Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights†

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CLINICAL RESEARCHHeart failure/cardiomyopathy

Exercise oscillatory breathing in diastolic heartfailure: prevalence and prognostic insights†

Marco Guazzi1*, Jonathan Myers2, Mary Ann Peberdy3, Daniel Bensimhon4,Paul Chase4, and Ross Arena3

1Cardiopulmonary Unit, University of Milano, San Paolo Hospital, Via A. di Rudinı, 8, 20142 Milano, Italy; 2VA Palo Alto Health Care System, Palo Alto, CA, USA;3Virginia Commonwealth University, Richmond, VA, USA; and 4LeBauer Cardiovascular Research Foundation, Greensboro, NC, USA

Received 24 April 2008; revised 22 August 2008; accepted 12 September 2008; online publish-ahead-of-print 4 October 2008

Aims Exercise intolerance occurs in both systolic and diastolic heart failure (HF). Exercise oscillatory breathing (EOB) is apowerful predictor of survival in patients with systolic HF. In diastolic HF, EOB prevalence and prognostic impact areunknown.

Methodsand results

A total of 556 HF patients (405 with systolic HF and 151 with diastolic HF) underwent cardiopulmonary exercisetesting (CPET). Diastolic HF was defined as signs and symptoms of HF, a left ventricular ejection fraction �50%,and a Doppler early (E) mitral to early mitral annulus ratio (E0) �8. CPET responses, EOB prevalence and itsability to predict cardiac-related events were examined. EOB prevalence in systolic and diastolic HF was similar(35 vs. 31%). Compared with the patients without EOB, patients with EOB and either systolic or diastolic HF hada higher New York Heart Association class, lower peak VO2 and higher E/E0 ratio (all P , 0.01). Univariate Coxregression analysis demonstrated that peak VO2, VE/VCO2 slope and EOB all were significant predictors ofcardiac events in both systolic and diastolic HF. Multivariable analysis revealed that EOB was retained as a prognosticmarker in systolic HF and was the strongest predictor of cardiac events in diastolic HF.

Conclusion EOB occurrence is similar in diastolic and systolic HF and provides relevant clues for the identification of diastolic HFpatients at increased risk of adverse events.

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IntroductionThe occurrence of symptoms and signs of heart failure (HF) withnormal ejection fraction (EF) and predominant anomalies ofactive relaxation and passive stiffness (i.e. diastolic HF) is increas-ingly recognized.1 This diagnosis carries a mortality risk that is cur-rently estimated to be similar to that seen in systolic HF, �15% peryear in older patients.2,3 Remarkably, in recent year’s survival rateof systolic HF has improved, whereas the prognosis for diastolic HFremains unchanged.2 This is at least in part attributable to the factthat the definition, diagnosis, and natural history of diastolic HF areless well characterized.4– 6

Limitation to physical activity occurs in conjunction with bothsystolic and diastolic HF and cardinal manifestations of exerciseintolerance are a reduction in peak oxygen consumption (VO2),

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an excessive ventilation to CO2 output rate (VE/VCO2),8 – 11 and

the occurrence of exercise oscillatory breathing (EOB).12 –14

These variables are established markers in the clinical and prognos-tic assessment of systolic HF, but their significance in diastolic HFhas not been fully explored.

There has been a recent appreciation for the clinical relevanceof EOB, a complex and intriguing pathophysiological phenomenoncharacterized by waxing and waning of tidal volume that leads toan oscillatory kinetics in measured VO2 and VCO2, reflecting aninstability in central and peripheral controllers of ventilation.Clinically, interest in EOB has arisen because of its strongprognostic power; in fact, recent reports have demonstrated thatEOB is actually superior to both peak VO2 and the VE/VCO2

slope15– 17 and may be valuable in the prediction of arrhythmiccardiac death.18

EOB has been substantially characterized in patients with sys-tolic HF, but no information is available on its prevalence or

* Corresponding author. Tel: þ39 02 5032 3144, Fax: þ39 02 5032 3144, Email: [email protected]† Presented in part at the 80th American Heart Association Scientific Session, Orlando, Florida, November 3–7, 2007.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: [email protected].

European Heart Journal (2008) 29, 2751–2759doi:10.1093/eurheartj/ehn437

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prognostic utility in diastolic HF. Such information would be helpfulin order to better stratify diastolic HF patients at increased risk.Therefore, the present study was aimed at elucidating the pre-valence and the prognostic relevance of EOB in diastolic HF com-pared with systolic HF.

MethodsThis was a multicentre study consisting of HF patients referred to thecardiopulmonary exercise laboratories at San Paolo Hospital, Milan,Italy, Virginia Commonwealth University, Richmond, Virginia, USA,VA Palo Alto Health Care System, Palo Alto, California, USA andLeBauer Cardiovascular Research Foundation, Greensboro, NC,USA. A total of 556 consecutive subjects diagnosed with HF whounderwent a symptom-limited cardiopulmonary exercise testing(CPET) between June 1998 and June 2007 were included. Subjectswith significant obstructive lung disease, evidenced by a forced expira-tory volume in 1 s �70%, or who were unable to perform a maximalexercise test, were excluded from the study.

Smokers were 15–20% of the population and were similarly distri-buted across different subgroups. All patients were in New York HeartAssociation (NYHA) functional classes II– III and 40 had been alreadyhospitalized for acute HF.

Inclusion criteria for systolic HF were signs and symptoms of HFwith a left ventricular (LV) EF � 40%.

Inclusion criteria for diastolic HF consisted of a diagnosis based on(i) signs and symptoms of HF (ii) presence of preserved LV systolicfunction (EF � 50%) as assessed by two-dimensional echocardio-graphy, and (iii) documentation of a mitral inflow early (E) velocityto mitral annulus early velocity (E0) �8.19,20 Approval of the Insti-tutional Review Board at each institution was obtained.

Cardiopulmonary exercise testing procedureand data collectionSymptom-limited CPET was performed in all patients after writteninformed consent had been obtained. Each centre used individualizedramp protocols and maximal tests were designed to obtain exerciseduration between 8 and 10 min. USA centres utilized a treadmill andthe Italian centre used a cycle ergometer. Potential bias related todifferent exercise modes can reasonably be excluded given that a pre-vious study has shown that comparing these two modes of exerciseyields identical predictive cut-off values for both peak VO2 and theVE/VCO2 slope.21 Ventilatory expired gas analysis was performedusing a metabolic cart at all four centres (Medgraphics CPX-D,Minneapolis, MN or Sensormedics Vmax, Yorba Linda, CA, USA).

Standard 12-lead electrocardiograms were obtained at rest, eachminute during exercise and for at least 5 min during the recoveryphase; blood pressure was measured using a standard cuff sphygmo-manometer. Minute ventilation (VE, BTPS), oxygen uptake (VO2,STPD), carbon-dioxide output (VCO2, STPD), and other cardiopul-monary variables were acquired breath-by-breath, averaged over30 s, and printed using rolling averages every 10 s. The V-slopemethod was used to measure the anaerobic threshold (AT).22 Differ-ent methods for calculating the VE/VCO2 slope have been proposed.We measured this variable by including all data points from the begin-ning to the end of exercise, in agreement with previous studies by ourgroup23 and others.24 Measurement of VE/VCO2 slope by using theentire data points may offer some advantages over the calculation ofthe first slope of VE/VCO2 relationship (from rest to the isocapnic buf-fering at ventilatory threshold). Specifically, in patients with EOB, cal-culation of first VE/VCO2 slope linear relationship may represent an

issue, because of the scattered distribution of breath-by-breathvalues, making it impossible to detect the ventilatory threshold. Itfollows that the use of the whole VE/VCO2 relationship for bothEOB and no-EOB patients allows a comparable measurementbetween groups. In addition, we deemed this calculation useful toprevent variability among laboratories.

Ten-second averaged VE and VCO2 data, from the initiation to peakexercise, were input into spreadsheet software (Microsoft Excel,Microsoft Corp., Bellevue, WA, USA) to calculate the VE/VCO2

slope through least squares linear regression (y ¼ mx þ b,m ¼ slope). Ten-second averaged VE data were also analysed todetermine if a subject demonstrated EOB during testing.

EOB was defined accordingly to the following criteria: (i) oscillationsof �60% of exercise data at an amplitude of .15%; (ii) minimalaverage amplitude of ventilatory oscillation of 5 L (peak value minusthe average of two in-between consecutive nadirs); (iii) a regular oscil-lation as defined by a SD of three consecutive cycle lengths (timebetween two consecutive nadirs) within 20% of the average.17,18

Different patters of oscillations may be encountered across the widespectrum of HF populations. As depicted in Figure 1, some noisy oscil-lations (A) may occur at early exercise that are considered as no-EOB(absence of criteria above-reported); an EOB pattern that may last forthe initial and intermediate phases of exercise and disappears after.60% of whole exercise (B) or EOB with cycles of very wide ampli-tude that last for the entire exercise duration (C). In patients withEOB that persisted for the whole exercise duration VO2 at peak exer-cise was calculated as average of the last 60 s of exercise.

Test termination criteria consisted of symptoms (i.e. dyspnoea and/or fatigue), ventricular tachycardia, �2 mm of horizontal or downsloping ST segment depression, drop of systolic blood pressure�20 mmHg during progressive exercise. A qualified exercise physio-logist with physician supervision conducted each exercise test.

EchocardiographyLV chamber dimensions were evaluated using standard procedures.LVEF was calculated from two-dimensional apical images accordingto the Simpson method. LV mass was calculated with the formula pro-posed by Devereux et al.25

Conventional Doppler and tissue Dopplerimaging measurementsMitral inflow measurements included peak early (E) and peak late (A)flow velocities, the deceleration time (DT) of early mitral flow velocity,the E/A ratio and the isovolumic relaxation time (IVRT). The tissueDoppler imaging of the mitral annulus was obtained from the apicalfour-chamber view. A 1.5 sample was placed sequentially at thelateral and septal annular sites. Analysis was performed for the early(E0) and late (A0) diastolic peak velocities. The ratio of early transmitralflow velocity to annular mitral velocity of the lateral LV wall (E/E0) wastaken as an estimate of LV filling pressure.26

EndpointsSubjects were followed for cardiac-related death after CPET throughhospital and outpatient medical chart review at the respectivecentres. Cardiac-related mortality was defined as death directly result-ing from failure of the cardiac system. An example fitting this definitionis myocardial infarction followed by cardiac arrest. Subjects were fol-lowed by the institution where CPET was conducted providing forthe high likelihood that all major events were captured. Clinicalfollow-up to ascertain predefined outcome was obtained every6 months. The last follow-up assessment was obtained at 4 years.

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Any death with a cardiac-related discharge diagnosis was considered anevent. Clinicians conducting the CPET were not involved in decisionsregarding the cause of death or heart transplant/LVAD implantation.

Statistical analysisIn an earlier study,11 the incidence of cardiac mortality at 1 year inpatients with EOB vs. no-EOB was 30 vs. 12%, respectively; thus, ifwe hypothesized a similar association in this study, a population of

126 patients would be needed to detect this difference witha ¼ 0.05 and a power of 0.90.

All continuous data are reported as means+SD. Categorical dataare reported as percentages or frequencies. Unpaired t-testing wasused to compare continuous data between subjects with no-EOBand that with EOB. Differences between no-EOB and EOB patientsfor systolic vs. diastolic HF were tested by two-way analysis of variance(ANOVA). Both main (no-EOB vs. EOB and systolic vs. diastolic HF)and interaction (EOB*HF type) effects were assessed. All tests weretwo-sided.

Variables included in the Cox regression model were only exercisevariables (peak VO2, VE/VCO2 slope and EOB). Peak VO2 andVE/VCO2 slope are the most established prognostic exercise indi-cators as suggested by several consistent studies. EOB is the new vari-able we are assessing, which has recently shown a strong prognosticvalue primarily in systolic HF.16– 18

Univariate Cox regression analysis was used to assess the prognosticability of EOB in the overall group. Multivariable Cox regression analy-sis was performed by using the forward stepwise method with entryand removal of P-value for multivariate analyses set at 0.05 and 0.10,respectively.

For variables included in the Cox regression analysis, proportionalhazards assumption was assessed by plotting log–log survival curves.These plots revealed all variables included in the analysis were parallel,satisfying the proportional hazards assumption. Kaplan–Meier analysisassessed the differences in survival between subjects with and withoutEOB in the overall group. The log-rank test determined statistical sig-nificance between groups in the Kaplan–Meier analysis. Statisticaldifferences with a P, 0.05 were considered significant.

Results

Follow-up on survivalAmong the 630 patients initially assessed, 48 did not fulfil the eli-gibility criteria; 15 patients did not provide their consent to beincluded in the study follow-up and 11 patients were excludedbecause lost at follow-up. The median follow-up duration was13 months with an interquartile range of 8 (25%) and 34 (75%)months for diastolic HF and of 6 (25%) and 31.3 (75%) monthsfor systolic HF. During this period, there were 99 major events(78 deaths, 5 LVADs, 16 transplants), with an overall annual mor-tality rate of 12.4% for the systolic HF group, and 17 major events(16 deaths, 1 transplant) with an annual mortality rate of 5.7% fordiastolic HF group. For diastolic HF group, the mean follow-up forsurvivors was 22.4+19.5 months and that for non-survivors was19.0+ 18.4 months. For systolic HF group, the mean follow-up forsurvivors was 17.6+15.4 months and that for non-survivors was17.6+ 17.5 months.

Baseline characteristicsThe EOB prevalence in patients with systolic vs. diastolic HF was35 and 31%, respectively. A total of 251 patients were tested ona bike and 305 on a treadmill. Interestingly, EOB prevalence was25% among those tested on a bike vs. 41.3% among those testedon a treadmill. Nonetheless, the prognostic characteristics ofEOB was the same for bike (hazard ratio: 3.6, 95% CI: 2.1–6.3,P , 0.001) and treadmill (hazard ratio: 3.2, 95% CI: 1.9–5.2,P , 0.001) tests.

Figure 1 Examples of different patterns of oscillatory venti-lation. (A) Some noisy oscillations may occur at early exercisethat are considered as no-exercise oscillatory breathing. (B) Anexercise oscillatory breathing pattern that may last for theinitial and intermediate phases of exercise and disappearingafter 60% of whole exercise. (C) Exercise oscillatory breathingwith very wide amplitude of cycles that persist for the entireexercise.

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Comparisons of key variables between no-EOB and EOB amongsubjects with systolic and diastolic HF are listed in Tables 1 and 2,respectively. For patients with systolic HF, no significant differenceswere detected between those with and without EOB in terms ofage, gender distribution, aetiology of cardiomyopathy, and EF.Conversely, EOB patients exhibited a higher NYHA functionalclass and fewer were taking beta-blockers. ACE-inhibitors anddiuretics were prescribed similarly between the subgroups.Among patients with diastolic HF, there were fewer females withEOB and NYHA functional class was higher. In addition, patientswith EOB were more frequently prescribed RAS inhibitors anddiuretics.

Echocardiographic characteristicsTable 3 reports the echocardiographic data. The two-way ANOVAanalysis documented a significant EOB main effect for both leftventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (P ¼ 0.04) with a significant main effectfor systolic vs. diastolic HF (P , 0.001). Diastolic HF patients hada significantly lower LVEDV and LVESV (P , 0.01) vs. systolic HF.An EOB and HF type interaction was detected for diastolic HFpatients with EOB who presented significantly lower LVEDV andLVESV compared with no-EOB systolic HF patients (P ¼ 0.001).As to left ventricular mass (LVM), there was a main effect forEOB and patients with no-EOB had a significantly lower LVM com-pared with EOB patients (P ¼ 0.02). The main effect for systolic vs.diastolic HF was also significant (P , 0.001). Systolic HF patientshad a significantly higher LVM. A significant interaction effect

between EOB and HF type was observed and diastolic HF patientswith EOB had a significantly lower LVM vs. systolic HF patients andEOB (P ¼ 0.003). A significant main effect for EOB was observed forLVM/LVEDV just in diastolic HF patients (P ¼ 0.002). A significantinteraction effect emerged between EOB and HF type with diastolicHF patients and EOB showing a higher LVM/LVEDV compared withsystolic HF patients and EOB. No main or interaction effectsemerged for IVRT, DT, and E/A ratio (P . 0.05). As to E/E’ lateral,there was a main effect for EOB. No-EOB vs. EOB patients hada significantly lower E/E’ lateral (P , 0.001). The main effect forsystolic vs. diastolic HF was also significant (P ¼ 0.001) in thatpatients with diastolic HF and no-EOB had a significantly lowerE/E0 lateral vs. systolic HF with EOB. There was, however, no inter-action effect between EOB and HF type (P ¼ 0.61).

Cardiopulmonary dataTwo representative cases of systolic and diastolic HF eithershowing a similar EOB pattern are reported in Figure 2.

Exercise gas exchange data are summarized in Table 4. Allpatients exercised above their AT and the mean peak respiratoryexchange ratio (RER) was �1.05 in all groups, suggesting thatthey developed significant metabolic acidosis and exercised closeto maximal intensity. At the two-way ANOVA analysis, therewas no main or interaction effect for peak RER. As to peak VO2

and VO2 at AT, there was a main effect for EOB. Patients withno-EOB had significantly higher values compared with the subjectswith EOB (P , 0.001). The main effect for systolic vs. diastolic HFwas not significant (P ¼ 0.07). There was, however, an interaction

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Table 1 Demographic and clinical characteristics according to presence or absence of exercise oscillatory breathing insystolic heart failure

Overall group (n 5 405) No-EOB (n 5 263) EOB (n 5 142) P-value (EOB vs. no-EOB)

Age, years 56.0+13.4 55.3+13.2 57.1+13.8 0.34

Gender (male/female), % 71/29 75/25 69/31 0.26

LV ejection fraction, % 25.3+7.9 25.5+8.0 25.2+7.7 0.88

NYHA (average) 2.4+ .76 2.3+0.76 2.6+ .72 ,0.001

Heart rate at rest, beats/min 74+24 72+28 74+30 0.47

Blood pressure at rest, mmHg

Systolic 118+25 120+26 117+26 0.43

Diastolic 72+24 74+25 70+27 0.81

Aetiology

Ischaemic (%) 203 (50) 123 (47) 80 (56) 0.12

Hypertensive (%) 122 (30) 82 (31) 40 (28) 0.35

Post-myocarditis (%) 40 (10) 28 (11) 12 (8) 0.44

Idiopathic (%) 40 (10) 30 (11) 10 (7) 0.31

Drug therapy distribution

Prescribed ACE-inhibitor (%) 312 (77) 200 (76) 111 (78) 0.60

Prescribed diuretic (%) 311 (76) 184 (70) 99 (70) 0.98

Prescribed beta-blocker (%) 296 (73) 200 (76) 95 (67) 0.007

Prescribed antialdosterone agents (%) 202 (50) 131 (50) 71 (50) 0.95

Prescribed inotropic agents (%) 162 (40) 121 (46) 77 (54) 0.55

NYHA, New York Heart Association.




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effect between EOB and HF type. Patients with diastolic HF andno-EOB had a significantly higher peak VO2 compared with thesubjects with systolic HF and no-EOB (P ¼ 0.005).

As to VE/VCO2 slope, there was a main effect for EOB; patientswith no-EOB had a significantly lower VE/VCO2 slope comparedwith EOB patients (P , 0.001). The main effect for systolic vs. dia-stolic HF was also significant (P ¼ 0.009). Patients with diastolic HFand EOB had a significantly lower VE/VCO2 slope compared with

the subjects with systolic HF. There was, however, no interactioneffect between EOB and HF type (P ¼ 0.90).

Cox regression analysesUnivariate Cox regression analysis demonstrated that EOB was asignificant predictor of cardiac mortality in both populations(Table 5A and B). At multivariable analyses, EOB was retained asprognostic indicator in systolic HF and emerged as the most

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Table 2 Demographic and clinical characteristics according to presence or absence of exercise oscillatory breathing indiastolic heart failure

Overall group (n 5 151) No-EOB (n 5 103) EOB (n 5 48) P-value (EOB vs. no-EOB)

Age, years 58.5+13.4 57.0+12.6 61.8+14.4 0.04

Gender (male/female), % 67/33 63/37 75/25 0.005

Left ventricular ejection fraction, % 47.8+7.8 47.8+7.9 47.6+7.8 0.83

NYHA (average) 2.0+0.85 1.8+0.78 2.6+0.0 ,0.001

Heart rate at rest, beats/min 78+28 77+30 78+29 0.06

Blood pressure at rest, mmHg

Systolic 125+26 126+26 124+26 0.67

Diastolic 84+25 83+24 84+26 0.62

Aetiology

Ischaemic (%) 75 (50) 50 (48) 25 (52) 0.73

Hypertensive (%) 45 (30) 34 (33) 11 (23) 0.24

Post-myocarditis (%) 8 (5) 6 (6) 2 (4) 0.1

Idiopathic (%) 23 (15) 13 (13) 10 (21) 0.08

Therapy distribution

Prescribed ACE-inhibitor (%) 108 (72) 46 (45) 26 (55) 0.015

Prescribed diuretics (%) 92 (61) 52 (51) 23 (49) 0.12

Prescribed beta-blockers (%) 84 (56) 46 (45) 26 (55) 0.018

Prescribed antialdosterone agents (%) 60 (40) 49 (48) 25 (52) 0.52

Prescribed inotropic agents (%) 27 (18) 51 (50) 24 (50) 0.64

NYHA, New York Heart Association.

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Table 3 Echocardiographic data characteristics of systolic and diastolic heart failure

Systolic HF Diastolic HF

No-EOB EOB No-EOB EOB

LVESV, mL 107.0+29.0 122.0+30.0* 100.3+32.0# 88.6+28.6*,§,#

LVEDV, mL 185.0+29.0 200.0+30.0* 160.0+31.0# 140+29.0*,§,#

LVM, g 221.0+21.0 237.0+20.0* 219.0+23.0§,# 215.0+22.7*,§,#

LVM/LVEDV, g/mL 1.19+2.0 1.20+1.0 1.37+1.5 1.53+1.2*,§,#

Mitral inflow pattern and tissue Doppler

IVRT, ms 99.0+7.0 92.0+6.0 92.0+4.0 90.0+3.0

E/A ratio 1.13+0.9 1.30+0.8 1.22+0.4 1.13+0.3

DT, ms 220+30 170+28 200+27 190+27

E/E0 lateral 9.0+1.0 12.0+3.0* 9.0+1.0§ 14.0+2.0@,#

*P , 0.05 vs. no-EOB; @P , 0.01 vs. no-EOB; §P , 0.01 vs. EOB systolic HF; #P , 0.01 vs. no-EOB systolic HF. Abbreviations: LVESV, left ventricular end-systolic volume;LVEDV, left ventricular end-diastolic volume; LVM, left ventricular mass; IVRT, isovolumic relaxation time; E, early mitral flow velocity; A, late mitral flow velocity; DT, decelerationtime; E0 , early annular mitral velocity.




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powerful indicator in diastolic HF (Table 6A and B). Thecardiac-related event rate was higher in systolic than diastolic HF.Specifically, 99 (24%) major cardiac-related events were observedamong patients with systolic HF (78 deaths, five LVADs, 16 trans-plants) and 17 (11%) major events were observed for those withdiastolic HF (16 deaths, one transplant).

When Cox regression analysis was performed looking at cardiacmortality without LVADs and transplants, EOB was prognostic inboth diastolic (x2 ¼ 12.0, hazard ratio: 5.4, 95% CI: 1.9–15.7,P ¼ 0.001) and systolic (x2 ¼ 21.3, hazard ratio: 3.0, 95% CI:1.9–4.8, P , 0.001) HF groups.

Looking also at predictive differences according to a peak RERcut-off of 1.05, it emerged that in the diastolic HF group, 44% ofpatients had RER �1.05. EOB was prognostic in this group(x2 ¼ 12.3, hazard ratio: 9.7, 95% CI: 2.1–45.7, P , 0.001) butnot in those with a RER , 1.05 (x2 ¼ 1.2, hazard ratio: 2.4, 95%CI: 0.48–12.5, P ¼ 0.27). The latter finding may be due to theless number of events in the latter group (only six).

In the systolic HF group, 53% had RER �1.05 and EOBwas prognostic in both patients with EOB and peak RER�1.05(x2 ¼ 7.6, hazard ratio: 2.1, 95% CI: 1.2–3.7, P ¼ 0.007), andbelow (x2 ¼ 11.7, hazard ratio: 2.8, 95% CI: 1.5–5.2, P ¼ 0.001).

Kaplan–Meier analysesKaplan–Meier analysis results for the four subgroups are illustrated inFigure 3. Survival rate was significantly lower in those with EOB andeither systolic or diastolic dysfunction. Patients with diastolic HF andEOB had a lower survival rate than systolic HF patients without EOB.

DiscussionResults of the present study define, for the first time, the preva-lence and the prognostic significance of exercise oscillatory gasexchange kinetics in patients with diastolic HF. EOB, a pheno-menon that has been traditionally linked to advanced systolicHF,12,27 is also part of the syndrome of diastolic HF and its recog-nition may help to identify a subset of diastolic HF patients atincreased risk of cardiac mortality.

Notably, as in systolic HF, EOB in diastolic HF showed aprognostic power superior to peak VO2 and the VE/VCO2

slope, parameters that have become standards regarding hearttransplantation urgency in advanced HF patients (peak VO2), andrisk stratification across HF populations with varying diseaseseverity (VE/VCO2 slope).8– 11

Figure 2 Representative cases of exercise oscillatory breathing patterns in systolic (A) and diastolic (B) heart failure.




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Diastolic heart failure, exercise gasexchange and ventilationThe natural history of diastolic HF is less well characterized thanthat of systolic HF; thus, precise management guidelines andoptimal therapeutic approaches can present a challenge for thesepatients. In particular, information on diastolic HF and CPET per-formance are limited. Six studies have investigated exercise

pathophysiology by gas exchange analysis,28– 33 although just onehas addressed prognosis.29 In these studies, disparate criteriawere used for diastolic HF definition, and there was a wide hetero-geneity among populations concerning age and gender distribution.However, although exercise performance and peak VO2 variedwidely across these studies, the cardiopulmonary exercisepattern common to all studies but one33 was an increasedVE/VCO2 slope and an excessive dyspnoea sensation. The presentobservations further support this evidence given that multivariableanalysis demonstrated that the VE/VCO2 slope outperformed peakVO2 in predicting cardiac events. In addition, these findings under-score the importance of addressing abnormalities in the exerciseventilatory pattern to better characterize symptomatic diastolicHF. Interestingly, patients with diastolic HF and a high VE/VCO2

Figure 3 Kaplan–Meier analysis for patients with no-exerciseoscillatory breathing and exercise oscillatory breathing for sys-tolic vs. diastolic heart failure subgroups.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 4 Cardiopulmonary exercise testing data of systolic and diastolic heart failure

Systolic HF Diastolic HF

No-EOB EOB No-EOB EOB

Peak RER 1.06+0.13 1.06+0.12 1.06+0.11 1.05+0.12

Peak VO2, mL O2 . kg21 . min21 15.5+5.0 12.1+3.8@ 17.8+5.5§,# 11.9+3.9@,#

VO2 at anaerobic threshold, mL O2 . kg21 . min21 10.6+5.0 9.2+4.0* 14.5+5.5§,# 9.6+3.9@

VE/VCO2 slope 35.3+10.1 39.7+9.1@ 32.8+7.9§,# 36.9+6.7@,#

*P , 0.05 vs. no-EOB; @P , 0.01 vs. no-EOB; §P , 0.01 vs. EOB systolic HF; #P , 0.01 vs. no-EOB systolic HF. RER, respiratory exchange ratio; VE, ventilation; VCO2, CO2

output.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 6 Multivariable Cox regression analysis forsystolic and diastolic heart failure

x2b Hazard ratio (95% CI) P-value

Systolic heart failure

VE/VCO2 slope 38.4 1.05 (1.03–1.07) ,0.001

EOBa 13.0 2.0 (1.3–3.1) ,0.001

Peak VO2 3.0 — 0.08

Diastolic heart failure

EOB 14.1 5.9 (2.1–16.9) ,0.001

VE/VCO2 slopea 6.5 1.09 (1.03–1.16) 0.01

Peak VO2 0.23 — 0.63

RER, respiratory exchange ratio; VE, ventilation; VCO2, CO2 output. aRetained inthe regression. bResidual x2.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 5 Univariate Cox regression analysis for systolicand diastolic heart failure

x2 Hazard ratio (95% CI) P-value

Systolic heart failure

VE/VCO2 slope 38.4 1.05 (1.03–1.07) ,0.001

Peak VO2 16.3 0.91 (0.86–0.95) ,0.001

EOB 22.8 2.5 (1.6–3.7) ,0.001

Diastolic heart failure

VE/VCO2 slope 11.9 1.10 (1.04–1.16) 0.001

Peak VO2 6.1 0.87 (0.77–0.97) 0.01

EOB 14.1 5.9 (2.1–16.9) ,0.001

RER, respiratory exchange ratio; VE, ventilation; VCO2, CO2 output.




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slope were more commonly observed in the EOB subgroup. Indeed,this population presented with an average VE/VCO2 slope of 37that, although a little lower than the average value of 40 observedin systolic EOB patients, is strongly predictive of worse prognosis.11

Exercise oscillatory breathing: clinicaland prognostic characteristicsBased on our numbers, the prevalence of abnormal ventilatoryoscillation in patients with diastolic HF approximates 30%, and issimilar to that observed in systolic HF in both the present and pre-vious reports.17,18 Likewise, as in systolic HF, a close link betweenEOB and clinical severity exists. Aside from the above-reporteddifferences in VE/VCO2 slope, the clinical picture of patientswith diastolic HF and EOB overlaps that observed among systolicHF patients with EOB; overall exercise performance and peakVO2 were similar and LV end-diastolic pressure (E/E0) was similarlyincreased. EOB diastolic HF patients exhibited normal LV chambersize, increased LV mass and a higher LV mass to volume ratio, pro-viding evidence of a remodelling pattern at high risk. The 1-yearmortality rate for diastolic HF is reported to be �15% in patients�65 years.3 The average age of present diastolic HF populationwas 62 years and this may explain the observed 1-year mortalityrate of 5.7%. Almost all cardiac events occurred in the EOB sub-group, with a 1-year event rate of 10%. It is also interesting tonote that in diastolic HF, presence of gas exchange oscillatory kin-etics during exercise yielded an event-free survival rate worse thanthat in systolic HF patients without EOB (83 vs. 75%; P , 0.001).

In a recent study by our group, primarily involving systolic HFpatients, we found EOB to be a potent predictor of suddencardiac death.18 In this study, we were unable to define whetherthis may also be the case in diastolic HF patients. Consideringthe unquestionable impact of sudden death on the naturalhistory of HF, further investigation in this area would be desirable.

Study limitationsDefinition of the mechanisms underlying EOB in diastolic HF wasbeyond the purposes of the study. Although our findings suggestsimilar EOB prognostic characteristics in diastolic as systolic HF,the pathogenetic mechanisms of the phenomenon in diastolic HFare unclear. However, it is tempting to speculate that an increasedfiling pressure at rest would lead to a further increase during exer-cise, leading to pulmonary interstitial fluid accumulation and stimu-lation of the J-receptors beyond normal reflexogenic control.34

A potential selection bias is represented by the fact that onlypatients who were referred to CPET were included. Thus, in astudy of prevalence, one may argue that, in most clinical settings,physician may favour referral of patients with systolic dysfunctionto CPET and even more, that populations of diastolic HF patientsreferred to a CPET evaluation may not be entirely representativeof the whole spectrum of diastolic HF patients.

Gender distribution was predominantly male for both systolicand diastolic HF, although EOB appeared to be independent ofgender. In addition, the average age of our diastolic HF patientswas somewhat lower compared with previous reports. This maybe unusual because of the well recognized higher diastolic HFrate in female and older populations. However, the lower

propensity of primary care providers to exercise older or femalepatients to exhaustion must be considered. These considerationsall together may offer a conceivable explanation on the differencesbetween our sample of diastolic HF study population and thebroader unselected samples of diastolic HF followed-up in largerepidemiological studies.

Conclusions and perspectivesThe current findings suggest that (i) in diastolic HF, EOB occur-rence and prevalence is similar to systolic HF; (ii) EOB recognitionimplements the ability to identify diastolic HF patients at increasedrisk; and (iii) confirmatory data and definitive strategies to treatoscillatory breathing patterns are warranted.

FundingThis work was supported by a grant provided by the Monzino Foun-dation, Milano, Italy.

Conflict of interest: none declared.

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Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights†

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