International Journal of Cardiology 184 (2015) 755–762

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Is low VO2max/kg in obese heart failure patients indicative of cardiac dysfunction? S.S. Hothi a,b,c,⁎, D.K. Tan d, G. Partridge e, L.B. Tan e a

Department of Cardiovascular Sciences Physiological Laboratory, University of Cambridge, UK Department of Biochemistry, University of Cambridge, UK d Newcastle Medical School, Newcastle, UK e Leeds Institute of Biomedical and Clinical Sciences, University of Leeds and Leeds General Infirmary, Leeds, UK b c

a r t i c l e

i n f o

a b s t r a c t 

Article history: Received 19 October 2014 Received in revised form 22 January 2015 Accepted 15 February 2015 Available online 17 February 2015 Keywords: Heart failure Cardiac function Obesity Cardiopulmonary exercise testing Oxygen consumption

Purpose: Low peak O2 consumption (VO2max/kg) has been widely used as an indirect indicator of poor cardiac fitness, and often guides management of patients with severe heart failure (HF). We hypothesized that it should be as good an indicator of cardiac dysfunction in obese and non-obese HF patients. Methods: We compared the cardiopulmonary exercise performance and non-invasive hemodynamics of 152 obese (BMI N 34 kg.m−2) and 173 non-obese (BMI ≤ 32) male HF patients in NYHA classes II and III, with reference to 101 healthy male controls. Their physical and cardiac functional reserves were measured during treadmill exercise testing with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output noninvasively during peak exercise. Data are given as mean ± SD. Results: Obese HF patients with BMI 40.9 ± 7.5 kg·m−2 (age 56.1 ± 14.0 years, NYHA 2.5 ± 0.5) exercised to acceptable cardiopulmonary limits (peak RER = 1.07 ± 0.12), and achieved a mean V O2max/kg of 18.6 ± 5.2 ml·kg−1·min−1, significantly lower than in non-obese HF counterparts (19.9 ± 5.6 ml·kg−1·min−1, P = 0.02, age 55.8 ± 10.6 years, BMI 26.6 ± 3.1, NYHA 2.4 ± 0.5, peak RER = 1.07 ± 0.09), with both lower than controls (38.5 ± 9.7 ml·kg−1·min−1, P b 10−6). In contrast, the uncorrected VO2max was higher in obese (2.31 ± 0.69 ml·min−1) than non-obese HF patients (1.61 ± 0.49 ml·min−1, P b 10−6). When cardiac dysfunction was evaluated directly, peak cardiac power was significantly greater in obese than non-obese HF patients (4.11 ± 1.21 W vs 2.73 ± 0.82 W, P b 10−6), with both lower than controls (5.42 ± 1.04 W, P b 10−6). Conclusion: These results demonstrate that VO2max/kg is not a generally reliable indicator of cardiac fitness in all patients. Instead, we found that despite having lower VO2max/kg, obese HF patients had stronger hearts capable of generating greater cardiac power than non-obese HF patients of equivalent clinical HF status. © 2015 Elsevier Ireland Ltd. All rights reserved. 







method for characterizing cardiac reserve and functional status in patients with chronic cardiac failure” [3]. Within a decade, Mancini and

1. Introduction 

Ever since A. V. Hill began measuring oxygen consumption (VO2max) 

in man in the early 1920's and found that peak exercise VO2max values are limited by cardiac inability to provide indefinitely escalating blood flow into the vasculature [1], exercise testing has been adopted as a fundamental method for obtaining valuable information about cardiac pump function [2]. This led Weber and colleagues to introduce cardiopulmonary exercise testing (CPX) as a tool to assess the extent of cardiac impairment in patients with heart failure (HF), and they concluded that CPX is “an objective, reproducible and safe non-invasive

⁎ Corresponding author at: Physiological Laboratory and Murray Edwards College, University of Cambridge, UK. E-mail address: [email protected] (S.S. Hothi).

http://dx.doi.org/10.1016/j.ijcard.2015.02.018 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.



colleagues first proposed that peak VO2max/kg below a cutoff level of 14 ml·kg−1·min−1 would demarcate the prognosis of end-stage HF patients and can be used as a powerful discriminator in selecting patients who would need cardiac transplantation [4]. This led to the establishment of this variable as a key indicator of cardiac dysfunction in clinical practice [5] and so far has been endorsed by international heart failure guidelines [6–8]. 

Inherent in the adoption of VO2max/kg as a criterion for selection of 

candidates for cardiac transplantation is the supposition that VO2max/kg is a reliable indicator of the severity of cardiac impairment. However, this clinical use contains two fundamental assumptions. The first is that peak oxygen uptake is closely related and proportional to cardiac 

functional reserve. The second is that normalizing V O2max with body

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S.S. Hothi et al. / International Journal of Cardiology 184 (2015) 755–762

Nomenclature BMI body mass index in kg·m−2 BSA body surface area in m−2 BM body mass in kg CPOmax peak cardiac power output in W CPX cardiopulmonary exercise testing ETPaCO2 end-tidal arterial partial pressure of carbon dioxide HF heart failure HRmax peak heart rate in min−1 MAPmax peak mean arterial pressure in mm Hg NOb non-obese Ob obese Q max peak cardiac output in l·min−1 RER respiratory exchange ratio (=VCO2/VO2) SV stroke volume in ml SW stroke work in g·m VO2max peak rate of O2 consumption in l·min−1 VO2max/kg peak rate of O2 consumption per unit body mass in l·min−1·kg−1 





 

in the NOb and Ob groups, respectively, P = 0.3001). For comparison with the male reference CPX data, only male HF patients were included in the present analyses. The clinical HF statuses of the Ob and NOb patients were rated using conventional functional grading of HF severity according to NYHA and Weber classifications [3]. Patients in NYHA functional class IV, or with angina as the limiting symptom for exercise, serious uncontrolled arrhythmias, severe lung disease or serious systemic diseases were not included in this study. Since the CPX tests were requested by the referring physicians for clinical indications, this anonymous retrospective study of exercise data was exempted from requiring approval by our Local Ethics Committee. 2.2. Exercise tests to measure peak oxygen consumption and cardiac reserve Cardiopulmonary exercise tests (CPXs) were conducted using the same protocols in patients and controls as previously described [16]. At the time of testing, all participants avoided consumption of food (for N3 h), caffeine (N6 h), alcohol (N12 h) and strenuous exercise (N24 h) prior to CPX. Maximum cardiopulmonary exercise testing was performed on a Marquette 2000 treadmill (Marquette Electronics, Milwaukee, USA) using standard Bruce, modified Bruce and other appropriate protocols depending on participants' estimated functional capacities aiming to complete the incremental test in around 10 min. All subjects performed symptom-limited maximal exercise tests. Heart rate and 12-lead ECGs were recorded continuously throughout the tests, and exercise duration and symptoms, including ratings of perceived exertion [17] were noted. Brachial arterial blood pressure was measured manually using conventional calibrated cuff sphygmomanometry at three-minute intervals throughout exercise and at peak exertion. Expired gases were collected throughout 



the protocol, and rates of oxygen consumption (VO2), carbon dioxide production (VCO2) 

and ventilation (VE), end-tidal partial pressure of carbon dioxide (ETPaCO2), tidal volume (V t ) and respiratory rate were recorded breath-by-breath using the Medgraphics Ultima CardiO2 gas exchange analysis system (Medical Graphics Corpo

mass corrects the confounding influence of body mass to allow a more equitable comparison between individuals of various body sizes. However, the validity of these assumptions has hitherto not been systematically ex

amined. It is well known that VO2max is influenced not only by cardiac functional reserve but also by other extra-cardiac factors [9,10]. In this study, we set out to test the hypothesis that peak O2 uptake normalized 

by body mass (VO2max/kg) is a reliable indicator of cardiac function, that is generally applicable to all patients with heart failure irrespective of body mass, by comparing it against a reference of directly measured cardiac function represented by peak cardiac power output during weightbearing treadmill exercise in a healthy population [11].

ration, Minnesota, USA). Peak O2 uptake (VO2max) was considered to have been attained when the highest value of oxygen uptake was reached in the final 20 s of exercise to vo

litional exhaustion, or a plateau in VO2 had been reached despite an additional increase in workload, a HR greater than 95% of the subject's age-predicted maximal value or a re



spiratory exchange ratio (RER = VCO2/VO2) exceeding 1.0. A second, single-stage exercise test targeted to equal or exceed the peak workload attained during the prior incremental test after a 3-min warm-up walk, was then performed to measure peak O2 uptake and 

peak cardiac output (Q max) using the CO2 re-breathing technique [18]. Whenever feasible, 

duplicate measurements of cardiac output (Q in l·min−1) were made by rebreathing either 10% CO2 at rest [19], or 4% CO2 at maximum exercise [20] from a gas mixture contained within twice the subject's tidal volume. Peak cardiac hydraulic power output 

(CPOmax) was derived from the measured BP and Q . 2.3. Data analyses 







Respiratory exchange ratio (RER = VCO 2/VO 2), minute ventilation (VE = Vt ×

2. Methods



2.1. Study populations Unselected consecutive male patients with moderately symptomatic HF in NYHA functional classes II and III, who underwent non-invasive hemodynamic monitoring during cardiopulmonary exercise stress testing (CPX) in a tertiary cardiology referral center were identified for inclusion in this investigation. The diagnosis of HF in each individual case was established by the patients' responsible cardiologists according to standard HF guidelines [12,13]. There was no significantly different incidence in the use of β-adrenoreceptor antagonists, ACE inhibitors, angiotensin II receptor antagonists or nitrates, and no overall difference in combined chronotropic modulating agents between the Ob group (117) and NOb group (130) (P = 0.9433). Each patient's NYHA functional classification was also assigned by the referring cardiologist. The data from patients were compared to a reference dataset obtained from control subjects (C) who were non-obese sedentary healthy volunteers from the age of 19 to 76 years participating in a prospective study reported previously [11], and who were normotensive, non-smokers, free of any known cardiovascular diseases and taking no medication. The mean body mass index (BMI) of this control population was 26.0 ± 3.1 (SD) kg·m−2, and for this investigation and as per standard practice [13], and acknowledging that an exact threshold for obesity as measured by BMI varies according to the population of interest [14,15], we defined the reference interval for normal BMI as two standard deviations (SD) above and below the mean. The upper limit of the reference range is therefore 32 kg·m− 2 and this was selected as the upper limit of BMI for inclusion of HF patients into the Non-Obese (NOb) cohort. For a clearer demarcation between the obese and non-obese HF cohorts of at least one BMI unit, we assigned the BMI of 34 kg·m−2 as the lower limit of patients for inclusion into the Obese (Ob) HF cohort. An additional sub-analysis (data not shown) in which a BMI of 30 or above defined obesity did not alter the key directional 



differences in VO2max/kg, VO2max or CPOmax. With these BMI selection criteria, 152 male patients (BMI = 40.9 ± 7.5 kg·m− 2) were included in the obese HF category, and 173 male patients (BMI = 26.6 ± 3.1 kg·m− 2) were included in the non-obese HF category for analyses. The proportion of CPX studies involving patients with coexistent valve disease was similar between groups (27 of 218, and 31 of 188 studies,

respiratory rate) and VO2/kg were calculated using conventional equations. The anaerobic threshold was determined using the V-slope method [21]. Cardiac output was calculated using the indirect Fick method and at least two measurements were taken in order to calculate a mean value. Mean arterial pressure (MAP in mm Hg) was calculated from the standard equation MAP = DBP + 0.412 ∗ (SBP − DBP) [22]. The cardiac power output 

(CPO) was calculated from the equation: CPO (watts) = (Q × MAP) × K, where K is the conversion factor into Watts (2.22 × 10−3) [23]. The systemic vascular resistance was 

calculated using the equation: SVR (dyne·s·cm−5) = (MAP / Q ) × 80. 2.4. Statistics All data were analyzed using SPSS. Data are presented as mean ± standard deviation, or as counts with proportions. Univariate comparisons were made between normally distributed data using Student's t-test for unpaired samples with two-tailed tests for continuous variables. Categorical data were compared using the Chi-squared test, except where sample sizes were less than 5, in which case the Fisher exact test was applied. A P value of b0.05 was considered to be statistically significant. P values are given down to a lowest value of 10−6.

3. Results 3.1. Demographics With the BMI selection criteria specified above, we found 152 unselected consecutive male HF patients with BMI N 34 kg·m− 2 (mean BMI = 40.9 ± 7.5 kg·m− 2) who performed CPX tests between 2001 and 2014 and they were allocated to the obese HF (Ob) group. For comparison, a cohort of 173 unselected male patients with HF and BMI b 32 kg·m−2 (mean BMI = 26.6 ± 3.1 kg·m−2) were included in the non-obese HF (NOb) group. If patients incurred interim changes in

S.S. Hothi et al. / International Journal of Cardiology 184 (2015) 755–762

A

clinical status and their clinicians re-evaluated them with repeat CPX testing, then more than one CPX test per patient would be included in the analysis thus providing a total of 188 and 218 CPX tests in the Ob and NOb groups respectively. All subjects in this study were male. The ages of the Ob and NOb HF patients were similar (Ob: 56.13 ± 14.02 years, NOb: 55.81 ± 10.58 years, P = 0.80), although they were older than the healthy controls (43.17 ± 18.12 years, P b 0.001) who were recruited in order to provide an even spread of subjects across the adult age range of 19 to 77 years [11]. As described below, age

757

200 Controls Non-Obese HF Obese HF

180 160

Height (cm)

140 120 100 80 60



40

was adjusted in the analyses of VO2 and CPO of patients. As shown in Fig. 1A and Table 1, the heights of the Ob and NOb HF patients were similar to each other (Ob: 174.82 ± 7.00 cm, NOb: 174.44 ± 7.24 cm, P = 0.60). The body masses (BMs) of the Ob patients were significantly greater than those of NOb HF patients (Ob: 125.28 ± 25.66 kg, NOb: 81.22 ± 11.98 kg, P b 10−6) whose BMs were similar to those of healthy controls (81.13 ± 10.63 kg, P = 0.95) (Fig. 1B). The BMIs and body surface areas (BSAs) of Ob HF patients (40.9 ± 7.5 kg·m−2) were also clearly greater (P b 10−6) than those of controls and NOb HF patients (C: 26.0 ± 3.1 kg·m−2, NOb: 26.6 ± 3.1 kg·m−2) (Fig. 1C). The clinical profiles of the two groups of HF patients showed similar prevalence of risk factors for heart failure, with the exception of a greater prevalence of hypertension in the Ob group (P = 0.01) and lower prevalence of non-ischaemic dilated cardiomyopathy in the Ob group (P b 0.05) compared to the NOb group (Table 1).

20 0

Controls Non-Obese

B

160 140

Obese

Controls Non-Obese HF Obese HF

Body Mass (kg)

120 100 80 60 40 20

3.2. Functional status of HF patients

0

Controls Non-Obese

The NYHA functional classes of the Ob & NOb HF patients (Table 1) were rather similar with 55.9% and 60.1%, respectively, in NYHA class II (P = 0.16), and 44.1% and 39.9%, respectively, in NYHA class III (P = 0.42). The average NYHA classes of the HF patients were similar at 2.45 ± 0.51 (Ob) and 2.43 ± 0.52 (NOb) (P = 0.66). The Weber classifications of HF severity of the Ob HF patients were 28.2% in Class A, 30.9% Class B, 36.7% Class C and 4.3% Class D. The corresponding Weber classes of the NOb HF patients were 41.7%, 30.7%, 23.4% and 4.1%. By assigning Arabic numerals to the Weber classification (A = 1, B = 2, C = 3, D = 4), the average Weber class of the NOb HF group was 1.90 ± 0.90, and that of the Ob HF group was worse at 2.17 ± 0.89 (P = 0.002), suggesting according to conventional belief that the Ob HF cohort had significantly worse clinical HF than the NOb cohort.

Obese

C 60

BMI (kg.m-2)

50

Controls Non-Obese HF Obese HF

40 30 20

10 0 Controls Non-Obese

Obese

3.3. Aerobic exercise capacity Both the Ob and NOb HF patients managed to exercise to acceptable cardiopulmonary limits during symptom-limited CPX tests, with both groups attaining similar RER at peak exercise (Ob: 1.07 ± 0.12, NOb: 1.07 ± 0.09, P = 0.20), although these values were significantly lower than the peak RER in the healthy controls (1.21 ± 0.09, P b 10−6). The end-tidal PaCO2 at peak exercise (ETPaCO2max) was significantly lower in the NOb HF patients compared to the Ob HF patients (NOb: 32.4 ± 6.5 mm Hg, Ob: 37.5 ± 7.2 mm Hg, P b 10− 6), and they were both lower than the ETPaCO2max of healthy controls (39.4 ± 5.0 mm Hg, P b 10−6 and P = 0.01 for NOb and Ob, versus control, respectively) suggesting a tendency towards hyperventilation amongst HF patients. The RERs at rest were statistically indistinguishable between the three groups (C: 0.87 ± 0.06, Ob: 0.87 ± 0.10, NOb: 0.88 ± 0.13; P N 0.1 for all comparisons), while the resting end-tidal PaCO2 showed slightly lower values in the non-obese HF patients (C: 36.2 ± 4.6, Ob: 36.5 ± 5.6, NOb: 33.6 ± 4.6, P = 0.00004 for NOb versus control, P b 10−6 for NOb versus Ob, P = 0.56 for Ob versus control). Of the three groups in this investigation, the Ob HF group had the low



est VO2max corrected for body mass, with a mean VO2max/kg of 18.6 ± 5.7 ml·kg−1·min−1 which was significantly lower than in the NOb HF group (19.9 ± 5.6 ml·kg−1·min−1, P = 0.02), and both NOb and Ob

Fig. 1. Mean body heights (A) of the 3 populations: healthy sedentary male control subjects, non-obese male heart failure (HF) patients and obese male HF patients. The error bars depict standard deviations. All P N 0.05. Mean body mass (B) of the 3 populations: healthy sedentary male control subjects, non-obese male heart failure (HF) patients and obese male HF patients. P b 10−6 Ob vs C and NOb. Body mass index (BMI) (C) of the 3 populations: healthy sedentary male control subjects, obese male heart failure (HF) patients and non-obese male HF patients. P b 10−6 Ob vs C and NOb.

groups had values significantly lower than in healthy control subjects (38.5 ± 9.7 ml·kg−1·min−1, P b 10−6). As shown in Figs. 2A and 3A, 

the VO2max/kg of both the Ob and NOb HF cohorts were lower than the 

VO2max/kg of healthy controls. The mean values of HF patients were clear

ly below that of healthy controls, while the mean VO2max/kg of Ob HF patients was slightly lower than that of NOb HF patients. In the Ob HF 

patient cohort, 31.9% (60 patients) of the recorded VO2max/kg readings were found to be ≤14 ml·kg−1·min−1 (commonly employed as cardiac transplant selection cut-off value [4]) compared to 19.3% (42 patients) in the NOb cohort (P = 0.0049, for Ob versus NOb patients). As reported previously [11], central hemodynamic variables and peak O2 uptake in control subjects are linearly related with age, thus by using the regression 

equations we can therefore assign the corresponding average VO2max/kg

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Table 1 Demographics of study subjects. Variables

Controls

Non-Obese HF

Obese HF

P (NOb vs C)

P (Ob vs C)

P (Ob vs NOb)

Subjects (n) CPX completed (n) Sex Age (years) Height (cm) Body mass (kg) BMI (kg·m−2) BSA (m2) HF etiology IHD DCM HTN AF Valve Dis DM Others Severity of HF NYHA II NYHA III Average NYHA class Weber Class A Weber Class B Weber Class C Weber Class D Average Weber class

101 101 M 43.2 ± 18.1 176.6 ± 7.1 81.1 ± 10.6 26.0 ± 3.1 1.98 ± 0.15

173 218 M 55.8 ± 10.6 174.4 ± 7.2 81.2 ± 12.0 26.6 ± 3.1 1.96 ± 0.17

152 188 M 56.1 ± 14.0 174.8 ± 7.0 125.3 ± 25.7 40.9 ± 7.5 2.36 ± 0.24 60 41 40 30 29 20 35

– – – b10−6 0.04 b10−6 b10−6 b10−6 – – – – – – – –

– – – 0.79 0.60 b10−6 b10−6 b10−6

74 72 9 34 40 15 33

– – – b10−6 0.011 0.95 0.10 0.34 – – – – – – – –

131 (60.1%) 87 (39.9) 2.4 ± 0.5 91 (41.7%) 67 (30.7%) 51 (23.4%) 9 (4.1%) 1.9 ± 0.9

105 (55.9%) 83 (44.1) 2.5 ± 0.5 53 (28.2%) 58 (30.9%) 69 (36.7%) 8 (4.3%) 2.2 ± 0.9

– – b10−6 – – – – b10−6

– – b10−6 – – – – b10−6

– – 0.66 – – – – 0.002

1 100 (99%) 1 (1%)

1.01

0.66 0.01 b0.05 0.63 0.61 0.18 NS

Values of variables are expressed as number (%) of patients or mean ± SD. Key. AF: atrial fibrillation/flutter, BMI: body mass index; BSA: body surface area; CPX: cardiopulmonary exercise test; DCM: dilated cardiomyopathy; DM: diabetes mellitus; HTN: hypertension; IHD: ischaemic heart disease; NYHA: New York Heart Association; Valve Dis: valvular heart disease.



values of healthy controls at different ages as 100%. The VO2max/kg of each HF patient can then be represented as a percentage of that of the average 

age-matched control. The relative V O2max/kg of the Ob HF patients (56.3 ± 15.7%) was lower than that of NOb HF patients (61.4 ± 18.5%, P = 0.01). Based on current conventional utility and interpretations 

of VO2max/kg, it would be inferred that the Ob HF cohort appear to have similar or slightly worse cardiac dysfunction than the NOb HF cohort. 

In contrast, the absolute VO2max (without normalization with BM) of Ob HF patients (2.31 ± 0.69 l·min−1) was markedly higher than that of NOb HF patients (1.61 ± 0.49 l·min− 1, P b 10−6), and closer to the values of healthy controls (3.09 ± 0.74 l·min−1, P b 10−6). As shown 

in Figs. 2B and 3B, the VO2max of the Ob HF patients was generally greater than that of NOb HF patients with a significant proportion (85.6%) of points overlapping with those of healthy controls, compared with only 49.5% of the NOb HF patients (P b 0.001). In relative terms, with reference to the controls (whose average values were set at 100%), the 

VO2max of the Ob HF cohort (86.6 ± 22.7% of average healthy controls) was significantly higher than that of the NOb HF cohort (61.4 ± 18.5%,

functional reserve showed that the Ob HF patient cohort had significantly more powerful hearts with a CPOmax of 4.11 ± 1.21 W, compared to the NOb cohort of HF patients which had a CPOmax of 2.73 ± 0.82 W (P b 10−6), and both HF groups had lower CPOmax than the control group (5.42 ± 1.04 W, P b 10−6 vs both NOb and Ob groups). Figs. 2C and 3C show that the CPOmax of Ob HF patients was generally higher than those of NOb HF patients, with 70.2% overlapping with the CPOmax of healthy control subjects, compared to only 24.8% of the NOb HF subjects overlapping with controls (P b 0.0001, for proportion of Ob versus NOb patients with values overlapping with controls). It is also evident that only 1 (0.5%) patient in the Ob HF cohort had CPOmax b 1.5 W (which is a cardiac power cut-point criterion for end-stage HF patients to be considered for cardiac transplantation in our department), whereas 17 (9%) of the NOb HF patients were in this category (P b 0.0001). Expressed as percentages of the predicted, the CPOmax of the ambulatory NOb HF patients was only 54.2 ± 16.0% of the equivalent CPOmax of the average age-matched healthy controls (P b 10−6, NOb vs C), while the Ob HF patients were significantly better than the NOb HF patients, at 81.3 ± 23.2% relative to the average of their age-matched healthy controls (P b 10−6 vs controls, P b 10−6 vs NOb).



P b 10−6), unlike in the case of VO2max/kg above. These data suggest that the cardiac fitness of Ob HF patients was actually better than the

3.5. Central hemodynamics during peak exercise



NOb HF patients, contrary to what the VO2max/kg data suggested. 3.4. Cardiac functional reserve Adopting a universally applicable definition of HF which has been stated as “the failure of the organ under physiological conditions to convert chemical energy into adequate hydraulic energy output at rates sufficient to maintain a circulation that copes with all physiological stresses” [24], the peak amount of hydraulic energy that the heart can impart into the circulation per unit time is the most comprehensive representation of how good the heart is in fulfilling its role as a pump, and it can be quantified by the variable CPOmax. This direct indicator of cardiac

As shown in Table 2, both the Ob and NOb groups of HF patients had chronotropic incompetence with their peak exercise heart rates (HRmax, Ob: 130.1 ± 24.5 min−1, NOb: 119.2 ± 27.4 min−1) significantly lower than those of healthy controls (174.0 ± 16.7 min−1, P b 10−6 for both the NOb and Ob groups versus control). This was in the context of similar rates of β-adrenoreceptor antagonist treatment in the Ob and NOb patients (n = 95 and 126, in the Ob and NOb groups, respectively, P = 0.061). One patient in the NOb group took ivabradine and none in the Ob subgroup. The peak cardiac outputs and mean arterial pressures of the three groups also showed a similar pattern being the highest in controls and lowest in NOb HF patients. However, the peak exercise stroke volumes were significantly greater in the Ob HF patients

S.S. Hothi et al. / International Journal of Cardiology 184 (2015) 755–762

A

80

VO2max(ml.kg-1.min-1)

3.6. Resting central hemodynamics and gas exchange

Controls Non-Obese HF Obese HF Mean Controls Mean Non-Obese HF Mean Obese HF

70 60

As shown in Table 2, at rest pre-CPX testing, the mean heart rate (HR) of Ob HF patients (76.1 ± 16.7) was similar to that of NOb HF patients (72.2 ± 15.4, P = 0.31). However, the mean HRs of Ob HF patients and NOb HF patients were both significantly higher than that of controls (65.7 ± 10.6) (P b 10−6 for Ob and NOb versus control). The resting stroke volume (SV) and cardiac output (CO) were also highest in the Ob HF patients, and the mean cardiac index (CI) was similar in controls and Ob HF patients (P = 0.42), and lowest in the NOb HF patients (P = 0.0006 and P = 0.0009 for NOb versus control, and NOb versus Ob, respectively). At rest the Ob HF patients did not show hypertension, with a mean systolic BP of 120.1 ± 19.6 mm Hg and diastolic BP of 72.5 ± 12.2 mm Hg. The resting mean systemic arterial pressure (MAP) of the NOb HF patients was lowest and both HF cohorts had lower MAPrest than controls. The resting systemic vascular resistance (SVR) of the NOb HF patient cohort was similar to that of healthy controls, and was lowest in the Ob HF patient cohort. In contrast, the resting cardiac power output (CPOrest) was highest in the Ob HF cohort (1.16 ± 0.35 W), which was significantly higher than in controls (1.02 ± 0.22 W, P b 0.0001) and the NOb HF cohort (0.82 ± 0.26 W, P b 10−6). The left ventricular stroke work (SW) of the Ob HF group was similar to that of controls (P = 0.39), and significantly higher than the NOb HF group (P b 10−6). The resting respiratory exchange ratios showed no significant differences between the three groups. The end-tidal PaCO2 of the Ob HF patients was similar to that of control subjects (P = 0.56), but in both groups was higher than those in NOb HF

50 40 30 20 CTx Cutoff

10 0 0

10

20

30

40

50

70

BMI (kg.m-2)

B

Controls Non-Obese HF Obese HF Mean Controls Mean Non-Obese HF Mean Obese HF

6000 5000

VO2max(ml.min-1)

60

4000 3000 2000

1000 0 10

20

30

40

50

60

70



BMI (kg.m-2)

C

patients (P b 0.001). The resting VO2 was highest in the Ob HF patients 

10

and lowest in the control subjects. However, the resting VO2max/kg of the Ob HF patients was statistically similar to controls (P = 0.48), but

Controls Non-Obese HF Obese HF Mean Controls Mean Non-Obese HF Mean Obese HF

9 8

CPOmax(W)

759

7



significantly lower than the VO2max/kg of NOb HF patients (P b 10−6). 4. Discussion

6 5



4 3 2

CTx Cutoff

1 0

0

10

20

30

40

50

60

70

BMI (kg.m-2) 

Fig. 2. The peak O2 consumption normalized by body mass (VO2max/kg) (A) in obese vs non-obese heart failure (HF) patients relative to healthy controls. The horizontal dashed line represents the established cardiac transplant (CTx) cutoff of 14 ml·kg−1·min−1. 

The VO2max/kg of both patient groups was similar although the mean of the obese was slightly lower (P b 0.05), and both lower than that of healthy controls (P b 10−6). The 

error bars depict standard deviations. The peak O2 consumption (VO2max) (B) in obese 

vs non-obese heart failure (HF) patients relative to healthy controls. The V O2max of obese HF patient was higher than that of non-obese HF patients (P b 10−6) although generally lower than that of healthy controls (P b 10−6). The error bars depict standard deviations. The peak cardiac power (CPOmax) (C) in obese vs non-obese heart failure (HF) patients relative to healthy controls. The mean CPOmax of obese HF patient was higher than that of non-obese HF patients (P b 10−6) although generally lower than that of healthy controls (P b 10−6). The error bars depict standard deviations.

A fundamental requirement for VO2max/kg to be a general indicator of cardiac fitness is that it needs to be universally applicable to all HF patients irrespective of variations in basic patient characteristics such as age, gender and body size. Of these, probably the most vexatious is the question about body size, because in cardiological practice, the variable V̇O2max has been almost invariably divided by body mass in the belief that this simple arithmetic manipulation will remove all confounding influences caused by variations in body size. The main finding from our investigation is that such a practice has been misplaced. Compared to similarly symptomatic non-obese HF patients and to healthy controls, we found that the obese HF patient group in our study has the lowest 

mean VO2max/kg, and this is conventionally interpreted as having the poorest cardiac function of the three cohorts. However, when we re

moved the body mass correction, the eventual VO2max of the Ob HF patients was found to be greater than in NOb HF patients, and much nearer to the values found in healthy controls. The question is which of the 

polar opposite inferences is correct: whether (i) the lower VO2max/kg 

is rightly indicative of worse HF in the Ob groups, or (ii) the higher V O2max is indicative of better cardiac function in the Ob than the NOb 

HF patients. The advocates of VO2max/kg would argue that the inference 

drawn from VO2max/kg is more likely to be correct because it is more consistent with a prevailing concept that obesity per se can induce the so-called obesity cardiomyopathy either directly or indirectly [25]. (137.1 ± 33.5 ml) compared to those of NOb HF patients (114.8 ± 30.5 ml, P b 10−6), and the latter values incidentally were rather similar to those of healthy controls (116.9 ± 18.5 ml, P = 0.39). Consequentially, the mean stroke work (Fig. 3D) of Ob HF patients (196.6 ± 56.8 g·m) was also highest compared to controls (192.0 ± 34.2 g·m, P b 10−6) and the NOb HF group (143.6 ± 43.8 g·m, P b 10−6).



Moreover, VO2max/kg is sometimes used to check the validity of subjective complaints of functional incapacity (NYHA classes) through the Weber grading of HF [3]. The opponents would argue that the division by total body mass effectively assumes that the entire body consists of homogeneously metabolizing tissues during exercise. This assumption is clearly unsound because the actively contracting muscles must be

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A

Controls Non-Obese HF Obese HF

50

C

Controls Non-Obese HF Obese HF

5 40 30 20

4 3 2

10

1

0

0

Controls Non-Obese

Controls Non-Obese

Obese

B

4500

D Controls Non-Obese HF Obese HF

4000 3500 3000 2500 2000 1500

Obese

300

Controls Non-Obese HF Obese HF

250

SWmax(g.m)

VO2max(ml..min-1)

7 6

CPOmax(W)

VO2max(ml.kg-1.min-1)

60

1000

200 150 100 50

500 0

0

Controls Non-Obese

Controls Non-Obese

Obese

Obese



Fig. 3. Peak O2 consumption corrected for body mass (VO2max/kg) (A) of healthy controls, non-obese and obese heart failure (HF) patients. The error bars represent the standard deviations. 

−6

P b 10 C vs NOb and Ob; P = 0.02 Ob vs NOb. Peak O2 consumption (VO2max) (B) of healthy controls, non-obese and obese heart failure (HF) patients. The error bars represent the standard deviations. P b 10−6 C vs NOb and Ob, and Ob vs NOb. Cardiac pumping capability, CPOmax: cardiac power output at peak exercise expressed in Watts, (C) of healthy controls, non-obese and obese heart failure (HF) patients. The error bars represent the standard deviations. P b 10−6 C vs NOb and Ob, and Ob vs NOb. Peak left-ventricular stroke work (SW) (D) of healthy controls, non-obese and obese heart failure (HF) patients. The error bars represent the standard deviations. P b 10−6 C vs NOb, and Ob vs NOb; P = 0.39 C vs Ob.



metabolizing much more than the likes of adipose tissues and bones. 



Since both VO2max/kg and VO2max are indirect indicators of cardiac dysfunction, an obvious way to resolve the dispute is to measure the cardiac function of the HF patients directly and to discover how good their failing hearts are relative to the reference population of disease-free controls. We found that the directly measured cardiac dysfunction in Ob HF patients was significantly less severe than in NOb HF patients. Our 

results show that the lower VO2max/kg of Ob HF patients gave an erroneous impression of lower cardiac and physical fitness. This finding sug

gests that the current practice of correcting V O2max by a simplistic division with body mass is unsound and not universally applicable across all ranges of patient body sizes, and should be questioned and replaced by alternative, better methods of cardiac evaluation [26–28]. For decades, the prevailing paradigm has been that morbid obesity predisposes to heart failure leading to obesity cardiomyopathy [29] sup

ported by the finding of low VO2max/kg measured during exercise testing to volitional exhaustion. This view has been extended by Gallagher and colleagues who claimed that obese subjects without “limiting cardiopulmonary disease” and referred for bariatric surgery have similar 

low VO2max/kg as in ambulatory HF patients with established systolic dysfunction in NYHA classes II–IV [30]. Our data are consistent with their measurements, but our further analyses have shown that their reliance 

onVO2max/kg as the indicator of cardiac fitness and inference that bariatric patients have impaired cardiac fitness equivalent to patients with moderate-to-severe HF is incorrect [31]. Another group went further and reported improvement in cardiac function after bariatric surgery which produced an average weight loss of about 45 kg and a significant 

increase in V O2max/kg from 19 ± 3.9 to 26.6 ± 5 ml·kg−1·min−1,

while the uncorrected VO2max decreased significantly from 2935 ± 771 to 2135 ± 681 ml·min−1 [32]. Since the publication of Weber's group in 1982, low VO2max/kg has been recognized as a key indicator of cardiac dysfunction [3]. The way 



that VO2max/kg had been established as a criterion for selection of cardiac transplant candidates was by relating it to the prognosis of HF patients, such as by showing that clear differences in prognosis are found above or below certain cut-off points between 10 and 

17 ml·kg −1·min− 1 [33]. One reason why V O2max was found to be prognostically predictive in end-stage HF patients is because it was a crucial departure from the traditional but misplaced belief that resting, rather than peak exertional, indicators of cardiac function were preferred representations of cardiac dysfunction and as prognostic indicators [34,35]. However, now that we have better variables representa

tive of true cardiac function, as shown in this investigation, VO2max/kg has been exposed to show a crucial flaw of inappropriate scaling. The 

necessity to include a string of caveats when employing VO2max/kg as a listing criterion for cardiac transplantation [6] betrays a rather awkward utility of this parameter. On reviewing the hemodynamic and gas exchange data displayed in Table 2, some important mechanistic information can be gleaned to elucidate a few pathophysiological processes responsible for the observed differences in cardiac fitness of the three populations. This may also help to confirm or challenge some established doctrines about HF, and to throw some light on the usefulness of some hemodynamic variables commonly used as indicators of cardiac dysfunction. The peak exercise heart rates of patients were lower than those of healthy controls, confirming that both the obese and non-obese HF patients are affected by chronotropic incompetence, as has been described

S.S. Hothi et al. / International Journal of Cardiology 184 (2015) 755–762

761

Table 2 Cardiopulmonary exercise hemodynamics and gaseous exchange. Variables Peak CPX HRmax (min−1) SVmax (ml) MAPmax (mm Hg) COmax (l·min−1) CImax (l·min−1·m−2) SWmax (g·m) SVRmax (dyn·s·cm−5) RERmax ETPaCO2max 

VO2max/kg (ml·kg−1·min−1) 

VO2max (ml·min−1) CPOmax (W) 

VO2max (% of Av Ctrl) 

VO2max/kg (% of Av Ctrl) CPOmax (% of Av Ctrl) At rest pre-CPX HRrest (min−1) SVrest (ml) MAPrest (mm Hg) COrest (l·min−1) CIrest (l·min−1·m2) SWrest (g·m) SVRrest (dyn·s·cm−5) RERrest ETPaCO2rest 

VO2rest/kg (ml·kg−1·min−1) 

VO2rest (ml·min−1) CPOrest (W)

Controls

Non-obese HF

Obese HF

P (NOb vs C)

P (Ob vs C)

P (Ob vs NOb)

173.9 ± 16.7 116.9 ± 18.5 120.8 ± 11.0 20.3 ± 3.9 10.3 ± 1.8 192.0 ± 34.2 495 ± 116 1.21 ± 0.09 39.4 ± 5.0 38.5 ± 9.7

119.2 ± 27.4 114.8 ± 30.5 92.2 ± 15.7 13.2 ± 3.1 6.8 ± 1.5 143.6 ± 43.8 589 ± 178 1.07 ± 0.09 32.4 ± 6.5 19.9 ± 5.6

130.1 ± 24.5 137.1 ± 33.5 105.5 ± 17.0 17.5 ± 4.0 7.4 ± 1.5 196.6 ± 56.8 509 ± 146 1.07 ± 0.12 37.5 ± 7.2 18.64 ± 5.17

b10−6 0.46 b10−6 −6 b10 b10−6 b10−6 b10−6 b10−6 b10−6 b10−6

b10−6 b10−6 b10−6 b10−6 b10−6 0.39 0.39 b10−6 0.01 b10−6

0.00003 b10−6 b10−6 b10−6 b10−6 b10−6 b10−6 0.20 b10−6 0.02

3091 ± 740

1607 ± 494

2312 ± 693

b10−6

b10−6

b10−6

5.42 ± 1.04 100 ± 13.8

2.73 ± 0.82 61.4 ± 18.5

4.11 ± 1.21 86.6 ± 22.7

b10−6 b10−6

b10−6 b10−6

b10−6 b10−6

100 ± 16.0

60.5 ± 16.6

56.3 ± 15.7

b10−6

b10−6

−6

b10−6

b10−6

b10−6 0.00001 b10−6 0.002 0.0006 −6 b10 0.66 0.31 0.00004 b10−6

b10−6 0.12 0.08 b10−6 0.42 0.39 −6 b10 0.46 0.56 0.48

0.31 b10−6 b10−6 0.02 0.0009 −6 b10 −6 b10 0.11 b10−6 b10−6

b10−6

b10−6

100 ± 16.2

54.2 ± 16.0

81.3 ± 23.2

65.7 ± 10.6 73.7 ± 18.0 95.7 ± 9.0 4.87 ± 1.20 2.47 ± 0.61 95.3 ± 21.4 1685 ± 509 0.87 ± 0.06 36.2 ± 4.6 3.43 ± 0.66

72.2 ± 15.4 63.0 ± 23.6 84.2 ± 13.5 4.33 ± 1.16 2.22 ± 0.59 72.5 ± 30.1 1658 ± 493 0.88 ± 0.13 33.6 ± 4.6 4.01 ± 0.83

76.1 ± 16.7 77.7 ± 24.4 92.1 ± 13.6 5.68 ± 1.47 2.41 ± 0.57 97.2 ± 32.9 1383 ± 403 0.87 ± 0.10 36.5 ± 5.6 3.37 ± 0.65

b10

275 ± 43

323 ± 64

416 ± 85

b10−6

1.02 ± 0.22

0.82 ± 0.26

1.16 ± 0.35

b10−6

0.0101

b10−6

0.00008

Data are presented as mean ± SD. Key: subscript “max” denotes value obtained at peak exercise; subscript “rest” denotes value obtained at rest. Av Ctrl: average, age-matched control; CI: cardiac index; CO: cardiac output; CPO: cardiac power output; ETPaCO2: end-tidal partial pressure of carbon dioxide; HR: heart rate; MAP: mean arterial pressure; RER: respiratory ex

change ratio; SV: stroke volume; SVR: systemic vascular resistance; SW: stroke work; VO2: rate of O2 consumption.

previously [36,37], although the chronotropic incompetence appears to be less severe in the obese HF cohort. In this study, cardiac fitness showed a pattern of being highest in the control subjects, intermediate in the Ob HF patients and lowest in NOb HF patients (Fig. 3C). Such a pattern was similarly found in some commonly used variables, includ





ing VO2max (Fig. 3B), HRmax, MAPmax, VEmax, and Q max. However, the Ob HF cohort had the highest values of SV max and SW max (Fig. 3D) 

and the lowest values of VO2max/kg (Fig. 3A), which suggest that these variables are unreliable indicators of true cardiac function, and when taken in isolation clinically, they can be misleading. This fact further illustrates the hazard of assuming any component aspects (e.g. SVmax, 

SWmax) of cardiac performance, or incorrect scaling (e.g. VO2max/kg) as representative, isolated indicators of overall cardiac function. The resting systemic vascular resistance of NOb HF patients was similar to those of controls, but that of Ob HF was significantly lower than either, suggesting the need to perfuse in-parallel the vasculature supplying the excessive adipose tissues. In contrast, during peak exercise, the SVRmax of Ob HF patients was not lower than in controls, partly accounted by the lower cardiac reserve than in controls (Table 2) and partly due to preferential redistribution of blood flow into the actively contracting muscles instead of the metabolically less active adipose tissues. 5. Limitations While heart rate and O2 uptake can be calculated respectively from non-invasive measurements of beat-by-beat cardiac contractions and breath-by-breath respiratory gas exchange, the technology for continuous measurements of cardiac output and arterial pressure reliably can only be accomplished with invasive means. However, it is considered unethical to inflict such invasive procedures to healthy volunteers or to HF patients without clear clinical indication. Moreover, invasive

instrumentation can also induce discomfort and pain, but more often, uncomplaining patients are often experiencing subclinical pain and vasovagal reactions which render the hemodynamic data rather variable and possibly unrepresentative of true responses to exercise. The retrospective nature of this study was a limitation but the inclusion of unselected cases of HF patients in the analyses minimized biases and provided data which represent usual clinical practice in a tertiary cardiological center and true functional differences between obese and nonobese HF patients. Thus, NOb patients could be compared to Ob patients, and both could be compared to a reference control population. As an indirect indicator of cardiac dysfunction [38], BNP biomarker levels would have been additionally informative, but this assay was not routinely available in the UK until recently. A prospective study of this scale and duration would require at least ten-fold costlier funding. Body composition data had not been routinely collected in clinical practice and should form an essential part of future prospective studies in order to find better scaling methods than division with body mass. Complementary information from imaging the heart of obese subjects was difficult to obtain because echocardiographic images are usually suboptimal due to body habitus and the use of microbubble contrast agents (e.g. Sonovue, Optison) or transesophageal echocardiography was not in routine clinical practice in our center. Other imaging modalities such as radionuclide scintigraphy, CT or MRI scanning would require equipment upgrades in order to accommodate the extra mass and sizes of the morbidly obese patients, and should be factored into future studies. 6. Conclusion 

Contrary to popular perception through usage of VO2max/kg data, we found that obese HF patients turned out to have stronger hearts capable of greater peak cardiac power generation than non-obese HF patients of

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equivalent clinical HF severity. Our results have shown that VO2max/kg is not a reliable indicator of cardiac fitness, and is not generally applicable to 

all HF patients irrespective of body masses. In obese patients, VO2max/kg is not indicative of true cardiac fitness. The results call into question and 

argue against the continued usage of VO2max/kg as a general indicator of cardiac fitness in all HF patients. Indeed, the evidence suggests that the 

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