Peak oxygen uptake in relation to total heart volume discriminates heart failure patients from healthy volunteers and athletes
© Engblom et al; licensee BioMed Central Ltd. 2010
Received: 23 April 2010
Accepted: 16 December 2010
Published: 16 December 2010
An early sign of heart failure (HF) is a decreased cardiac reserve or inability to adequately increase cardiac output during exercise. Under normal circumstances maximal cardiac output is closely related to peak oxygen uptake (VO2peak) which has previously been shown to be closely related to total heart volume (THV). Thus, the aim of this study was to derive a VO2peak/THV ratio and to test the hypothesis that this ratio can be used to distinguish patients with HF from healthy volunteers and endurance athletes. Thirty-one patients with HF of different etiologies were retrospectively included and 131 control subjects (60 healthy volunteers and 71 athletes) were prospectively enrolled. Peak oxygen uptake was determined by maximal exercise test and THV was determined by cardiovascular magnetic resonance. The VO2peak/THV ratio was then derived and tested.
Peak oxygen uptake was strongly correlated to THV (r2 = 0.74, p < 0.001) in the control subjects, but not for the patients (r2 = 0.0002, p = 0.95). The VO2peak/THV ratio differed significantly between control subjects and patients, even in patients with normal ejection fraction and after normalizing for hemoglobin levels (p < 0.001). In a multivariate analysis the VO2peak/THV ratio was the only independent predictor of presence of HF (p < 0.001).
The VO2peak/THV ratio can be used to distinguish patients with clinically diagnosed HF from healthy volunteers and athletes, even in patients with preserved systolic left ventricular function and after normalizing for hemoglobin levels.
Heart failure (HF) is a complex syndrome associated with a variety of etiologies and clinical presentations  which implies a major diagnostic challenge. The accuracy of diagnosis by clinical means alone is often inadequate [2, 3]. According to the definition of HF, patients should exhibit typical symptoms or signs such as breathlessness or fatigue at rest or during exercise, pulmonary congestion or ankle swelling, and objective evidence of cardiac dysfunction at rest . However, ACC/AHA have identified 4 stages (A-D) with emphasis on the evolution and progression of HF, where stage A defines patients who are at high risk for developing HF but has no structural disorder of the heart and no signs or symptoms of HF . Thus, there is a need for diagnostic methods that can objectify early signs of decreased cardiac performance in order to optimize management and treatment to prevent or delay progression of the disease and consequently improve patient prognosis.
Cardiac performance can be assessed by maximal exercise testing with measurements of respiratory gas exchange to determine peak oxygen uptake (VO2peak), shown to be closely correlated to maximal cardiac output [5, 6]. This method is predominantly used in evaluation of patients with established HF under consideration for heart transplantation [7, 8]. Experimental animal studies [9, 10] and a recent study in humans  have shown that VO2peak is closely correlated to the total heart volume (THV). Hence, a physiologically enlarged heart has a proportionally increased VO2peak. A decreased cardiac reserve and inability to increase cardiac output to meet the metabolic requirements during exercise might be the first sign of HF .
Cardiovascular magnetic resonance (CMR) is well suited for determination of the THV, given the completely three dimensional nature of the technique. CMR is also considered the gold standard for determination of cardiac function and dimensions .
Therefore, the aim of this study was to use maximal exercise testing with measurements of respiratory gas exchange and CMR to derive a VO2peak/THV-index as a novel measure of the cardiac reserve and to test if this can be used to distinguish patients with HF from healthy volunteers and endurance athletes with physiologically enlarged hearts.
Study population and design
This study follows the Declaration of Helsinki and was approved by the regional ethics committee. All study subjects gave their informed consent to participate in the study.
Thirty-one patients (5 females) who had been clinically diagnosed with HF with varying etiology were retrospectively enrolled and compared with 60 healthy volunteers (20 females) from the local community and 71 elite athletes (30 soccer players [12 females], 23 European handball players [12 females] and 18 triathletes [6 females]) prospectively enrolled in the study. All underwent both CMR and maximal incremental exercise testing on ergometer cycle, with measurement of respiratory gas exchange, within a month for the patients and within a week for the healthy volunteers and athletes. Hemoglobin level was assessed within 2 weeks of the exercise test in patients and on the day of the exercise test in healthy volunteers and athletes who gave their consent for blood sampling.
CMR and analysis
CMR was performed on a 1.5 T system (Philips Intera CV; Philips, Best, The Netherlands) with a cardiac synergy coil. All subjects were placed in supine position. Cine short-axis gradient-recalled echo images covering the entire heart from base of the atria to the ventricular apex were acquired using a steady state free precession sequence - slice thickness = 8 mm, field-of-view = 340 mm, repetition time = 3.14 ms, echo time = 1.58 ms.
For viability assessment in the patients, late gadolinium enhancement (LGE) images were acquired 20--30 minutes after intravenous injection of an extracellular gadolinium-based contrast agent (gadoteric acid, Gd-DOTA, 0.2 mmol/kg, Guerbet, Gothia Medical AB, Billdal, Sweden). An inversion-recovery (IR) sequence was applied in the corresponding short-axis planes as for the cine images. Typical IR sequence parameters were: slice thickness = 8 mm, repetition time = 3.9 ms, echo time = 1.2 ms, in-plane resolution = 1.5 × 1.5 mm and flip angle = 15° with acquisition every heartbeat. The inversion time, typically 200--300 ms, was manually adjusted to null the signal from remote myocardium .
Furthermore, endocardial borders of the left ventricular (LV) myocardium were manually delineated in end-diastolic and end-systolic short-axis images, enabling calculation of LV end-diastolic and end-systolic volumes (LVEDV and LVESV) as well as LV ejection fraction (LVEF). In addition, the epicardial borders of the left ventricle were delineated for determination of LV mass (LVM).
Myocardial scar/fibrosis was assessed by manual delineation of the hyperenhanced myocardium in the LGE short-axis images.
Exercise test with respiratory gas analysis
A maximal incremental exercise test was performed using an electronically braked cycle ergometer (Siemens Ergomed 940, Upplands Väsby, Sweden) with respiratory gas analysis equipment (Oxycon Champion, Jaeger, Hochberg, Germany). The test protocols were chosen to yield exercise duration of approximately 8-12 minutes, yielding starting stress between 10-150 W with 10-30 W increment per minute. Peak oxygen uptake was defined as the highest value reached at the end of exercise and expressed both as ml min-1 (VO2peak) and ml min-1 kg-1 (VO2peakkg).
A 12-lead ECG was acquired throughout the test. Blood pressure was measured by sphygmanometer in the supine position before exercise, every two minutes during exercise on the ergometer cycle and in the supine position at rest after exercise.
A ratio between VO2peak and THV was derived. Furthermore, the ratio was also normalized to hemoglobin levels to partly compensate for differences in oxygen delivery capacity in peripheral tissue in the presence of anemia. The VO2peak/THV ratio was also compared to levels of plasma amino terminal pro-brain natriuretic peptide (pro-BNP) for the patients who had a pro-BNP taken within 4 months of the exercise test.
Values are shown as mean ± standard deviation. Univariate linear regression analysis was used to assess the correlation between VO2peak and THV as well as body weight. Unpaired T-test was used to assess differences between variables where normal distribution was assumed. The Mann-Whitney test was used to assess differences where normal distribution could not be assumed. Forward stepwise multivariate regression analysis was performed to assess the independent predictive values of THV, LVEF, LVEDV, VO2peak, VO2peakkg and the VO2peak/THV ratio for presence of HF. Receiver operating characteristic (ROC) analysis was performed to test the ability of the VO2peak/THV ratio to distinguish between HF patients and controls. All statistical analysis was performed using SPSS 16.0 (Chicago, IL, USA). A p-value of <0.05 was considered statistically significant.
n = 60
n = 71
n = 31
35 ± 11
26 ± 7***
54 ± 12***
75 ± 11
75 ± 11
80 ± 15
1.77 ± 0.08
1.78 ± 0.08
1.74 ± 0.08
127 ± 9
126 ± 9
107 ± 12***
74 ± 8
72 ± 8
69 ± 9**
VO2peak (ml min-1)
3102 ± 696
3866 ± 747***
1309 ± 430***
VO2peakkg (ml min-1 kg-1)
41 ± 7
52 ± 7***
16 ± 5***
183 ± 31
223 ± 39***
280 ± 132***
105 ± 25
130 ± 34***
177 ± 87***
793 ± 128
947 ± 169***
1201 ± 460***
62 ± 6
58 ± 6**
37 ± 22***
The inter-observer variabililty for measuring THV was -5±37 ml (r2 = 0.96, p < 0.001).
Peak oxygen uptake vs cardiac characteristics and body weight
In 68% (21/31) of the HF patients a pro-BNP was taken 11 ± 25 days from the exercise test. There was a significant correlation between decreasing VO2peak/THV ratio and increasing pro-BNP (r2 = 0.42, p = 0.002).
Forward stepwise multivariate regression analysis for prediction of heart failure
VO2peak (ml min-1)
VO2peakkg (ml min-1 kg-1)
This study shows that a VO2peak/THV ratio can be used to distinguish patients with HF from healthy volunteers and athletes, even in patients with preserved systolic LV function and after normalizing for hemoglobin levels.
Clinical use of the proposed VO2peak/THV ratio
It is expected that the VO2peak/THV ratio will drop in the presence of HF, since cardiac output, and consequently VO2peak, is disproportional to the metabolic requirements of the peripheral tissue in the situation of a failing heart. However, when and in which stage of HF development the VO2peak/THV ratio decreases is not known. A decreased VO2peak/THV ratio could potentially be seen in patients with no symptoms at rest and in the absence of significant structural cardiac abnormalities.
Currently, maximal exercise test with analysis of respiratory gases and analysis of VO2peak is predominantly used in patients with terminal HF under consideration for heart transplantation . The present study suggests that assessment of VO2peak in relation to THV for determination of a VO2peak/THV ratio can be of potential use even in non-terminal and early stage HF, maybe even before the patient exhibit symptoms, such as in stage A HF . Another possible application of a VO2peak/THV ratio is in management of patients with a history of endurance training and a sudden change in exercise capacity. These patients might perform within normal limits during a maximal exercise test with analysis of respiratory gases when compared to age and gender matched controls. However, in relation to THV the working capacity might be decreased which would be detected by a low VO2peak/THV ratio as an indicator of early stage HF. This is supported by the findings that the healthy volunteers and the HF patients with overlapping VO2peak showed a significant difference in VO2peak/THV ratio with almost no overlap, indicating that the ratio has additional diagnostic value. Furthermore, LVEF was not statistically significant different between the two overlapping groups. Thus, VO2peak/THV provides diagnostic information beyond LVEF.
Even though there was a significant difference between control subjects and HF patients with regard to LVEF in the present study, almost 30% of the patients had normal LVEF. However, these patients had significantly lower VO2peak/THV ratio than the control subjects with almost no overlap. Thus, VO2peak/THV ratio may also be used as a marker of HF in patients with preserved systolic LV function.
Heart failure is often described based on clinical symptoms as being mild, moderate, or severe. Mild HF is used for patients with no significant physical limitations due to dyspnoea or fatigue and severe HF is used for patients who are markedly symptomatic with a need for frequent medical attention. Moderate HF is used for the remaining patients. For clinical management of HF patients and for randomized clinical trials, the New York Heart Association (NYHA) functional classification [22, 23] is often employed. However, the accuracy of diagnosing HF by clinical means alone is often inadequate [2, 3]. Hence, there is a need for objective measures of cardiac performance in order to determine the efficiency of different therapeutic strategies in randomized clinical trials.
The clinical use a VO2peak/THV ratio could potentially complement commonly used cardiac diagnostic biomarkers such as ECG and biochemical markers. A commonly used biochemical marker for severity of HF is pro-BNP, which has been shown to correlate with the severity of HF [24, 25]. In the present study, the VO2peak/THV ratio was shown to correlate with pro-BNP, indicating that the ratio can potentially serve as a measure for severity of HF.
Normalization of peak oxygen uptake to cardiac dimension rather than body weight
Lower limits for VO2peak are usually determined in relation to body weight and used to determine if a patient is suitable for heart transplantation or not [26, 27]. However, the present study show a considerable variability in VO2peak for a given body weight (Figure 2B). Total heart volume, however, was shown to be closely correlated to VO2peak in healthy volunteers and athletes but not in HF patients. Thus, for the non-failing heart, the VO2peak/THV ratio is preserved in the presence of a physiologically enlarged heart, whereas for the failing heart the VO2peak/THV ratio is not preserved as THV increases due to pathological enlargement of the heart. This suggests that VO2peak should be normalized to THV and not to body weight. This is in line with a recent paper by Saltin et al  and experimental animal studies [9, 10] showing that VO2peak is determined primarily by cardiac dimension and not peripheral factors such as the efficiency of oxygen uptake in peripheral tissue . This is also supported by the present study showing that a VO2peak/THV ratio is significantly lower in HF compared to healthy volunteers and athletes even after normalizing for hemoglobin levels.
Determination of total heart volume
In the present study THV was determined by CMR, which is considered the gold standard for assessing cardiac dimensions and function . In situations when CMR is not available or is contraindicated, i.e. in patients with biventricular pacing, THV could potentially also be determined by low dose-cardiac CT, preferably gated. However, non-gated examinations would also be possible if CT thorax is performed for other reasons, since THV varies little during the cardiac cycle [15, 17, 18]. Three dimensional echocardiography might potentially also be used to determine THV, although this technique may suffer from incomplete coverage of the tissue within the pericardium. By using the THV, enlargement of all cardiac chambers including the atria is considered. Enlargement of the left atrium has been shown to provide prognostic value in HF patients with normal LVEF .
The results of the present study should be interpreted in the light of some limitations. The number of patients in the present study is limited and the patients were retrospectively included with clinically diagnosed HF and clinically determined etiology. Thus, no specific HF inclusion criteria based on biochemical markers, ECG or echocardiographic variables were applied. Furthermore, the patients had different etiologies and different stages of HF. However, this pilot study can be considered a proof of the concept study for determining a VO2peak/THV ratio as an objective measure of cardiac capacity, independent of HF etiology.
Due to symptoms during the exercise test, HF patients might not reach VO2peak representative of the individual's actual maximal oxygen uptake capacity. For this reason VO2peak is referred to as peak and not maximal oxygen uptake in the present study.
There was a significant difference in mean age between the patient population and the control groups. However, the slight decrease in VO2peak/THV ratio found with increased age in the healthy volunteers (21-65 years) is negligible compared to the decrease in VO2peak/THV ratio found in the HF patients.
Since VO2peak can not be obtained in HF patients with acute decompensation, the VO2peak/THV ratio can not be used in these patients. The VO2peak/THV ratio might, however, be of significant benefit when the HF diagnosis is uncertain, such as in the situation of stage A HF or if the progression of the disease is less clear.
Furthermore, the prognostic value of the VO2peak/THV ratio also remains to be determined in prospective follow-up studies of different patient groups with established HF or at risk for developing HF.
The VO2peak/THV ratio can be used to distinguish patients with known HF from healthy volunteers and athletes, even in patients with preserved systolic LV function and after normalizing for hemoglobin levels.
We thank our technicians Ann-Helen Arvidsson and Christel Carlander for their invaluable assistance with data acquisition.
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