© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Assessment of the functional status of heart failure in non ischemic dilated cardiomyopathy: an echo-dobutamine study
2nd Department of Cardiology, Onassis Cardiac Surgery Center, 356 Sygrou Avenue, GR-17674 Athens, Greece
* Corresponding author. Tel.: +30-1-9406-184 or +30-1-9393-372; fax: +30-1-9393-373 or +30-1-9393-331. E-mail address: elbee@ath.forthnet.gr (I.A. Paraskevaidis)
Received 16 September 1998; accepted 1 December 1998
| Abstract |
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Background: The functional status of heart failure (HF) is conventionally evaluated by peak exercise oxygen consumption (VO2 max). Dobutamine echocardiography can be used to evaluate myocardial reserve. The aim of this study was to estimate the functional status of chronic HF in patients with dilated cardiomyopathy, by investigating the changes in echo-variables, as assessed by echo-dobutamine, in relation with VO2 max. Methods and results: A low infusion rate echo-dobutamine test (10 µg/kg/min) was performed in 30 patients with dilated cardiomyopathy and 1 h later VO2 max was measured. VO2 max (ranging from 7.6 to 23 ml/kg/min, mean 14.06±0.64 ml/kg/min) was correlated with the changes (values obtained after inotropic stimulation minus those obtained at baseline) in left ventricular end-systolic diameter (r:0.80, p:0.001), in left ventricular end-systolic posterior wall thickness (r:0.73, p:0.001) and in left ventricular heart-rate corrected mean velocity of circumferential fiber shortening (Vcfc)/end-systolic meridional wall stress ratio (r:0.64, p:0.0001). A negative correlation was found between VO2 max and the changes in end-systolic meridional wall stress (r: –0.76, p:0.001). After dobutamine infusion Vcfc/systolic meridional wall stress ratio increased in patients with VO2 max >14 ml/kg/min but decreased in patients with VO2 max <14 ml/kg/min (0.0001±0.0001 vs –0.0002±0.0003 circxcm2/gxs, p:0.0001). End-systolic meridional wall stress was decreased in patients with VO2 max >14 ml/kg/min but increased in patients with VO2 max <14 ml/kg/min (–126.97±34.24 vs 205.77±56.71 g/cm2, p:0.0001). Conclusion: The changes in echo-variables assessed by echo-dobutamine are well correlated with VO2 max and seem to be accurate for evaluating the functional status of chronic HF in patients with dilated cardiomyopathy.
KEYWORDS Cardiomyopathy; Contractile function; Heart failure; Inotropic agents; Transplantation
| 1 Introduction |
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Despite continuing advances in the diagnosis and therapy of heart failure (HF) the mortality of this syndrome remains high [1]. Although various parameters have been used to assess the severity of congestive HF [2, 3], they have several potential limitations [4]. Recent American Heart Association consensus reports have recommended that peak exercise oxygen consumption (VO2 max) can be used to evaluate objectively the functional status of HF [5]. Specifically, it has been suggested that, in spite of similar left ventricular ejection fraction, patients with VO2 max more than 14 ml/kg/min have a far better prognosis than those with VO2 max less than 14 ml/kg/min [6]. However, several groups have found no statistical difference in survival between patients with VO2 max levels in the range of 10 to 14 ml/kg/min and those with levels in the range of 14 to 18 ml/kg/min [7].
Although, several echocardiographic indexes have been proposed as prognostic indicators in chronic HF [8, 9]; these indexes represent the functional status of the heart at rest. In patients with HF, both the response of cardiac output to exercise and VO2 max provide valuable independent prognostic information regarding the functional status of the failing heart [10], indicating that the ability of the failing heart to maintain an adequate cardiac output depends on its functional reserve.
Dobutamine stress echocardiography is receiving increasing attention in relation to patients with coronary artery disease [11]. Moreover, by its well known direct positive inotropic action, it is known to increase cardiac performance in patients with HF [12]. In this regard, it has been suggested that dobutamine can be used in order to evaluate myocardial reserve, which is a better descriptor of the functional status of the heart than rest indexes or indexes based on volumetric measurements [13]. This has been confirmed in several subgroups of patients with chronic heart failure due to coronary artery disease [14], left ventricular hypertrophy [15], dilated cardiomyopathy [16], or after cardiac transplantation [17].
The aim of this study was to estimate the functional status of chronic HF in patients with dilated cardiomyopathy, by investigating the changes in echo-variables, assessed by echo-dobutamine, in relation with VO2 max.
| 2 Methods |
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2.1 Study patients
Thirty one consecutive patients with documented dilated cardiomyopathy were studied. Thirty patients (97%) 21 men and 9 women, mean age 55±10 years, with good quality M-mode and 2-dimensional echocardiography were recruited for analysis. The cause of dilated cardiomyopathy was idiopathic in 25 patients while an evidence of myocarditis based on clinical, ECG and echocardiographic findings, was reported in five patients. Nine patients were in New York Heart Association functional class II, thirteen were in class III, and eight were in class III–IV. Diagnosis of dilated cardiomyopathy was based on the echocardiographic findings of a dilated left ventricle (left ventricular end-diastolic diameter >60 mm) with severely affected systolic function; fractional shortening <20% and ejection fraction below 35%. In no case was a significant regional wall motion abnormality recorded by two-dimensional echocardiography. Coronary angiography performed in all patients revealed no coronary artery disease. All patients were in sinus rhythm and were under digoxin, angiotensin-converting enzyme inhibitors and diuretic drugs in adequate doses. Patients with rhythm disturbances, ischemic cardiomyopathy, more than mild valvular heart disease, or regional wall motion abnormalities were excluded. Transthoracic echocardiography was performed and the echocardiographic variables were measured at baseline and after dobutamine infusion. One hour later VO2 max was calculated. All patients gave informed consent.
2.2 Echocardiography
Measurements and tracings were carried out according to the principle of the leading edge, in accordance with the recommendations of the American Society of Echocardiography [18]. Left ventricular dimensions and wall thickness were measured from parasternal targeted M-mode echocardiographic recordings. Care was taken to record the largest and smallest left ventricular dimensions present between the tips of the mitral valve leaflets and the superior aspect of the papillary muscles. End-diastolic diameter was taken at the Q wave of the electrocardiogram. End-systolic dimension was determined to be the shortest distance between walls rather than at the time of peak downward septal motion [19]. Using a Hewlett-Packard (Sonos 1000 or 2500) ultrasound device the following echocardiographic variables were measured at baseline and after the end of 10 µg/kg/min of dobutamine infusion: (1) Left ventricular end-diastolic (LVEDD) and end-systolic diameter (LVESD) and the derived fractional shortening, FS=[(LVEDD–LVESD)/LVEDD]x100; (2) maximal ventricular septum and posterior wall thickness (PWTH) in systole(s); (3) end-systolic meridional wall stress, calculated using the formula: systolic blood pressurexLVESDx1.35/4xPWTHsx(1+PWTHs)/LVESD [20](systolic blood pressure was represented by brachial artery systolic pressure and was measured every minute with a cuff sphygmomanometer); Although the above variables are easily calculated by echocardiography, care must be taken to make accurate calculations. (4) left ventricular heart-rate corrected mean velocity of circumferential fiber shortening (Vcfc), calculated as follows: Vcfc=(%FS/LVET)xRR [20]. (LVET represents left ventricular ejection time in milliseconds from the opening to the closing clicks of the aortic valve flow velocity envelope by continuous-wave Doppler imaging); (5) Vcfc/systolic meridional wall stress ratio; (6) cardiac output, calculated as the product of stroke volumexheart rate (stroke volume, was calculated according to the formula:
/4x(aortic diameter)2xaortic velocity–time integral. Aortic diameter was measured in a two-dimensional parasternal long axis view, just below the aortic orifice, from the inner echo at rest only, because the aortic valve is thought to remain constant during exercise or dobutamine infusion [21]. Aortic velocities were measured by continuous Doppler in an apical five chamber view; (7) from 2D echocardiography and using the modified Simpsons rule technique, end-diastolic and end-systolic volumes were calculated and ejection fraction was derived [(end diastolic-end systolic volume)/end diastolic volume]x100. Vcfc/end systolic meridional wall stress ratio was also measured as an index of myocardial contractile reserve. The latter index is a preload and heart rate-independent index of contractility that incorporates afterload [15]. The changes in the above echocardiographic variables after dobutamine infusion were also calculated. Changes represent the values obtained after inotropic stimulation minus those obtained at baseline. All measurements were made at a speed paper of 100 mm/s and represent the average of the measurements of five consecutive beats. In all cases echocardiograms were analyzed by two independent expert observers. In cases of discrepancy the average was calculated and the mean value was reported.
2.3 Dobutamine infusion
Dobutamine was infused intravenously in two steps after establishment of a stable hemodynamic state (heart rate, blood pressure). The duration of each step was 5 min and the maximal end dose of dobutamine infused was 10 µg/kg/min [22]. At each step dobutamine infusion was increased by 5 µg/kg/min, reaching 10 µg/kg/min at the second step. Every minute during the protocol, systolic, diastolic and hence mean arterial blood pressure (Siemens, Sirecust 888 device), heart rate and a 12-lead electrocardiogram were recorded.
2.4 Cardiopulmonary exercise testing
Exercise testing with respiratory gas exchange measurements was performed while patients exercised on a treadmill according to the Dargie protocol [23]. Oxygen consumption, carbon dioxide production and respiratory exchange ratio were measured continuously during exercise using the Medgraphics CPX/MAX automated gas exchange measuring system, which provides the above gas exchange data for each individual breath (which can then be averaged over a 5 s interval). Blood pressure was measured with a mercury sphygmomanometer and the electrocardiogram was monitored continuously with a computer-assisted system (Marquette Electronics Inc.). Patients were familiar with exercise testing and they were encouraged to exercise until symptoms forced them to stop. All patients terminated the test because of dyspnea or fatigue, and in all patients the gas exchange anaerobic threshold (the point at which carbon dioxide production increased disproportionately in relation to oxygen consumption) and a respiratory exchange ratio >1.0 were reached. Peak oxygen consumption (ml/min/kg) at peak exercise was calculated as the mean of values during the last minute of exercise.
2.5 Statistical analysis
All values are expressed as mean±standard error. An unpaired two-tailed t-test was used to compare values between groups; a paired two-tailed t-test was used to compare the differences between values in the same group before and after inotropic stimulation. Linear regression analysis was employed for the assessment of the correlation between VO2 max and the echocardiographic measurements. To assess reproducibility (inter-and intra-observer variability) root mean square differences between duplicate determinations was performed. A p value <0.05 was considered statistically significant.
| 3 Results |
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No major side effects were reported during dobutamine infusion. The VO2 max measured in all patients ranged from 7.6 to 23 ml/kg/min (mean 14.06±0.64 ml/kg/min).
3.1 Echocardiographic measurements
The echocardiographic measurements of the whole study group at baseline and after dobutamine infusion are shown in Table 1. The changes in the echocardiographic variables are also reported in Table 1. After dobutamine infusion statistically significant increases in fractional shortening (p:0.004) and ejection fraction (p:0.005) were observed. Systolic blood pressure increased at borderline significance (p:0.06), while mean blood pressure significantly decreased (p:0.000). Heart rate, stroke volume and consequently cardiac output significantly increased (p:0.02, p:0.0000 and p:0.0000, respectively). Vcfc and Vcfc/end-systolic meridional wall stress significantly increased (p:0.001 and p:0.04, respectively). The other echocardiographic variables did not change significantly after inotropic stimulation.
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The correlation between VO2 max and the changes in echocardiographic variables are shown in Table 2.
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3.2 Response of echocardiographic variables to dobutamine in patients with high vs those with low VO2 max
The study population was further divided in two groups; Group I (17 patients), comprised patients with VO2 max more than 14 ml/kg/min (mean 16.36±0.66 ml/kg/min) and group II (13 patients) patients with VO2 max less than 14 ml/kg/min (mean 11.1±0.49 ml/kg/min).
The values of the echocardiographic variables before and after inotropic stimulation with dobutamine are shown in Tables 3 and 4
. In Table 5 are shown the significant changes of the echocardiographic variables; in group I posterior wall systolic thickness increased, whereas in group II it decreased (p:0.0001). End systolic diameter end-systolic meridional wall stress and end-diastolic diameter decreased in group I but increased in group II (p:0.001), (p:0.0001), (p:0.003), respectively. Shortening and ejection fraction increased more in group I than in group II (p:0.02 for both). Vcfc increased in group I but was unchanged in group II (p:0.02). Vcfc/end-systolic meridional wall stress increased in group I but decreased in group II (p:0.0001). After dobutamine infusion the changes in the other echocardiographic variables were not statistically different between the groups.
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Plotting the variables VO2 max vs. the changes in Vcfc/end-systolic meridional wall stress ratio (Fig. 1), VO2 max vs the changes in left ventricular end systolic diameter, (Fig. 2), and VO2 max vs the changes in left ventricular posterior wall thickness (Fig. 3), on a scatterplot shows the linear relationship and in addition we can make the following observations. Firstly, the trend line (linear regression model) of the above variables cuts the x axis at the value 12, 13, or 14 ml/kg/min for VO2 max respectively indicating that we may expect an improvement in myocardial reserve even for values of VO2 max less than 14 ml/kg/min. Secondly, changes in echo-dobutamine variables that correspond to the range of 10–14 ml/kg/min of VO2 max, fall very near to the zero line and some of them are even positive or negative, expressing an improvement in myocardial reserve.
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3.3 Ten month follow-up
During the ten month follow-up, two patients from group II died (6.6% of the whole study group) and two patients underwent heart transplantation. All patients from group I remained alive and none required heart transplantation.
3.4 Intra- and inter-observer variability
Intra- and inter-observer variability of the echocardiographic measurements at baseline and after dobutamine infusion are given in Table 6.
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| 4 Discussion |
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The results of this study showed that in patients with non ischemic dilated cardiomyopathy left ventricular systolic performance indexes, contractility status and stroke volume were increased after inotropic stimulation. A correlation between VO2 max and the changes in echocardiographic variables assessed by echo dobutamine was also detected.
4.1 Echocardiographic changes during dobutamine infusion. Possible explanations
Similarly to previous reports [14, 24]we observed, that after low dose dobutamine infusion cardiac contractility, stroke volume, heart rate and consequently cardiac output were increased. Although, the changes in systolic posterior wall thickness and in left ventricular end systolic diameter probably represent the simple easy way, to measure the functional status of heart failure, Vcfc/end-systolic meridional wall stress ratio represents another index which incorporates afterload. Since left ventricular afterload increased after dobutamine infusion it seems that augmenting myocardial contractility (Vcfc and in Vcfc/end-systolic meridional wall stress ratio) in these patients did not result in a decrease in left ventricular internal load [16]. Vcfc incorporates heart rate which might have variable effect on force–frequency relationship in patients with dilated cardiomyopathy. However, in our series, heart rate did not vary significantly between groups before and after inotropic stimulation, indicating that in low dose dobutamine administration heart rate does not significantly influence the contractile status of the failing heart [14, 16]. Wall stress reflects the combined effects of instantaneous peripheral loading conditions and factors internal to the heart [25]. The ability of the ventricle to unload itself is crucial to the maintenance of normal myocardial mechanics since it is the wall stress that determines the overall extent and mean velocity of fiber shortening [26]. In this study the response of systolic meridional wall stress to inotropic stimulation was different between the groups, indicating that the myopathic left ventricle might have an abnormal distribution of fiber shortening [16]. This different response of the left ventricle to inotropic stimulation seems to represent a different stage of the same disease process [16]. The results of this study also showed that after dobutamine infusion there is a correlation between peak exercise VO2 and the changes in left posterior wall systolic thickness, end systolic diameter, end-systolic meridional wall stress, end diastolic diameter. Previous reports have demonstrated that, in patients with severely affected left ventricular systolic function, end-systolic and end-diastolic volumes (and, consequently, in patients without wall motion abnormalities, end-systolic and end-diastolic diameter) are prognostic indexes [27]. The prognostic value of posterior wall thickness in dilated cardiomyopathy has also been reported [9].
Myocardial contractile reserve represents the common denominator of both Vcfc/end-systolic meridional wall stress ratio and VO2 max and may, therefore, explain the correlation between these two parameters in patients with heart failure. However, apart from central, peripheral factors may also contribute substantially to lower VO2 max seen in chronic heart failure. In this respect these two indexes may measure different aspects of heart failure, although both of them reflect functional status of heart failure.
Although VO2 max <14 ml/kg/min has been used as an objective index of the functional status of the heart, it has been shown to improve with vasodilator and exercise therapy in patients with HF [28, 29]. Accordingly, the results of this study showed that the cut-off point of VO2 max may not be 14 ml/kg/min (indeed it may be lower, depending on other factors). This may indicate an improvement not only in functional capacity but also in prognosis.
4.2 Study limitations
(1) The heterogeneous contractile responses to dobutamine observed in this study among patients with chronic HF have been reported previously [16]and may reflect differences in β1-adrenoreceptor density, which was not investigated in this study. Although the response to dobutamine may underestimate the contractile reserve of the failing myocardium, the magnitude of the drugs effect appears to decline as left ventricular function deteriorates; the latter is accompanied by a reduction in β-adrenoreceptor density [30]. (2) Brachial arterial pressure was used to calculate peak systolic blood pressure. Although numerous validation studies have been performed [31], we recognize that brachial arterial pressure is only an estimate of left ventricular ejection pressure and not a direct measurement. Additionally, there is a lack of synchrony of estimates of ventricular pressure (which occurred at early or mid ejection) and those of cavity dimensions and wall thickness which occurred at end-ejection). However, since the main interest of this study was to estimate wall stress before and after inotropic stimulation, we assumed that the method used in this study for the measurement of peak systolic blood pressure had little influence on the final result. Although the peak (as opposed to end-systolic) pressure was used in this study, previous reports have shown that this substitution is reasonable [32]. (3) Although, the most satisfactory estimates of stroke volume are made using pulsed Doppler aortic velocities were measured by continuous Doppler in an apical five chamber view since the main interest of this study was the changes in velocity time integral which occurred after inotropic stimulation and not the absolute values.
4.3 Clinical implications
The results of this study showed that echo-dobutamine indices could provide clinical and prognostic information complementary to the VO2 max value for a given patient, since the numerical approach does not necessarily shed light on pathophysiology and prognosis. Furthermore, patients should be reevaluated after 6 months, since they sometimes improve their functional capacity. There is growing evidence that VO2 max is influenced by non cardiac factors, [33, 34]. In this respect dobutamine echocardiography might be an alternative tool in the detection of the functional status of the heart, especially in those patients with VO2 max levels between 10 and 14 ml/kg/min.
| 5 Conclusion |
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The changes in echocardiographic variables assessed by echo-dobutamine are well correlated with VO2 max and seem to be an accurate index for evaluating the functional status of chronic HF in patients with dilated cardiomyopathy.
Time for primary review 26 days.
| Acknowledgements |
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We thank George Tentis, PhD for assistance with statistical analysis and Eleni Binou for her secretarial assistance.
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