1Department of Cardiovascular Medicine and Internal Medicine, Ospedali Riuniti, Bergamo, Italy
2Department of Echocardiography, CNR, Institute of Clinical Physiology, Via Moruzzi 1, Pisa 56123, Italy
Received 23 February 2005; revised 21 June 2005; accepted 14 July 2005; online publish-ahead-of-print 16 August 2005.
* Corresponding author. Tel: +39 50 3152400; fax: +39 50 3152374. E-mail address: picano{at}ifc.cnr.it
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Abstract |
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Methods and results We enrolled 137 consecutive patients referred for dobutamine stress echo. To build the PVR, the force was determined at different heart rate increments during stepwise dobutamine infusion as the ratio of the systolic pressure/end-systolic volume index. The PVR at increasing heart rate was flat-biphasic in 65 and up-sloping in 72 patients: 42 patients underwent surgery and 95 patients were treated medically (median follow-up, 18 months; interquartile range, 1224). Events occurred in 18 patients (death in eight, acute heart failure in 10); a flat-biphasic PVR was independent predictor of events (RR=10.16, P<0.01).
Conclusion PVR is feasible during dobutamine stress. This index of global contractility is reasonably simple, does not affect the imaging time, and only minimally prolongs the off-line analysis time. It allows unmasking quite different, and heterogeneous, contractility reserve patterns underlying a given ejection fraction at rest. The best survival is observed in patients with up-sloping PVR, whereas flat-biphasic pattern is a strong predictor of cardiac events.
Key Words: Bowditch treppe Forcefrequency relationship Dobutamine stress echocardiography Heart failure
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Introduction |
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The aim of the study was to assess the feasibility of a non-invasive estimation of PVR at increasing heart rates during dobutamine stress in the echo lab and to relate PVR to clinical events in the subset of medically treated patients.
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Methods |
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Data acquisition
Baseline and dobutamine stress echocardiography
All patients underwent transthoracic echocardiography at baseline. Intravenous access was secured, and dobutamine was infused with 3 min dose increments starting from 5 µg/kg per minute and increasing to 10, 20, 30, and 40 µg/kg, with atropine co-administration up to 1 mg.
Left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were measured from apical four- and two-chamber view by an experienced observer using the biplane Simpson method.9 Only representative cycles with optimal endocardial visualization were measured and the average of three measurements was taken. The endocardial border was traced, excluding the papillary muscles. The frame captured at the R-wave of the ECG was considered to be the end-diastolic frame, and the frame with the smallest LV cavity the end-systolic frame. Images were acquired at baseline and at each 10-beat frequency increase during stress.
Data analysis
Regional wall motion analysis
Regional wall motion was assessed according to the recommendations of the American Society of Echocardiography from 1 (normal) to 4 (dyskinetic) in a 16-segment model of the left ventricle.10
Blood pressure analysis
One investigator recorded all blood pressures at rest and during each individual study step. The blood pressure recording was made using a sphygmomanometer and the diaphragm of a standard stethoscope.11
Volume analysis
After completion of the study, echocardiographic images were read by one experienced cardiologist unaware of the identity of the patient. The EDV and the ESV were measured at rest and at each step. All volume measures were normalized by dividing by body surface area.
Ejection fraction analysis
Left ventricular ejection fraction (LVEF) was measured at rest and at each stress step. LVEF contractile reserve (5% vs. baseline) was calculated as the difference (in absolute value) from baseline to peak stress.
End-systolic pressurevolume determination
To build the forcefrequency relationship, the force was determined at each step as the ratio of the systolic pressure (cuff sphygmomanometer)/end-systolic volume index (biplane Simpson rule/body surface area). At each heart rate step, three cardiac cycles were memorized and the end-systolic volume was calculated as the mean value. The forcefrequency relationship was built off-line. The slope of the relationship was calculated as the ratio between SP/ESV (systolic pressure/end-systolic volume) index increase (from baseline to peak stress) and heart rate increase (from baseline to peak stress). The PVR was defined up-sloping when dobutamine-induced SP/ESV index increase was higher than 25th percentile values of the entire study group (Figure 1A), flat when within the 25th percentile values (Figure 1C); biphasic, with an initial up-sloping followed by a later down-sloping trend, when peak dobutamine SP/ESV index was lower than intermediate stress values12,13 (Figure 1B). The critical heart rate was defined as the heart rate at which SP/ESV index reached the maximum value during progressive increase in heart rate.12 In biphasic pattern, the critical heart rate was the heart rate beyond which SP/ESV index declined by 5%.
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Limits of agreement between readings were estimated as mean difference (bias) ±2 SD of the differences, as described by Bland and Altman.
Comparing the readings of two observers, the limits of agreement for baseline echo were 18.617.5 mL (ESV) and 11.612.7% (EF%). At intraobserver analysis, the limits of agreement were 7.17.5 mL (ESV) and 6.88.1% (EF%). Mean inter- and intraobserver differences for ESV were 0.6 and 0.3%, respectively. Mean inter- and intraobserver differences for EF% were 0.7 and 0.6%, respectively. Both for intraobserver and interobserver analysis, >95% of the differences were between d2 SD and d+2 SD.
Follow-up data
Follow-up visits occurred at 6-month steps in medically treated patients. Cardiac events (total mortality, heart failure-related hospitalization) were the primary endpoints. Hospital and physician records and death certificates were used to ascertain the cause of death, which was attributed to a cardiac aetiology if a cardiac illness provoked the final presentation or if death was sudden and unexpected. Patients with NYHA class improvement were also considered.
Statistical analysis
SPSS 11 for Windows was utilized for statistical analysis. The statistical analyses included descriptive statistics (frequency and percentage of categorical variables and mean and standard deviation of continuous variables). Pearson's 2 with Fisher's exact test for categorical variables and the MannWhitney test for continuous variables for intergroup comparisons were performed to confirm significance (using Monte Carlo method for small sample comparisons). Our significance tests were two-sided, in the sense that sufficiently large departures from the null hypothesis, in either direction, were judged significant.
Spearman rank correlation and partial Spearman rank correlation tests were used for correlation analyses.
The follow-up analyses included KaplanMeier survival curves and Cox proportional hazards models.
The following covariates were analysed: demographics (age, sex, BSA), incoming disease, medical therapy (beta-blockers, Ca-blockers, digoxin, diuretics, nitrates, ACE-inhibitors), echocardiographic data [resting and peak stress LVEF, LVEF contractile reserve (5% vs. baseline), wall motion score index (WMSI) at rest and peak stress, change in wall motion score index (the difference in wall motion score index from rest to peak stress), resting and peak stress SP/ESV index, flat-biphasic or up-sloping PVR, critical heart rate]. To check the proportional hazard assumption, i.e. that the hazard ratio for two subjects with fixed predictors is constant over time, log(log[survival probability]) for different categories was plotted against time to ensure that the curves were reasonably parallel. In general, all proportionality assumptions were appropriate.
Assumption of linearity was assessed by the ANOVA test of linearity and by visual inspection of events' incidence rates in deciles of the continuous variables. Obvious deviations from linearity were seen in resting and peak stress LVEF, peak WMSI, resting and peak stress SP/ESV index, CHR. On the basis of this, we used these variables as dichotomous variables in all analyses: the deciles 15 vs. deciles 610 for rest LVEF, cut-off value 0.36; the deciles 14 vs. deciles 510 for peak LVEF, cut-off value 0.41; the deciles 14 vs. deciles 510 for peak WMSI, cut-off value 1.64; the deciles 16 vs. deciles 710 for rest SP/ESV index, cut-off value 3.17; the deciles 12 vs. deciles 310 for peak SP/ESV index, cut-off value 1.74; the deciles 12 vs. deciles 310 for rest CHR, cut-off value 100 b.p.m.
To assess independent correlates of variations, groups of variables (demographics, incoming disease, medical therapy, resting and stress echocardiographic data) were first examined in separate regression models with simultaneous introduction of covariates, as depicted in Table 3. Those variables, significant at the P<0.1 level in these initial models, were simultaneously entered in a summary regression model.
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A subgroup of 62 patients with symptoms at the time of testing (NYHA class=II or III) was analysed for symptom improvement in the follow-up using the same covariates. In this subgroup, obvious deviations from linearity were seen only in peak SP/ESV index (cut-off value 2.98, deciles 15 vs. deciles 610) and in critical heart rate (cut-off value 100 b.p.m., deciles 13 vs. deciles 410). Because the assessment was only being done every 6 months and these are not just right-censored data, but also left-censored data, independent predictors were further analysed by means of follow-up life tables in which the period of observation was divided into smaller time intervals. For each interval, all people who have been observed at least that long are used to calculate the probability of a terminal event occurring in that interval. The probabilities estimated from each of the intervals are then used to estimate the overall probability of the event occurring at different time points. Life tables and Gehan's generalized Wilcoxon test were used to compare patients with and without symptom improvement. A P-value less than 0.05 was considered to be statistically significant.
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Results |
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Relation between PVR and EF
Resting EF was normal in 27 patients and abnormal in 110 patients. Patients with normal resting EF had frequently abnormal (flat-biphasic) PVR, and a good proportion of patients with abnormal resting EF had normal PVR (Figure 2). Peak EF was also unable to separate patients with normal and abnormal PVR, although in this case there was a clear trend to more abnormal PVR in patients with lowest values of peak EF.
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The remaining 91 patients were treated medically. Patients were followed for a median of 18 months (range 124, interquartile range 624). Events occurred in 18 (cardiac death in eight, hospital readmission for heart failure symptoms in 10) patients (Figure 3).
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The overall event-free survival for the 37 patients with LVEF <5% was 65% compared with 91% for the 54 patients with
LVEF >5% (Log rank=8.4, P=0.004). The overall event-free survival for the 43 patients with flat-biphasic PVR was 63% compared with 96% of the 48 patients with up-sloping PVR (Log rank=13, P=0.0003) (Figure 4).
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At the initial regression models, predictors of improved symptoms were age (RR=0.96, 95% CI=0.931.004, P=0.074) and critical heart rate (RR=3.14, 95% CI=1.079.17, P=0.036); at the summary model, the only independent predictor was critical heart rate (RR=2.90, 95% CI=1.127.49, P=0.028).
The best cut-off value for improved symptoms was 100 b.p.m.; 30 (67%) of the 45 patients with critical heart rate
100 b.p.m. vs. five (29%) of the 17 patients with critical heart rate <100 b.p.m. improved symptoms (Gehan's generalized Wilcoxon test=11.3, P=0008) (Figure 5).
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Discussion |
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Previous studies have used the PVR to assess LV contractility with invasive7,12,1518 or non-invasive3,4,1921 measurements. The approach used in the present study extends to dobutamine stress, the methodology previously proposed with exercise3 and pacing stress.4 All the studies are based on non-invasive volume and pressure measurements. LVEDV and LVESV were measured from apical four- and two-chamber view by an experienced observer using the modified Simpson's rule. This method of LV volume calculation during echo is widely used and accepted: the intraobserver and interobserver reproducibility of the method is high9,22 with improved results with the use of harmonic imaging.
Calculation of the systolic PVR requires measurement of the LV pressure in systole. Because only non-invasive measurements were available, systolic cuff pressure was used as a surrogate for end-systolic pressure. This certainly introduces an approximation; nevertheless, there is a tight relationship between peak and end-systolic pressure, and furthermore, any error is systematically distributed along the whole PVR, probably not affecting the slope values.20,21,23
Comparison with previous studies
Several experimental and clinical studies suggest that latent LV dysfunction may be manifested as limited contractile reserve in response to adrenergic stimuli5,6 represented by exercise12 or direct catecholamine infusion.7,12
Barghava et al.7 studied the response to progressive increases in heart rate by atrial pacing before and during dobutamine infusion in three normal subjects and in five patients with severe DCM. The slopes of the relations between frequency and force in control subjects were positive at baseline, and the mean slope increased substantially during dobutamine infusion. In patients with heart failure, the PVR was depressed and flattened. Dobutamine infusion shifted this relation upward slightly, without increase in mean slope, indicating lack of amplification.
Inagaki et al.12 demonstrated that during atrial pacing, the forcefrequency relationship was biphasic in seven patients with severe LVH irrespective of LV function, but was preserved in 10 patients with less severe LVH and in 10 control subjects. The biphasic PVR was reversed to a normal ascending slope in the seven patients with severe LVH during isoproterenol-induced tachycardia. The authors concluded that a biphasic PVR at physiological pacing rates is one of the earliest markers of the transition from physiological to pathological LVH in patients with hypertension.
The results of the present study are broadly consistent with the previous evidences suggesting that the challenge of inotropic reserve with catecholamine infusion is useful to unmask depressed contractile reserve in a left ventricle with latent dysfunction.
PVR and prognostic implications
Several attempts have been done in the past to transfer the forcefrequency relationship from the experimental lab to clinical applications.3,4,7,12,1519 Extensive data exist demonstrating that the forcefrequency relation is profoundly modified in heart failure,8 ischaemic,7 dilated,7,16,18 or hypertrophic17 cardiomyopathy, and hypertensive12,15 and valvular13,19 diseases. However, prognostic data are conspicuously lacking to date. Our data demonstrate that patients with lack of normalization by dobutamine of an abnormal flat-biphasic PVR had worse prognosis. Patients able to express continuously increasing contractility reserve at heart rates >100 b.p.m. (despite symptoms on physiological effort) are more likely to improve clinically under optimal medical treatment.
Limitations of the study
The assessment of PVR during dobutamine infusion involves both the forcefrequency relationship and the effect of inotropic stimulation. Previous reports demonstrated that beta-adrenergic stimulation-induced enhancement of the PVR is impaired in heart failure,68 whereas in initial, subtle, myocardial dysfunction, a biphasic PVR during pacing can be reversed to up-sloping PVR by dobutamine.12 To calculate the actual forcefrequency relationship (i.e. a pure index of contractility) one should perform this measurement with pacing to increase the heart rate, in the absence of inotropic stimulation. This is certainly feasible, even in a totally non-invasive way, in patients with permanent pacemakers.4 The changes in the adrenergic level during dobutamine infusion can be the base to get a clinical comparison in failing hearts of the PVR in the basal state (i.e. with pacing) and during adrenergic stimulation, as occurs during beta-agonists infusion.12
Near future technical improvement such as use of tonometry and transfer function for pressure measurement and 3D echo for volume measurement could improve assessment in non-geometric ventricles.
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Conclusions |
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Acknowledgements |
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Conflict of interest: none declared.
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References |
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