (119877 square cubic = 0996 Figure 3(a)) at peakstress (119877 square cubic = 0989 Figure 3(b)) A lower fitexists between ventricular-arterial coupling ratio (119864LVI119864aI)reserve and ejection fraction reserve (119877 square linear = 0561Figure 3(c)) Compared with exercise and dobutamine testspatients undergoing dipyridamole had a lower peak stresscardiac index (dipyridamole = 28 plusmn 11 Lsdotminsdotmminus2 versus

exercise = 37 plusmn 12 Lsdotminsdotmminus2 versus dobutamine = 4 plusmn13 Lsdotminsdotmminus2 119875 lt 001)

33 Followup Data During a median followup of 19 months(interquartile range 8ndash36) 50 deaths and 84 hospitalizationsfor heart failure occurred Of the 84 patients with hospital-izations for heart failure 3 underwent heart transplant and27 a cardiac resychronization therapy defibrillator implantAccording to physiopathological data the event rate washigher in dilated ischemic and idiopathic dilated cardiomy-opathy (Table 1) Changes from rest to peak stress (Δ values =reserve) were tested as predictors of main outcomemeasurescombined death and heart failure hospitalization Receiver-operating-characteristic curves and the corresponding areasunder the curve show the predictor performance of hemody-namic changes during stress in the exercise dipyridamole anddobutamine subsets (Figure 4) The optimal cut point valuesfrom the receiver-operator characteristic curves were chosenby use of the Youden index In the whole group of patientsa cut point value for 119864LVI reserve of 065mmHgsdotmLminus1sdotmminus2predicted events with a sensitivity of 64 and a specificity of79 (area under the curve = 072 95 CI 0684 to 0756


Table 2 Stress echocardiography induced variation in cardiovascular hemodynamics

119899 () or mean plusmn SD Exercise stress echo Dipyridamole stress echo Dobutamine stress echoPatients 172 (19) 482 (54) 237 (27)Age years 59 plusmn 13

sect 63 plusmn 12 66 plusmn 10Males 133 (77) 287 (60)lowast 173 (73)Body mass index (kgm2) 187 plusmn 018Dagger 185 plusmn 02lowast 181 plusmn 018Left ventricular ejection fraction ()

Rest 53 plusmn 14Dagger 50 plusmn 17lowast 39 plusmn 15Peak stress 60 plusmn 17Dagger 57 plusmn 18lowast 51 plusmn 17Reserve 7 plusmn 9Dagger 7 plusmn 8lowast 12 plusmn 9

Heart rate times systolic blood pressureRest 9546 plusmn 2461Dagger 9579 plusmn 2393lowast 8253 plusmn 2058Peak stress 22652 plusmn 6430sect 11035 plusmn 2749lowast 18027 plusmn 6118Reserve 13105 plusmn 5875sect 1455 plusmn 2131lowast 9773 plusmn 6219119864LVI119864aI

Rest 133 plusmn 070Dagger 123 plusmn 070lowast 079 plusmn 056Peak stress 2 plusmn 134Dagger 176 plusmn 115lowast 136 plusmn 098Reserve 067 plusmn 096 053 plusmn 078 057 plusmn 062119864LVI mmHgsdotmLminus1sdotmminus2

Rest 586 plusmn 421Dagger 537 plusmn 321lowast 317 plusmn 242Peak stress 12 plusmn 91sect 628 plusmn 417 646 plusmn 612Reserve 618 plusmn 61sect 091 plusmn 246lowast 329 plusmn 417119864aI mmHgsdotmLminus1sdotmminus2

Rest 428 plusmn 139para 497 plusmn 282lowast 413 plusmn 15Peak stress 61 plusmn 27sect 419 plusmn 256 435 plusmn 176Reserve 165 plusmn 195

sectminus078 plusmn 142lowast 022 plusmn 162

SWI mmHgsdotmLminus1sdotmminus2

Rest 3465 plusmn 1156Dagger 3594 plusmn 1457lowast 3082 plusmn 1235Peak stress 4963 plusmn 1705sect 3624 plusmn 1440lowast 4274 plusmn 1665Reserve 1498 plusmn 1607para 30 plusmn 1035lowast 1192 plusmn 1330

PVA mmHgsdotmLminus1sdotmminus2

Rest 5248 plusmn 1947Dagger 5971 plusmn 2159 5844 plusmn 2234Peak stress 6852 plusmn 2209Dagger 5202 plusmn 2018lowast 6728 plusmn 2598Reserve 1604 plusmn 1790sect minus395 plusmn 1226lowast 884 plusmn 1769

Stroke volume index (mLm2)Rest 296 plusmn 86 293 plusmn 106 286 plusmn 95Peak stress 302 plusmn 87Dagger 323 plusmn 116 329 plusmn 102Reserve 06 plusmn 96

sect 31 plusmn 75 44 plusmn 91End-systolic pressure (mmHg)

Rest 117 plusmn 19sect 122 plusmn 20lowast 107 plusmn 18

Peak stress 165 plusmn 30sect 112 plusmn 19lowast 130 plusmn 28

Reserve 47 plusmn 25sect

minus10 plusmn 15lowast 23 plusmn 25Heart rate (bpm)

Rest 73 plusmn 14 71 plusmn 14 70 plusmn 14Peak stress 122 plusmn 21

para 89 plusmn 16lowast 123 plusmn 24Reserve 49 plusmn 19

para 18 plusmn 13lowast 53 plusmn 28Cardiac index (Lsdotminsdotmminus2)


sect 2847 plusmn 1106lowast 4008 plusmn 1338Reserve 1540 plusmn 1153

sect 803 plusmn 795lowast 2023 plusmn 1101


Table 2 Continued

119899 () or mean plusmn SD Exercise stress echo Dipyridamole stress echo Dobutamine stress echoSVR (dynsdotsminus1sdotcmminus5)

Rest 1972 plusmn 696para 2287 plusmn 1113 2187 plusmn 820Peak stress 1576 plusmn 880Dagger 1524 plusmn 911lowast 1213 plusmn 481Reserve minus442 plusmn 619

sectminus763 plusmn 668lowast minus974 plusmn 652

sectSignificant differences between exercise and both dipyridamole and dobutamine patients Daggersignificant differences between exercise and dobutamine ptslowastsignificant differences between dipyridamole and dobutamine patients parasignificant differences between exercise and dipyridamole patients119864LVI119864aI ventricular-arterial coupling ratio 119864aI effective arterial elastance 119864LVI left ventricular end-systolic elastance PVA pressure-volume area SVRsystemic vascular resistance and SWI stroke work index

119875 = 0000 Youden index = 144) In the whole group ofpatients a cut point value for 119864LVI119864aI reserve of 035predicted events with a sensitivity of 55 and a specificity of83 Youden index = 138 (area under the curve = 071 95CI 0671 to 0748 119875 = 0000)

34 Comparison of the Coupling Ratio Reserve and Its Com-ponents as Prognostic Predictors between Different StressesThe 119864LVI119864aI reserve was smaller (119875 lt 001) in patientswith events compared to patients without events for allthree stress modalities (Figure 5(c)) This was almost entirelydue to a smaller increase (119875 lt 001) in 119864LVI fromrest to peak exercise in exercise and dobutamine stress(Figure 5(a)) interestingly despite a blunted increase incontractility in dipyridamole tests coupling differences werestill present for a greater negative arterial elastance reserve indipyridamole group patients with follow-up events Despitehigher peak 119864LVI mean values for exercise and dobutamineversus dipyridamole patients who experienced events inthe followup had similar flat contractile and ventricular-arterial coupling reserveThe optimal 119864LVI reserve cutoff was134mmHgsdotmLminus1sdotmminus2 for exercise 046mmHgsdotmLminus1sdotmminus2

for dipyridamole and 056mmHgsdotmLminus1sdotmminus2 for dobutaminetests The optimal 119864LVI119864aI reserve cutoff was 039 forexercise 026 for dipyridamole tests and 022 for dobutaminetests (Table 3 and Figure 4)

Patients with negative stress echocardiographymay expe-rience an adverse outcome which can be identified byend-systolic elastance index (119864LVI) reserve and ventricular-arterial coupling ratio (119864LVI119864aI) reserveThese data confirmand expand previous observations suggesting the additionalvalue of these relatively novel indexes over regional wallmotion analysis [4 7 8 25] At rest in healthy individualsventricular-arterial coupling is maintained within a narrowrange which allows the cardiovascular system to optimizeenergy efficiency at the expense of mechanical efficacyDuring stress an acutemismatch between the ventricular andarterial systems occurs due to a disproportionate increasein ventricular systolic elastance index 119864LVI (versus arterialelastance 119864aI) to ensure that sufficient cardiac performanceis achieved to meet the increased energetic requirements ofthe body As a result ventricular-arterial coupling (119864LVI119864aI)increased in normals from an average of 16 to 31 in exerciseto 26 in dipyridamole to 26 in dobutamine stress echosTheend-systolic elastance index (119864LVI) reserve and ventricular-arterial coupling ratio (119864LVI119864aI) reserve were markedly

lower at peak stress in dilated ischemic and idiopathic dilatedcardiomyopathy patients (Figure 2) Obviously follow-upevent frequency was higher inmore severely diseased groupsHowever an adverse outcome could be still identified by119864LVIreserve and119864LVI119864aI reserve (Figure 4)The119864LVI119864aI reservewas nearly three times less in patients with versus withoutfollow-up events in the exercise dipyridamole and dobu-tamine groups (Figure 5) Several papers linked contractilereserve to prognosis demonstrating more follow-up eventsin the presence of blunted contractile reserve [4 7 8 25ndash28] But longitudinal studies to evaluate whether alterationsin 119864LVI119864aI reserve provide any prognostic information foradverse outcomes such as heart failure are lacking [3] Atthe experimental level some reports link acute heart failureand dilated ischemic cardiomyopathy to altered ventricular-arterial coupling ratio In tachycardia-induced heart failurein anesthetized dogs [29] a coupling defects occurred earlyprior to significant pump dysfunction In dilated ischemiccardiomyopathy in rats characterized by infarct expansionventricular-arterial coupling progressively deteriorated [30]For humans at rest [31] 41 patients with previous myocar-dial infarction were enrolled Ventricular-arterial couplingassessed by echocardiography demonstrated good accuracyin predicting long-term cardiovascular mortality comparablewith that of BNP Our data demonstrated that patientswith negative stress echocardiography may experience anadverse outcome which can be identified by end-systolicelastance index (119864LVI) and ventricular-arterial coupling ratio(119864LVI119864aI) reserve Our work adds two clinically relevantpieces of information as follows

(1) 119864LVI and 119864LVI119864aI reserve during exercise dipyrida-mole and dobutamine stress echocardiographiesclearly outperforms ejection fraction reserve(Figure 4)

(2) A prognostically relevant cutoff value of 119864LVI and119864LVI119864aI reserve can be assessed regardless of thestress employed (Figure 5)

35 Limitations Some of the methodological issues per-taining to the noninvasive assessment of ventricular-arterialcoupling ratio (119864LVI119864aI) and its components during stressechocardiography should be highlighted [3]The noninvasivemeasurement of end-systolic elastance index (119864LVI) fromend-systolic pressureend-systolic volume index ratio has itsown limitations (1) It assumes that119881


when no pressure is generated) is negligible compared with


0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF

6040200minus20minus40

6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)

Figure 3 Scatter plot relating ventricular-arterial coupling ratio (119864LVI119864aI) and left-ventricular ejection fraction (LVEF) (a) Resting values(b) peak stress values (c) 119864LV119868119864aI and LVEF reserve values Green circles patients with follow-up events Blue circles patients withoutfollow-up events 119864aI arterial elastance index 119864LVI LV end-systolic elastance index 119864LVI119864aI ventricular-arterial coupling ratio

end-systolic volume 1198810has not been well characterized in

humans particularly during exercise In healthy adult dogsLittle and Cheng [32] found that although the absolute valuesof1198810did not significantly change during exercise119881

0as a per-

centage of end-systolic volume increased by 9 In contrastin healthy subjects Starling [21] found that 119881

0 both in abso-

lute values and as a percentage of end-systolic volume didnot appreciably change during dobutamine infusion (2) Theformula used to noninvasively estimate end-systolic pressure

(end-systolic pressure = 09 lowast systolic blood pressure) has notbeen validated during exercise In this regard methodologiesthat use radial applanation tonometry may be of help asthey allow noninvasive and accurate estimations of centralsystolic blood pressure at rest and during exercise at leastin the supine position and at low intensities of exercise [33]However we should emphasize that the ventricular-arterialcoupling ratio is not affected by central pressures because thepressure terms in the numerator and the denominator are


Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00

AUC998779 0871 (0802ndash0940)998779 0661 (0550ndash0772)998779 0704 (0624ndash0785)998779CI 0572 (0456ndash0687)998779PVA 0582 (0471ndash0693)998779LVEF 0589 (0480ndash0698)

ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)

Figure 4 Receiver-operating-characteristic curves and the corresponding areas under the curve (AUC) shows the predictor performance ofventricular-arterial coupling reserve its components and hemodynamic changes (Δ) during stress in the exercise (EX) dipyridamole (DIP)and dobutamine (DOB) subsets CI cardiac Index 119864aI arterial elastance index 119864LVI LV end-systolic elastance index 119864LVI119864aI ventricular-arterial coupling ratio LVEF left ventricular ejection fraction and PVA pressure-volume area


P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e

(c)Figure 5 Ventricular-arterial coupling reserve its components in patients with versus without follow-up events Bars show changes fromrest to peak stress (reserve) in the patients who underwent exercise (green bars) dipyridamole (yellow bars) and dobutamine (red bars) stressechocardiographies (a) 119864LVI LV end-systolic elastance index reserve (b) 119864aI arterial elastance index reserve and (c) 119864LVI119864aI ventricular-arterial coupling ratio reserve

canceled out and the noninvasive values of 119864LVI119864aI can beregarded as relatively accurate On the other hand the valuesof 119864LVI and 119864aI should be viewed as approximations Bloodpressuremeasurements are simpler andmore accurate duringpharmacological stress echocardiography (dipyridamole ordobutamine) since no movement-related artifacts can occur[1] Also volume measurement is simpler during pharmaco-logical stress echocardiography with the patient lying down

on the left side for an optimal visualization of the cardiacstructures especially during dipyridamole stress echo due tothe low heart rate values at peak stress [34]

Wall Motion Score Index and Stress 41 patients were excludedfor unsatisfactory echo imagingWe previously demonstratedin 73 patients undergoing stress echocardiography that ofall the potential 1241 segments 1214 (978) were visualized


Table 3 Prognostic value of stress-induced variation in cardiovascular hemodynamics in patients with negative stress echocardiography

AUC 95 CI 119875 = Cut point Sensitivity Specificity Youden indexExercise stress echo

ELVI reserve mmHg sdotmLminus1 sdotmminus2 0871 0802ndash0940 0000 134 86 83 169119864aI reserve mmHg sdotmLminus1 sdotmminus2 0661 0550ndash0772 0007 1 65 66 13ELVI119864aI reserve 0704 0624ndash0785 0000 039 57 90 146Cardiac index reserve L sdotmin sdotmminus2 0572 0456ndash0687 0200 mdash mdash mdash mdashPVA reserve mmHg sdotmLminus1 sdotmminus2 0582 0471ndash0693 0145 mdash mdash mdash mdashLV ejection fraction reserve 0589 0480ndash0696 0084 mdash mdash mdash mdashSVR reserve dyn sdot sminus1 sdot cmminus5 0440 0325ndash0555 0307 mdash mdash mdash mdash

Dipyridamole stress echoELVI reserve mmHg sdotmLminus1 sdotmminus2 0648 0597ndash0698 0000 046 54 90 144119864aI reserve mmHg sdotmLminus1 sdotmminus2 0547 0465ndash0629 0213 mdash mdash mdash mdashELVI119864aI reserve 0696 0645ndash0748 0000 026 60 82 142Cardiac index reserve (L sdotmin sdotmminus2) 0663 0592ndash0734 0000 0657 58 75 133PVA reserve mmHg sdotmLminus1 sdotmminus2 0516 0439ndash0593 0677 mdash mdash mdash mdashLV ejection fraction reserve () 0606 0545ndash0667 0003 9 41 85 126SVR reserve (dyn sdot sminus1 sdot cmminus5) 0452 0367ndash0537 0204 mdash mdash mdash mdash

Dobutamine stress echoELVI reserve mmHg sdotmLminus1 sdotmminus2 0848 0789ndash0906 0000 056 80 73 153119864aI reserve mmHg sdotmLminus1 sdotmminus2 0688 0605ndash0770 0000 056 46 86 132ELVI119864aI reserve 0729 0648ndash0811 0000 022 74 62 136Cardiac index reserve (L sdotmin sdotmminus2) 0594 0497ndash0692 0062 mdash mdash mdash mdashPVA reserve mmHg sdotmLminus1 sdotmminus2 0496 0386ndash0607 0984 mdash mdash mdash mdashLV ejection fraction reserve () 0589 0488ndash0691 0080 mdash mdash mdash mdashSVR Reserve (dyn sdot sminus1 sdot cmminus5) 0416 0308ndash0525 0107 mdash mdash mdash mdashELVI119864aI ventricular-arterial coupling ratio 119864aI effective arterial elastance ELVI left ventricular end-systolic elastance PVA pressure-volume area and SVRsystemic vascular resistance

at rest and 1146 (923) at peak stress The inter-observeragreement for 2D echo was good at rest (120581 value = 075)and at peak stress (120581 value = 070) The agreement betweenthe two observers was further evaluated by separating thetotal population according to image quality at peak stress andpatient decubitus during the stress (semi-supine decubitus forexercise and left lateral decubitus for pharmacological stres-sors) In the presence of a bad quality image the agreementbetween the two observers decreases significantly in the caseof semi-supine decubitus (120581 value = 088 with good qualityimages and 069 with bad quality images) Moreover whenpatients reached high heart rates agreement between the twoobservers significantly decreased both in left lateral and semi-supine decubitus (120581 value pharmacological stress heart ratelt100 bpm = 083 heart rate ge 100 bpm = 049 exercise stressheart rate lt 100 bpm = 088 and heart rate ge 100 bpm = 078)[35]

4 Conclusions

Patients with negative stress echocardiography may experi-ence an adverse outcome which can be identified by end-systolic elastance index and ventricular-arterial couplingratio reserve

Acknowledgment

The authors are grateful to Alison Frank for copyeditingproofreading the English language in this paper

References

[1] R Sicari PNihoyannopoulos A Evangelista et al ldquoStress echo-cardiography expert consensus statement executive summaryEuropean Association of Echocardiography (EAE) (a registeredbranch of the ESC)rdquo European Heart Journal vol 30 no 3 pp278ndash289 2009

[2] T Bombardini D Cini G Arpesella and E Picano ldquoWEBdownloadable software for training in cardiovascular hemody-namics in the (3-D) stress echo labrdquoCardiovascular Ultrasoundvol 8 no 1 article 48 2010

[3] P D Chantler E G Lakatta and S S Najjar ldquoArterial-ventricu-lar coupling mechanistic insights into cardiovascular perform-ance at rest and during exerciserdquo Journal of Applied Physiologyvol 105 no 4 pp 1342ndash1351 2008

[4] A Grosu T Bombardini M Senni V Duino M Gori andE Picano ldquoEnd-systolic pressurevolume relationship duringdobutamine stress echo a prognostically useful non-invasiveindex of left ventricular contractilityrdquo European Heart Journalvol 26 no 22 pp 2404ndash2412 2005


[5] T BombardiniM J Correia C Cicerone E Agricola A Ripoliand E Picano ldquoForce-frequency relationship in the echocar-diography laboratory a noninvasive assessment of Bowditchtrepperdquo Journal of the American Society of Echocardiographyvol 16 no 6 pp 646ndash655 2003

[6] E Agricola T Bombardini M Oppizzi et al ldquoUsefulness oflatent left ventricular dysfunction assessed by Bowditch Treppeto predict stress-induced pulmonary hypertension inminimallysymptomatic severe mitral regurgitation secondary to mitralvalve prolapserdquoThe American Journal of Cardiology vol 95 no3 pp 414ndash417 2005

[7] P Otasevic Z B Popovic J D Vasiljevic R Vlahovic L PrataliA Vlahovic et al ldquoRelation of myocardial histomorphometricfeatures and left ventricular contractile reserve assessed byhigh-dose dobutamine stress echocardiography in patients withidiopathic dilated cardiomyopathyrdquo European Journal of HeartFailure vol 7 pp 49ndash56 2005

[8] T Bombardini M Galderisi E Agricola V Coppola G Mot-tola and E Picano ldquoNegative stress echo further prognosticstratification with assessment of pressure-volume relationrdquoInternational Journal of Cardiology vol 126 no 2 pp 258ndash2672008

[9] RM LangM Bierig R B Devereux et al ldquoRecommendationsfor chamber quantification a report from the American Societyof Echocardiographyrsquos guidelines and standards committee andthe Chamber Quantification Writing Group developed in con-junction with the European Association of Echocardiographya branch of the European Society of Cardiologyrdquo Journal of theAmerican Society of Echocardiography vol 18 no 12 pp 1440ndash1463 2005

[10] E Picano W Mathias Jr A Pingitore R Bigi andM PrevitalildquoSafety and tolerability of dobutamine-atropine stress echocar-diography a prospective multicentre studyrdquo the Lancet vol344 no 8931 pp 1190ndash1192 1994

[11] N B Schiller P M Shah M Crawford et al ldquoRecom-mendations for quantitation of the left ventricle by two-dimensional echocardiography American Society of Echocar-diography Committee on Standards Subcommittee on Quan-titation of Two-Dimensional Echocardiogramsrdquo Journal of theAmerican Society of Echocardiography vol 2 no 5 pp 358ndash3671989

[12] R P Kelly C-T Ting T-M Yang et al ldquoEffective arterial elas-tance as index of arterial vascular load in humansrdquo Circulationvol 86 no 2 pp 513ndash521 1992

[13] K SunagawaW LMaughan D Burkhoff and K Sagawa ldquoLeftventricular interaction with arterial load studied in isolatedcanine ventriclerdquo The American Journal of Physiology vol 14no 5 pp H773ndashH780 1983

[14] G J Dehmer B G Firth S E Lewis J T Willerson and L DHillis ldquoDirect measurement of cardiac output by gated equilib-rium blood pool scintigraphy validation of scintigraphic vol-ume measurements by a nongeometric techniquerdquo The Ameri-can Journal of Cardiology vol 47 no 5 pp 1061ndash1067 1981

[15] C-H Chen B Fetics E Nevo et al ldquoNoninvasive single-beat determination of left ventricular end-systolic elastance inhumansrdquo Journal of the American College of Cardiology vol 38no 7 pp 2028ndash2034 2001

[16] A Cohen-Solal B Caviezel T Laperche and R GourgonldquoEffects of aging on left ventricular-arterial coupling in manassessment by means of arterial effective and left ventricularelastancesrdquo Journal of Human Hypertension vol 10 no 2 pp111ndash116 1996

[17] P S SabaM J RomanAGanau et al ldquoRelationship of effectivearterial elastance to demographic and arterial characteristics innormotensive andhypertensive adultsrdquo Journal ofHypertensionvol 13 no 9 pp 971ndash977 1995

[18] S S Najjar S P Schulman G Gerstenblith et al ldquoAgeand gender affect ventricular-vascular coupling during aerobicexerciserdquo Journal of the American College of Cardiology vol 44no 3 pp 611ndash617 2004

[19] M M Redfield S J Jacobsen B A Borlaug R J Rodehefferand D A Kass ldquoAge- and gender-related ventricular-vascularstiffening a community-based studyrdquo Circulation vol 112 no15 pp 2254ndash2262 2005

[20] D Burkhoff and K Sagawa ldquoVentricular efficiency predicted byan analytical modelrdquo The American Journal of Physiology vol250 no 6 pp R1021ndashR1027 1986

[21] M R Starling ldquoLeft ventricular-arterial coupling relations inthe normal human heartrdquoTheAmerican Heart Journal vol 125no 6 pp 1659ndash1666 1993

[22] A Cohen-Solal B Caviezel D Himbert and R Gourgon ldquoLeftventricular-arterial coupling in systemic hypertension analysisby means of arterial effective and left ventricular elastancesrdquoJournal of Hypertension vol 12 no 5 pp 591ndash600 1994

[23] P D Chantler V Melenovsky S P Schulman et al ldquoThesex-specific impact of systolic hypertension and systolic bloodpressure on arterial-ventricular coupling at rest and duringexerciserdquoTheAmerican Journal of Physiology vol 295 no 1 ppH145ndashH153 2008

[24] P A Pellikka V L Roger R B McCully et al ldquoNormalstroke volume and cardiac output response during dobutaminestress echocardiography in subjects without left ventricular wallmotion abnormalitiesrdquoTheAmerican Journal of Cardiology vol76 no 12 pp 881ndash886 1995

[25] L Cortigiani T Bombardini A Corbisiero A Mazzoni FBovenzi and E Picano ldquoThe additive prognostic value ofend-systolic pressure-volume relation in patients with diabetesmellitus having negative dobutamine stress echocardiographyby wall motion criteriardquo Heart vol 95 no 17 pp 1429ndash14352009

[26] T Bombardini E Nevola A Giorgetti P Landi E Picano andD Neglia ldquoPrognostic value of left-ventricular and peripheralvascular performance in patients with dilated cardiomyopathyrdquoJournal of Nuclear Cardiology vol 15 no 3 pp 353ndash362 2008

[27] Q Ciampi L Pratali R Citro B Villari E Picano and R SicarildquoClinical and prognostic role of pressure-volume relationshipin the identification of responders to cardiac resynchronizationtherapyrdquo The American Heart Journal vol 160 no 5 pp 906ndash914 2010

[28] C A Vigliano P M Cabeza Meckert M Diez et al ldquoCardi-omyocyte hypertrophy oncosis and autophagic vacuolizationpredict mortality in idiopathic dilated cardiomyopathy withadvanced heart failurerdquo Journal of the American College ofCardiology vol 57 no 14 pp 1523ndash1531 2011

[29] S D Prabhu ldquoAltered left ventricular-arterial coupling precedespump dysfunction in early heart failurerdquoHeart and Vessels vol22 no 3 pp 170ndash177 2007

[30] I Ahmet M Krawczyk P Heller C Moon E G Lakatta andM I Talan ldquoBeneficial effects of chronic pharmacological ma-nipulation of 120573-adrenoreceptor subtype signaling in rodent di-lated ischemic cardiomyopathyrdquo Circulation vol 110 no 9 pp1083ndash1090 2004

[31] F Antonini-Canterin R Enache B A Popescu et al ldquoPrognos-tic value of ventricular-arterial coupling and B-type natriuretic


peptide in patients after myocardial infarction a five-yearfollow-up studyrdquo Journal of the American Society of Echocardio-graphy vol 22 no 11 pp 1239ndash1245 2009

[32] W C Little and C P Cheng ldquoEffect of exercise on left ventric-ular-arterial coupling assessed in the pressure-volume planerdquoThe American Journal of Physiology vol 264 no 5 pp H1629ndashH1633 1993

[33] J E Sharman R Lim A M Qasem et al ldquoValidation of a gen-eralized transfer function to noninvasively derive central bloodpressure during exerciserdquoHypertension vol 47 no 6 pp 1203ndash1208 2006

[34] T Bombardini S Gherardi P Marraccini M C SchlueterR Sicari and E Picano ldquoThe incremental diagnostic valueof coronary flow reserve and left ventricular elastance duringhigh-dose dipyridamole stress echocardiography in patientswith normal wall motion at restrdquo International Journal ofCardiology 2013

[35] L Pratali S Molinaro A I Corciu E M Pasanisi M Scaleseand R Sicari ldquoFeasibility of real-time three-dimensional stressechocardiography pharmacological and semi-supine exerciserdquoCardiovascular Ultrasound vol 8 no 1 article 10 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


2 Methods21 Patients From January 2003 1174 patients underwentstress echocardiography in seven quality-controlled stressecho laboratories (Pisa Potenza Benevento Cesena Berg-amo and Belgrade) Informed consent was obtained fromall patients (or their guardians) before testing and thestudy protocol was approved by the institutional ethicscommittee Stress echo data were collected and analyzed bystress echocardiographers not involved in patient care Thedata of 258 of these patients have been already publishedregarding aspects related to feasibility [4 5] diagnostic results[6 7] and short-term outcome [8] Exclusion criteria weresignificant congenital heart disease unsatisfactory imagingof left ventricle at rest or during stress atrial fibrillationpositive stress echocardiography severe mitral regurgitationor no available followup data From the initial population of1174 patients 118 were excluded for stress echo positivity 11for congenital heart disease 18 for atrial fibrillation 41 forunsatisfactory echo imaging and 32 were lost at follow-up63 patients with severe stress mitral regurgitation underwentsurgical repair of 118 patients with positive stress 2 had hearttransplants 40 had percutaneous coronary interventions25 coronary artery bypass grafting (8 with left ventricularremodeling 4 with mitral valve repair) and 51 were followedon medical therapy Thus the study population included 891patients 593 (67) men 298 (33) women mean age 63(SD 12) years ejection fraction 47 plusmn 12 (Figure 1) withnegative stress echo by wall motion criteria and follow-updata Patients were categorized ex-post as normals 119899 = 91idiopathic dilated cardiomyopathy 119899 = 222 known coronaryartery disease 119899 = 331 (dilated ischemic cardiomyopathy 119899 =102 not dilated 119899 = 229) diagnostic tests 119899 = 162 hyper-tensive 119899 = 85 Diagnostic tests were stress tests in patientswith low pretest probability of CAD ECG abnormalities atrest or exercise electrocardiography and no LV dilation Thecharacteristics of the study patients are reported in Table 1Patients with normal rest and peak normal left ventricularfunction no drug therapy were the normals Diagnosis ofcoronary artery diseasewas based upon history ofmyocardialinfarction or coronary revascularization andor presence ofge1 angiographically documented coronary stenosis gt 50Thediagnosis of idiopathic dilated cardiomyopathywasmadeon the basis of echocardiography (left ventricular dilationand diffuse hypocontractility) and coronary angiography (nosignificant coronary artery stenosis)

Stress echocardiography was performed on anti-ischemicmedical therapy in 510 patients (57) (Table 1) The stressorused (exercise dipyridamole dobutamine) was chosen onthe basis of specific contraindications local facilities andphysicianrsquos preferences Dobutamine was the preferred stres-sor in case for viability assessment [1] Figure 1 shows leftventricular ejection fraction values in this patient population

22 Stress Protocol Two-dimensional echocardiography and12-lead electrocardiographic monitoring were performed incombination with semisupine bicycle exercise high-dose(up to 40 120583gkgmin) dobutamine or high-dose dipyri-damole (84mgkgmin over 6min) according to protocols

suggested by the European Association of Echocardiography[1] guidelines During the procedure blood pressure andthe electrocardiogram were recorded each minute The testwas stopped in cases of obvious severe inducible wallmotion abnormalities intolerable symptoms or limiting sideeffects including hypertension (systolic blood pressure gt220mmHg diastolic blood pressure gt 120mmHg) hypoten-sion (relative or absolute gt30mmHg decrease in bloodpressure) supraventricular arrhythmias (supraventriculartachycardia or atrial fibrillation) ventricular arrhythmias(ventricular tachycardia frequent polymorphous prematureventricular beats) and bradyarrhythmias Amaximal test wasdefined by the achievement of 85 of age-predicted maximalheart rate andmaximal drug dose in pharmacological studies

23 Echocardiographic Analysis Echocardiographic imageswere semiquantitatively assessed using a 17-segment four-point scale model of the left ventricle [1] A wall motionscore index was derived by dividing the sum of individualsegment scores by the number of interpretable segments Leftventricular ejection fraction was assessed using the biplaneSimpson method [9] Ischemia was defined as stress-inducednew wall motion abnormality or worsening of pre-existingwall motion abnormality or biphasic response (ie low-dose improvement followed by high-dose deterioration) Byselection all patients had negative stress echo by wall motioncriteria Improvement of wall motion score index betweenresting and peak of stress indicated myocardial viability [10]

24 Volume Analysis All patients underwent transthoracicechocardiography at baseline and at peak of stress Aftercompletion of the study echocardiographic images were readby one experienced cardiologist unaware of the identity ofthe patient Left ventricular end-diastolic and end-systolicvolumes were measured from apical four- and two-chamberviews using the biplane Simpson method [11] Only repre-sentative cycles with optimal endocardial visualization weremeasured and the average of three measurements was takenThe endocardial border was traced excluding the papillarymuscles The frame captured at the R wave of the ECG wasconsidered to be the end-diastolic frame and the frame withthe smallest left ventricular silhouette the end-systolic frameAll cardiac volumes were normalized to body surface areayielding their respective indexes end-systolic volume indexand stroke volume index

25 Blood Pressure Analysis One nurse recorded blood pres-sures at rest and during each individual study The bloodpressure recording was made using a sphygmomanometerand the diaphragm of a standard stethoscope Systolic bloodpressure and diastolic blood pressure was obtained in theright arm (with patient lying in a left rotated supine positionduring pharmacological stress) Patients were told to let theirright hand go limp when blood pressure was measuredEnd-systolic pressure was approximated as 09x brachialsystolic blood pressure a noninvasive estimate of end-systolicpressure that accurately predicts pressure-volume loop mea-surements of end-systolic pressure [12] Pulse pressure was


DCM

DC

CAD

HYP

Test

NL

20 40 60 80

Stre

ss E

X

100

100

100

100

100

100

30 plusmn 6

33plusmn 7

57 plusmn 9

53plusmn 11

59 plusmn 10

63 plusmn 5

LVEF

(a)

DCM

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

IP

300

30

030

030

030

0

28 plusmn 9

59plusmn 9

61 plusmn 5

61plusmn 7

59 plusmn 5

LVEF

(b)

DCM

DC

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

OB

150

150

150

150

150

150

30 plusmn 7

28plusmn 6

54 plusmn 8

55plusmn 9

57 plusmn 9

60 plusmn 7

LVEF

(c)





Males 52 (57) 73 (45) 47 (55) 173 (76) 87 (85) 161 (73)120594



























0)2) [13]













0

4

8

12

DCMDCCADHYPTestNL

ELV

I res

erve

(mm

Hgmiddot

mLminus

1middotm

minus2)

(a)

0

4

8

12

DCMDCCADHYPTestNL

EaI

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(b)

00

05

10

15

DCMDCCADHYPTestNL

ELV

IEaI

rese

rve

(c)

0

minus500

minus1000

minus1500

EXDIPDOB

DCMDCCADHYPTestNL

SVR

rese

rve (

dynmiddot

sminus1middotcm

minus5)

(d)

0

minus1000

3000

1000

2000

EXDIPDOB

DCMDCCADHYPTestNL

PVA

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(e)

0

3

1

2

EXDIPDOB

DCMDCCADHYPTestNL

CI re

serv


minus2)

(f)
































Table 2 Continued
















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















DCM

DC

CAD

HYP

Test

NL

20 40 60 80

Stre

ss E

X

100

100

100

100

100

100

30 plusmn 6

33plusmn 7

57 plusmn 9

53plusmn 11

59 plusmn 10

63 plusmn 5

LVEF

(a)

DCM

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

IP

300

30

030

030

030

0

28 plusmn 9

59plusmn 9

61 plusmn 5

61plusmn 7

59 plusmn 5

LVEF

(b)

DCM

DC

CAD

HYP

Test

NL

20 40 60 80

Stre

ss D

OB

150

150

150

150

150

150

30 plusmn 7

28plusmn 6

54 plusmn 8

55plusmn 9

57 plusmn 9

60 plusmn 7

LVEF

(c)





Males 52 (57) 73 (45) 47 (55) 173 (76) 87 (85) 161 (73)120594



























0)2) [13]













0

4

8

12

DCMDCCADHYPTestNL

ELV

I res

erve

(mm

Hgmiddot

mLminus

1middotm

minus2)

(a)

0

4

8

12

DCMDCCADHYPTestNL

EaI

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(b)

00

05

10

15

DCMDCCADHYPTestNL

ELV

IEaI

rese

rve

(c)

0

minus500

minus1000

minus1500

EXDIPDOB

DCMDCCADHYPTestNL

SVR

rese

rve (

dynmiddot

sminus1middotcm

minus5)

(d)

0

minus1000

3000

1000

2000

EXDIPDOB

DCMDCCADHYPTestNL

PVA

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(e)

0

3

1

2

EXDIPDOB

DCMDCCADHYPTestNL

CI re

serv


minus2)

(f)
































Table 2 Continued
















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Males 52 (57) 73 (45) 47 (55) 173 (76) 87 (85) 161 (73)120594



























0)2) [13]













0

4

8

12

DCMDCCADHYPTestNL

ELV

I res

erve

(mm

Hgmiddot

mLminus

1middotm

minus2)

(a)

0

4

8

12

DCMDCCADHYPTestNL

EaI

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(b)

00

05

10

15

DCMDCCADHYPTestNL

ELV

IEaI

rese

rve

(c)

0

minus500

minus1000

minus1500

EXDIPDOB

DCMDCCADHYPTestNL

SVR

rese

rve (

dynmiddot

sminus1middotcm

minus5)

(d)

0

minus1000

3000

1000

2000

EXDIPDOB

DCMDCCADHYPTestNL

PVA

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(e)

0

3

1

2

EXDIPDOB

DCMDCCADHYPTestNL

CI re

serv


minus2)

(f)
































Table 2 Continued
















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























0

4

8

12

DCMDCCADHYPTestNL

ELV

I res

erve

(mm

Hgmiddot

mLminus

1middotm

minus2)

(a)

0

4

8

12

DCMDCCADHYPTestNL

EaI

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(b)

00

05

10

15

DCMDCCADHYPTestNL

ELV

IEaI

rese

rve

(c)

0

minus500

minus1000

minus1500

EXDIPDOB

DCMDCCADHYPTestNL

SVR

rese

rve (

dynmiddot

sminus1middotcm

minus5)

(d)

0

minus1000

3000

1000

2000

EXDIPDOB

DCMDCCADHYPTestNL

PVA

rese

rve (

mm

Hgmiddot

mLminus

1middotm

minus2)

(e)

0

3

1

2

EXDIPDOB

DCMDCCADHYPTestNL

CI re

serv


minus2)

(f)
































Table 2 Continued
















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































Table 2 Continued
















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0 20 40 60 80 100LVEF rest

DeathHF

NoYes

8

6

4

2

0

rest

ELV

IEaI

(a)

0 20 40 60 80 100LVEF peak

DeathHF8

6

4

2

0

NoYes

pea

kE

LVIE

aI(b)

LVEF reserve

DeathHF


6

4

2

0

minus2

minus4

NoYes

rese

rve

ELV

IEaI

(c)




0as a per-


0 both in abso-




Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Stress EX

00 02 04 06 08 10

Sens

itivi

ty10

08

06

04

02

00


ELV I

ELV I

1minus specificity

EaIEaI

(a)

Stress DIP


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

ELV I

ELV I

1minus specificity

EaIEaI

(b)

Stress DOB


00 02 04 06 08 10

Sens

itivi

ty

10

08

06

04

02

00

1minus specificity

ELV I

ELV IEaI

EaI

(c)



P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















P lt 001

P lt 001

P lt 001

Plt

005

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(a)

P lt 001

P lt 001

P lt 006

8

6

4

2

0

minus2

No YesDeathHF

ELV

I res

erve

(mm

Hglowast

mLminus

1lowast

mminus2)

(b)

P lt 001

P lt 001

P lt 001

08

06

04

02

00

No YesDeathHF

EXDIPDOB

ELV

IE

aI re

serv

e












4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























4 Conclusions


Acknowledgment


References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















clinical study end-systolic elastance and ventricular...

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