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Body Habitus Considerations During Right Heart Catheterization

Background Obese and overweight body habitus are common among patients undergoing right heart catheterization for suspected pulmonary hypertension, but previous studies have described only patients with severe obesity. This study examined the effect of body habitus on intracardiac pressures, thermodilution cardiac output (TDCO), indirect Fick (iFick) cardiac output (CO), and pulmonary vascular resistance (PVR) in subjects with normal cardiopulmonary hemodynamics. Methods A retrospective analysis was conducted on healthy volunteers and patients referred for right heart catheterization for dyspnea of unknown origin with normal hemodynamics. Of the 65 subjects (53 ± 14 years; 51% female), 31% were normal weight, 49% were overweight, and 20% had obesity, as defined by a body mass index of 30-39.9 kg/m2. Mixed venous oxygen saturations and intracardiac pressures were compared across body mass index categories. Agreement between iFick CO calculated by 3 formulae, and TDCO and PVR was examined. Results No differences in intracardiac pressures were observed, but mixed venous oxygen saturations were lower in the obese group. iFick CO underestimated TDCO, particularly with the LaFarge formula, with a systematic difference of 0.33 L/min for every 1 L/min increase in CO. This difference was largest in the obese group—on average by 23% ± 10%, translating to an overestimation of PVR by 34% ± 16% on average. Conclusions In individuals without severe obesity, intracardiac pressures are not different, but mixed venous oxygen saturations are lower. Obesity confounds estimations of CO and PVR by iFick methods, which could result in inappropriate hemodynamic classification. These data can inform best practices in hemodynamic assessment of populations with obesity.

overweight or have obesity may indicate adaptation of cardiovascular physiology to changes in body habitus. 7,8 Patients with class III or greater obesity (body mass index [BMI] ≥ 40 kg/m 2 ) have shown increases in cardiac output (CO) and ventricular filling pressures, although less is known about populations with lessextreme ranges of body habitus. [8][9][10] Second, obesity may confound adjustments that are already made when considering morphometric data 11 ; for example, obesity may confound the use of formulae employed to estimate indirect Fick (iFick) CO, which were derived from relatively lean patients. [12][13][14] The objective of this study was to understand the effect of body habitus on hemodynamic assessment, particularly the mPAP, mPAWP, CO measured by thermodilution (TDCO) and iFick methods, and derived PVR. In a population with normal resting and exercise hemodynamics, we compared individuals of normal weight, those who were overweight, and those with class I or class II obesity as defined by BMI. 5 As an internal control, we compared men and women, as the effect of sex on body morphometrics and hemodynamics is better understood. 15

Study population
Subjects were selected from 2 databases. The first database included healthy volunteers from the community who participated in a physiologic study of RHC during rest and exercise. Hemodynamics from this cohort have been published. 3 Inclusion criteria were age ≥ 45 years, normal sinus rhythm, QRS duration of < 110 ms, no prior history of coronary disease, heart failure, diabetes mellitus, hypertension, and not taking medications or hormone replacements.
The second database included patients who underwent RHC at rest and with exercise for the assessment of dyspnea of unknown origin (DUO). Individuals with normal hemodynamics at rest and during exercise were included. DUO patients were excluded if mPAP > 20 mm Hg at rest, or if DmPAP/DCO > 3 WU and/or if DmPAWP/DCO > 2 mm Hg/L*min −1 during exercise.

Cardiac catheterization standard operating procedures
A balloon-tipped fluid-filled 7F or 7.5F catheter was inserted percutaneously and advanced into the pulmonary artery under fluoroscopic guidance. Pressure transducers were zeroed at the midaxillary level, and simultaneous right atrial, right ventricular, and pulmonary artery pressures were recorded continuously. The balloon was inflated intermittently to record the mPAWP. Mixed venous blood was sampled for oximetry to calculate iFick CO, and TDCO was measured in triplicate with less than 10% variation between measurements. Our procedures for exercise have been published previously. 3,15 Subjects were excluded if they did not have resting data available for both TDCO and iFick CO.

Clinical and hemodynamic data
Demographic variables including age, sex, height, and weight were extracted from databases. In addition to BMI, body surface area (BSA) was calculated by the Dubois formula -0.007184 x Height (cm) 0.725 x Weight (kg) 0.425 . Hemodynamic variables extracted included resting right atrial and pulmonary artery pressures, end-expiratory mPAWP, heart rate, and TDCO. The arterial, and mixed venous oxygen saturations were recorded, as was hemoglobin concentration. Arterial and mixed venous oxygen content was calculated using concordance entre le calcul du DC selon le principe iFick au moyen de 3 formules, ainsi que le DCTD et la RVP. R esultats : Les pressions intracardiaques n'ont montr e aucune diff erence, mais les saturations veineuses mixtes en oxyg ene etaient plus faibles chez les sujets ob eses. Le DC calcul e selon le principe iFick a d emontr e une sous-estimation du DCTD, particuli erement lors du calcul au moyen de la formule LaFarge, qui a r ev el e une diff erence syst ematique de 0,33 L/min a chaque augmentation du DC de 1 L/min. Cette diff erence qui etait plus importante chez les sujets ob eses (en moyenne de 23 % § 10 %, se traduisait en moyenne par une surestimation de la RVP de 34 % § 16 %). Conclusions : Chez les individus non atteints d'une ob esit e s erieuse, les pressions intracardiaques ne sont pas diff erentes, mais les saturations veineuses mixtes en oxyg ene sont plus faibles. L'ob esit e fait remettre en cause les estimations du DC et de la RVP par les m ethodes iFick, lesquelles pourraient donner lieu a une classification h emodynamique erron ee. Ces donn ees peuvent permettre d' etablir des pratiques exemplaires lors de l' evaluation h emodynamique des populations atteintes d'ob esit e. CO. This difference was largest in the obese group-on average by 23% § 10%, translating to an overestimation of PVR by 34% § 16% on average. Conclusions: In individuals without severe obesity, intracardiac pressures are not different, but mixed venous oxygen saturations are lower. Obesity confounds estimations of CO and PVR by iFick methods, which could result in inappropriate hemodynamic classification. These data can inform best practices in hemodynamic assessment of populations with obesity. standard formulae, as was the arteriovenous oxygen (a-vO 2 ) difference.
Estimated resting oxygen consumption (VO 2 ) was calculated by the Dehmer, Bergstra, and LaFarge formulae defined by the following equations: Resting VO 2 was calculated as TDCO * a-vO 2 difference. CO estimated by iFick methods was calculated as VO 2 (mL/ min) / a-vO 2 difference and converted to L/min.

Statistical analysis
Statistical analyses were performed using GraphPad Prism v.8.4.2 (La Jolla, CA). Continuous variables are presented as mean § standard deviation or median (interquartile range), and categorical variables are presented as percentages.
Between-group comparisons of BMI categories were conducted using a one-way analysis of variance. Comparisons of variables derived from different methods of CO measurements were conducted using a one-way repeated-measures analysis of variance. Significant main effects were analyzed post hoc using Tukey's multiple comparisons test. Independent-sample Student t tests were used to determine statistical significance in subjects stratified by sex. Bland Altman plots assessed the agreement between methods of assessment for VO 2 or CO, and PVR and 95% limits of agreement (LOA) were reported. Linear regression analyses were employed to assess the proportional bias for the overall cohort, and to assess the relationship of the morphometric variables height, weight, BMI, and BSA to TDCO, VO 2 , and the a-vO 2 difference. P < 0.05 was considered statistically significant.

Study population and characteristics
A summary of subject selection is presented in Figure 1, and clinical characteristics are shown in Table 1. The database of healthy subjects contained 36 individuals, 8 of whom were excluded due to incomplete data. The median age was 56 years; 50% were female; and the median BMI was 26.3 kg/ m 2 . The proportions of healthy subjects with a BMI of 18.5-24.9 kg/m 2 , 25-29.9 kg/m 2 , and 30-39.9 kg/m 2 were 39%, 57%, and 4%, respectively.
The DUO patient database contained 137 participants, of which 37 were eligible for analysis. The median age was 52 years; 51% were female; and the median BMI was 28.1 kg/ m 2 . The proportions of these patients with a BMI of 18.5-24.9 kg/m 2 , 25-29.9 kg/m 2 , and 30-39.9 kg/m 2 were 24%, 43%, and 33%, respectively.
By design, DUO patients were hemodynamically normal at rest and with exercise. Eighteen patients (28%) had a risk factor for PH (history of venous thromboembolism or connective tissue disease), and 15 patients (23%) had a cardiovascular risk factor. The final dataset for analysis consisted of 65 subjects (51% female): the proportions with a BMI of 18.5-24.9 kg/m 2 , 25-29.9 kg/m 2 , and 30-39.9 kg/m 2 were 31%, 49%, and 20%, respectively.

Thermodilution cardiac output: associations with morphometric variables
Hemodynamic characteristics for the overall cohort, men, women, and by BMI categories are given in Table 2. In this study, we assumed that TDCO was the reference standard for assessment of CO. TDCO in the overall cohort was 5.24 L/min. As expected, TDCO and stroke volume were significantly higher in men compared to women, and they correlated as expected with height and weight, as shown in Figure 2A. TDCO also significantly correlated to BSA (P < 0.001, R 2 = 0.21). We did not observe a significant relationship between TDCO (P = 0.20, R 2 = 0.03) and stroke volume (P = 0.13, R 2 = 0.04) with increasing BMI.
Hemoglobin concentration is higher in men than women, and in subjects with a BMI of 30-39.9 kg/m 2 . The a-vO 2 difference and calculated VO 2 is also higher in men than women, and in subjects with a BMI of 30-39.9 kg/m 2 compared to the other 2 BMI groups. Figure 2B illustrates the relationship between height, weight, and the a-vO 2 difference. The mixed venous oxygen saturation was not different between men and women. However, in subjects with a BMI between 30-39.9 kg/m 2 , compared to the other 2 BMI groups, we observed that the higher a-vO 2 difference was related in part to a significantly lower mixed venous oxygen saturation; consistent with this, we observed a strong correlation between weight and the a-vO 2 difference (P < 0.0001, R 2 = 0.28).
Contrasting CO and VO 2 derived by thermodilution and iFick methods iFick calculations for VO 2 and CO are shown in Table 3 alongside TDCO derived VO 2 . We observed a positive trend toward increasing VO 2 (P < 0.0001) and CO (P = 0.20) with BMI by iFick formulae and thermodilution. However, iFick CO and VO 2 from the LaFarge formula significantly underestimated TDCO measurements in the overall cohort and across BMI categories (P < 0.0001). The mean percentage difference between VO 2 or CO calculated by the LaFarge formula and TDCO was −18% § 13%, in individuals with a BMI of 18.5-24.9 kg/m 2 , increasing to −23% § 10% in the BMI 30-39.9 kg/m 2 group. Similarly, the iFick CO and VO 2 from the Dehmer formula significantly underestimated CO compared to TDCO in the overall cohort and across BMI groups. The percentage difference between VO 2 or CO calculated by the Dehmer formula and TDCO was 0% § 19% in the BMI 18.5-24.9 kg/m 2 group, increasingly significantly to −15% § 13% in the BMI 30-39.9 kg/m 2 group (P = 0.04). Percentage differences were quantitatively smaller with the Dehmer formula compared to the LaFarge formula. Finally, the iFick CO and VO 2 calculated using the Bergstra formula  were not significantly different from TDCO in the overall cohort or across BMI categories. Figure 3, A-C demonstrates the agreement between the TDCO and iFick estimations of CO. The LaFarge iFick CO underestimates TDCO with an absolute value to the bias of 1.07 L/min (95% LOA −0.64 L/min to 2.78 L/min), with a significant slope (P = 0.0058) such that for every 1 L/min increase in CO, the LaFarge CO underestimated TDCO by 0.33 L/min. Similarly, the Dehmer iFick CO demonstrated a smaller bias in the agreement with TDCO, with an absolute value of 0.36 L/min (95% LOA −1.58 L/min to 2.29 L/ min); again, with a significant slope to the bias (P < 0.0001) for every 1 L/min increase in CO, the Dehmer CO underestimated TDCO by 0.62 L/min. Finally, the Bergstra iFick CO

Pulmonary vascular hemodynamics: associations with morphometric variables
There were no differences between BMI categories and no significant BMI relationships for mean right atrial pressure, pulmonary artery pressures, and mPAWP (Table 2). TDCOderived PVR is included in Table 3. There was no significant difference in PVR between men and women or across BMI categories. PVR agreement was examined between values calculated from TDCO and iFick methods and is presented in Figure 4, A-C. The iFick PVR by the LaFarge formula overestimated TDCO-derived PVR with an absolute value to the bias of 0.37 WU (95% LOA −1.15 to 0.42) with a significant slope (P < 0.0001) such that for every 1 WU increase, the iFick LaFarge formula overestimates PVR by 0.31 WU. A systematic bias or significant slope to the bias was not observed between TDCO PVR and the Bergstra or Dehmer PVR.
The mean percentage difference between PVR calculated with TDCO vs iFick CO was different among BMI groups, particularly with the LaFarge and Dehmer formulae (Fig. 5). For the Dehmer formula, the mean percentage difference in PVR from the TDCO-derived value was 3% § 19% in the BMI 18.5-24.9 kg/m 2 group, increasing to 21% § 17% in the BMI 30-39.9 kg/m 2 group. With respect to the LaFarge formula, the percentage difference in PVR from the TDCOderived value was overestimated, with a mean percentage difference of 25% § 19% among the BMI 18.5-24.9 kg/m 2 group, increasing to 34% § 16% in the BMI 30-39.9 kg/m 2 group. PVR calculated by the LaFarge-derived CO was ≥ 3 WU in 8% of individuals with a BMI of 30-39.9 kg/m 2 .

Discussion
We assessed the effect of body morphometrics, classified by BMI, on hemodynamic measurements obtained by RHC in subjects with otherwise normal hemodynamics, at rest and during exercise. Our data reinforce previous recommendations to avoid iFick estimations in favour of TDCO or direct Fick CO methods.

The relationship of body habitus to TDCO and a-vO 2 difference
Prior studies 9,10 examining the associations of body habitus to invasive hemodynamics were primarily focused on subjects with severe obesity, with BMIs ≥ 40 kg/m 2 . We aimed to extend our understanding of lessextreme ranges of body habitus, which are more reflective of patients requiring RHC today, by looking at individuals with class I or class II obesity. Although BMI was related to CO in subjects with severe   obesity, we observed that height and weight were more strongly related to TDCO than BMI across a modest BMI range. Our findings were consistent with previous observations that CO and stroke volume are more closely related to fat-free mass and its determinants, particularly height. As expected, TDCO was larger in men compared to women. 15,16 We had the opportunity to examine directly measured mixed venous oxygen saturations and a-vO 2 differences across BMI groups. We observed relationships between a-vO 2 differences and body size that stood in contrast to those observed with CO. In this regard, the comparison of men and women was instructive. As expected, commensurate with greater body size and CO, men demonstrated higher hemoglobin concentration, and greater VO 2 and a-vO 2 differences compared to women, but with no differences in mixed venous oxygen saturation. In contrast, individuals with a BMI of 30-39.9 kg/m 2 demonstrated higher VO 2 and a-vO 2 differences, but at the expense of increasing oxygen extraction and a more depressed mixed venous oxygen saturation. We also observed that the a-vO 2 difference was more strongly related to weight than to height. The a-vO 2 difference is a measure of tissue oxygen extraction, and it reflects the oxidative function of metabolically active mass. Our findings may suggest that increased oxygen extraction is an adaptation to sustain a larger body habitus, although the site of extraction is unclear, as adipose tissue has a low metabolic rate. 17 Another interpretation is perhaps that CO in individuals with obesity is insufficient relative to body habitus, thus requiring a greater a-vO 2 difference. Consistent with our findings, Alexander et al. 17 showed that significant weight loss among severely obese subjects was associated with significant reduction in the a-vO 2 difference and CO.
In the population studied, we did not find evidence of any relationships between obese body habitus and pulmonary artery pressures, or right-and left-sided filling pressures. This evidence is in contrast to previous studies that have demonstrated an association between obesity and elevated right atrial pressure and mPAWP. 8,9 These studies, however, predominately included diseased populations and individuals with severe obesity.

Implications for catheterization laboratory practices
It has been demonstrated that there is only modest agreement between iFick methodologies and TDCO, and that TDCO is a better predictor of all-cause mortality. 18,19 iFick formulae were derived from populations across varying age ranges extending to very young subjects, for whom findings are less generalizable to patients requiring RHC today. 13,14,20 Among patients undergoing RHC for suspected PH, iFick generally underestimates CO compared to TDCO. [18][19][20] The present study extends these findings by demonstrating the effect of body habitus to confound estimates of VO 2 , and therefore calculated CO. There was a slope to the bias such that iFick methods demonstrated increasing differences from TDCO as CO increases, and because individuals with a BMI ≥ 25 kg/m 2 have a larger CO, these systematic differences will occur more frequently than they do in individuals with a BMI of 18.5-24.9 kg/m 2 . We identified several issues, particularly with the LaFarge formula, which underestimated TDCO to a greater degree in women than in men, and further systematically underestimated TDCO across BMI groups, with the greatest differences in the BMI 30-39.9 kg/m 2 group. A similar pattern was identified using the Dehmer formula, which also underestimated CO as BMI increased, particularly in the BMI 30-39.9 kg/m 2 group. 18 If there is no other option but to employ an iFick estimate of CO, our results suggest that the Bergstra formula demonstrated the best agreement with TDCO across BMI categories.
Our study extends previous invasive hemodynamic investigations by inclusion of subjects with a more modest BMI range of overweight and obese body habitus, whereas previous hemodynamic research has focussed on patients with severe obesity. 20 Our findings are relevant to patients undergoing RHC for the evaluation of suspected PH, a condition that exhibits a female predilection, and the proportion of patients with a BMI ≥ 30 kg/m 2 is approximately 50%. 21 Obviously, inaccurate estimation of CO will affect the calculation of PVR. In a proportion of our cohort with otherwise normal hemodynamics, use of the LaFarge formula yielded a calculated PVR ≥ 3 WU, the current threshold for classification of pre-capillary pulmonary vascular disease. A PVR threshold of 3 WU is also used to differentiate between isolated post-capillary PH and combined pre-and post-capillary PH. Calculation of PVR from iFick methods can result in misdiagnosis of PH and lead to inappropriate and possibly dangerous treatment methods for RHC patients. We showed that overestimation of PVR was more likely in women and individuals with a higher BMI, based on the underestimation of CO by the iFick formulae. Our findings emphasize the importance of best practices for accurate hemodynamic assessment as the prevalence of obesity trends upward in North America. 7

Limitations
There are limitations to consider in this analysis. We attempted to study the effect of body habitus in subjects with normal resting and exercise hemodynamics, but some individuals had DUO and comorbid medical conditions. The use of BMI to evaluate body habitus also has limitations, and we did not have measures of body composition for the direct assessment of fat-free mass, or other measures of cardiometabolic changes. 16

Conclusions
This hemodynamic study examined a cohort of subjects who demonstrated a range of body habitus levels. Obesity systematically alters assessment of VO 2 , CO, and PVR by the iFick formulae, potentially leading to misclassification of PH patients. Among individuals with a BMI of 30-39.9 kg/m 2 , we observed alterations in physiology, including a lowered mixed venous oxygen saturation and a larger a-vO 2 difference. The effect of body habitus on circulatory physiology bears further study.

Funding Sources
This research was supported by the Ontario Research Fund.

Disclosures
The authors have no conflicts of interest to disclose.