Effect of Obesity on Mortality in Pulmonary Hypertension, Does Obesity Paradox Exist?

Effect of Obesity on Mortality in Pulmonary Hypertension, Does Obesity Paradox Exist? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Obesity on Mortality in Pulmonary Hypertension, Does Obesity Paradox Exist? Raju M Reddy, Akram Khan, Saminder Singh, Bashar Alzghoul, Sherie Gause, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-540969/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Obesity is reported to have a protective effect on mortality in pulmonary hypertension (PH), a phenomenon known as obesity paradox. However, the data is conflicting with some studies showing decreased mortality while other studies found no effect of obesity on mortality. Therefore, we performed a meta-analysis to examine the effect of obesity on mortality in PH. Only patients with PH diagnosed by right heart catheterization were included. We also performed a sub-group analysis of subjects with pre-capillary PH only. A total of seven studies met the inclusion criteria with a sample size of 79,577 patients. Obese subjects had lower mortality compared to non-obese subjects in the mixed PH group (hazard ratio 0.67, 95% CI 0.51-0.87, P<0.00001) and in the pre-capillary PH group (hazard ratio 0.74; 95% CI 0.58-0.96; P<0.00001). Body mass index ≥ 30 kg/m 2 may be associated with reduced mortality but these results must be interpreted with caution. Pulmonology obesity pulmonary hypertension mortality body mass index Figures Figure 1 Introduction Obese patients with left sided heart failure have higher survival rates compared to their non-obese counterparts, a phenomena known as obesity paradox [ 1 ]. Similar findings have been reported in patients with pre-capillary pulmonary hypertension (PH) also but the association of obesity paradox with mortality in PH remains controversial. This relationship, if any, is not well understood clinically or physiologically. Methods To further examine this association, we sought to examine the effect of obesity on PH mortality by performing a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) 2015 Statement guidelines [ 2 ]. A literature search utilizing major electronic databases including PubMed, Cochrane library, and Embase was performed using the MeSH term “obesity AND pulmonary hypertension”. Only studies with hemodynamic data obtained by right heart catheterization and reported mortality outcomes were included. We used the generic inverse variance to calculate the pooled hazards ratio of mortality using random effects model. After the final review by two authors (RR, YZ), seven studies met inclusion criteria for the analysis of which four were prospective observational studies and three were retrospective registry-based studies. Two studies included subjects with pre-capillary PH, post-capillary PH and combined pre and post-capillary PH [ 3 , 4 ], while the other five studies included only subjects with pre-capillary PH [ 5 – 9 ]. All studies classified obese individuals as those with body mass index (BMI) ≥ 30 kg/m 2 . Five studies [ 3 , 6 – 9 ] compared obese (BMI ≥ 30 kg/m 2 ) versus non-obese subjects while two studies [ 4 , 5 ] compared obese (BMI ≥ 30 kg/m 2 ) versus normal weight subjects (BMI 18-24.9 kg/m 2 ). We performed a sensitivity analysis by including only studies that included patients with pre-capillary PH. The main outcome was all-cause mortality. Results The final analysis included seven studies totaling 79,577 patients; 49,607 (62.3%) were obese subjects defined as BMI ≥ 30 kg/m 2 , and 29,970 (37.7%) non-obese or normal weight subjects. Obese subjects had significantly reduced mortality when compared to non-obese subjects in the mixed PH patient population (Hazard ratio 0.67, 95% CI 0.51–0.87, P < 0.00001) as well as in subjects with pre-capillary PH (Hazard ratio 0.74; 95% CI 0.58–0.96; P < 0.00001) (Figure A). Discussion Our study showed that obesity is present in 62.3% of subjects with PH and was associated with a significant reduction in mortality among subjects with both precapillary PH as well as combined pre and postcapillary PH when compared with non-obese subjects. This finding was consistent in all included studies except the study by Weatherald et al., who found no effect of obesity on mortality [ 8 ]. The mechanism of the protective effect of obesity on mortality in cardiovascular disease is unknown but a few hypotheses have been explored. Adiponectin, a hormone derived from adipocytes, is thought to play a protective role in cardiovascular diseases by decreasing inflammatory cytokines such as tumor necrosis factor α levels and inhibition of NF-κβ activity [ 10 ]. In a study by Kumada et al., low levels of adiponectin were associated with the development of coronary artery disease and myocardial infarction in humans [ 11 ]. Similarly, in animal models of PH, it has been shown that adiponectin is associated with reduced smooth muscle cell proliferation and decreasing levels of inflammatory cytokines [ 10 ]. Thus, patients who are normal or underweight may lose the protective effect of adiponectin. In addition, adipose tissue secretes apelin, an adipokine, which is known to promote vasodilation by activating nitric oxide synthase [ 12 ]. Whether the vasodilatory effect of apelin exits in obese PH patients remains unknown and is an area for further research. While these findings are interesting, they should be interpreted with caution for several reasons. First, the hemodynamic variables between the two patient groups were different. In the three of the included studies [ 5 , 6 , 9 ], obese patients tended to have higher pulmonary artery wedge pressures suggesting that they may have occult left ventricular diastolic dysfunction despite meeting criteria for pre-capillary PH at the time of right heart catheterization [ 13 ]. In addition, obese patients in the same studies had higher cardiac output [ 5 , 8 ] and lower PVR [ 5 , 8 ] which could also contribute to improved outcomes in these patients[ 14 ]. Second, rather than obesity conferring a protective effect, it is also possible that low BMI may simply be a manifestation of declining health due to right ventricular dysfunction. This decline in right ventricular failure may manifest as cardiac cachexia; characterized by congestion of hepatic and splanchnic beds, intestinal dysmotility and protein malabsorption [ 15 ]. Third, BMI does not capture body composition accurately. The implication that higher BMI is related to higher fat mass is not necessarily true. Thus, a better predictor of mortality could be the total fat mass or the pattern of distribution of fat (central vs. peripheral). In a study of heart failure patients by Sutter et al., a J-shaped mortality curve was seen where patients with the lowest BMI and higher BMI (BMI > 35 kg/m 2 ) had higher mortality compared to the overweight BMI 25–35 kg/m 2 group [ 16 ]. On further analysis, it was found that having a higher lean body mass despite being overweight conferred a protective effect and that higher body fat percentage in the obese population was detrimental. A similar J-shaped mortality curve was also observed in patients with pre-capillary PH [ 8 ]. While these studies did not examine the body mass composition, it is possible that the morbidly obese PH patients who had a higher mortality had a higher fat mass percentage. Our analysis is limited by its heterogeneity. Many potential reasons account for this. First, studies included used various definitions of PH. To minimize the impact of the variation, we only included studies that reported hemodynamics obtained by right heart catheterization and also performed a sub-group analysis for patients with pre-capillary PH. Second, three of the seven included studies were retrospective. Given that PH is a rare disease, data gathering is often limited to retrospective data from registries. Third, the confounding variables used in studies differed which could have affected the hazard ratios obtained when studying the impact of obesity in PH patients. In summary, we found that obese PH patients had lower mortality compared to non-obese patients. This ‘obesity paradox’ in PH is a noteworthy finding and warrants further studies. Given the pathobiologic complexities of PH, it is possible that there are different phenotypes of obesity that confer either protective or pathologic effects on pulmonary vascular disease. Future studies examining the association between BMI and PH may help better define this relationship by studying the effect of body composition and body fat distribution on outcomes in PH. With the precise causal effects of obesity in PH being unknown, future registry-based studies could increase long term follow up of patients and closely track body composition to more precisely determine the effect of obesity in PH. Declarations Funding : none Conflicts of Interest : All authors declare that they have no conflicts of interests to declare related to this work Availability of Data and Material : Data available on request Authors’ Contributions : Raju Reddy (data curation, conceptualization, methodology, investigation, writing – original draft, writing – reviewing and editing); Akram Khan (methodology, investigation, writing – original draft, writing – reviewing and editing); Saminder Singh (data curation, conceptualization, methodology, investigation, writing – original draft, writing – reviewing and editing); Bashar Alzghoul (methodology, investigation, writing – original draft, writing – reviewing and editing); Sherri Gause (methodology, investigation, writing – original draft, writing – reviewing and editing); Nalini Colaco (methodology, investigation, writing – original draft, writing – reviewing and editing); Jeffrey Robinson (data curation, conceptualization, methodology, investigation, writing – original draft, writing – reviewing and editing); Yazan Zayed (data curation, conceptualization, methodology, investigation, writing – original draft, writing – reviewing and editing) References Sharma A, Lavie CJ, Borer JS, Vallakati A, Goel S, Lopez-Jimenez F, Arbab-Zadeh A, Mukherjee D, Lazar JM. Meta-analysis of the relation of body mass index to all-cause and cardiovascular mortality and hospitalization in patients with chronic heart failure. Am. J. Cardiol. [Internet] Elsevier Inc.; 2015 [cited 2021 Apr 17]; 115: 1428–1434Available from: https://pubmed.ncbi.nlm.nih.gov/25772740/. Kamioka H. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015 statement. Japanese Pharmacol. Ther. 2019; 47: 1177–1185. Zafrir B, Adir Y, Shehadeh W, Shteinberg M, Salman N, Amir O. The association between obesity, mortality and filling pressures in pulmonary hypertension patients; The “obesity paradox.” Respir. Med. [Internet] Elsevier Ltd; 2013; 107: 139–146Available from: http://dx.doi.org/10.1016/j.rmed.2012.10.019. Trammell AW, Hemnes AR, Tseng V, Shah AJ, Phillips LS, Hart CM. Influence of Body Weight and Diabetes Mellitus in Patients With Pulmonary Hypertension. Am. J. Cardiol. [Internet] Elsevier Inc.; 2020; 134: 130–137Available from: https://doi.org/10.1016/j.amjcard.2020.07.062. Min J, Feng R, Badesch D, Berman-Rosenzweig E, Burger C, Chakinala M, De Marco T, Feldman J, Hemnes A, Horn EM, Lammi M, Mathai S, McConnell JW, Presberg K, Robinson J, Sager J, Shlobin O, Simon M, Thenappan T, Ventetuolo C, Al-Naamani N. Obesity in pulmonary arterial hypertension the pulmonary hypertension association registry. Ann. Am. Thorac. Soc. 2021; 18: 229–237. Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: A reveal registry analysis. Chest [Internet] The American College of Chest Physicians; 2013; 144: 169–176Available from: http://dx.doi.org/10.1378/chest.11-3241. Strange G, Lau EM, Giannoulatou E, Corrigan C, Kotlyar E, Kermeen F, Williams T, Celermajer DS, Dwyer N, Whitford H, Wrobel JP, Feenstra J, Lavender M, Whyte K, Collins N, Steele P, Proudman S, Thakkar V, Keating D, Keogh A. Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand. Hear. Lung Circ. [Internet] Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ); 2018; 27: 1368–1375Available from: http://dx.doi.org/10.1016/j.hlc.2017.08.018. Weatherald J, Huertas A, Boucly A, Guignabert C, Taniguchi Y, Adir Y, Jevnikar M, Savale L, Jaïs X, Peng M, Simonneau G, Montani D, Humbert M, Sitbon O. Association Between BMI and Obesity With Survival in Pulmonary Arterial Hypertension. Chest [Internet] Elsevier Inc; 2018; 154: 872–881Available from: https://doi.org/10.1016/j.chest.2018.05.006. Frank RC, Min J, Abdelghany M, Paniagua S, Bhattacharya R, Bhambhani V, Pomerantsev E, Ho JE. Obesity Is Associated With Pulmonary Hypertension and Modifies Outcomes. J. Am. Heart Assoc. 2020; 9: e014195. Perrotta F, Nigro E, Mollica M, Costigliola A, D’agnano V, Daniele A, Bianco A, Guerra G. Pulmonary hypertension and obesity: Focus on adiponectin [Internet]. Int. J. Mol. Sci. MDPI AG; 2019 [cited 2021 Mar 31].Available from: https://pubmed.ncbi.nlm.nih.gov/30791536/. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler. Thromb. Vasc. Biol. [Internet] Arterioscler Thromb Vasc Biol; 2003 [cited 2021 Mar 31]; 23: 85–89Available from: https://pubmed.ncbi.nlm.nih.gov/12524229/. Japp AG, Cruden NL, Amer DAB, Li VKY, Goudie EB, Johnston NR, Sharma S, Neilson I, Webb DJ, Megson IL, Flapan AD, Newby DE. Vascular Effects of Apelin In Vivo in Man. J. Am. Coll. Cardiol. [Internet] J Am Coll Cardiol; 2008 [cited 2021 Apr 1]; 52: 908–913Available from: https://pubmed-ncbi-nlm-nih-gov.liboff.ohsu.edu/18772060/. Robbins IM, Hemnes AR, Pugh ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman JH. High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ. Hear. Fail. [Internet] Lippincott Williams and Wilkins; 2014 [cited 2021 Mar 31]; 7: 116–122Available from: https://pubmed.ncbi.nlm.nih.gov/24297689/. McLaughlin V V., Shillington A, Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation [Internet] Circulation; 2002 [cited 2021 Mar 31]; 106: 1477–1482Available from: https://pubmed.ncbi.nlm.nih.gov/12234951/. Melenovsky V, Kotrc M, Borlaug BA, Marek T, Kovar J, Malek I, Kautzner J. Relationships between right ventricular function, body composition, and prognosis in advanced heart failure. J. Am. Coll. Cardiol. [Internet] J Am Coll Cardiol; 2013 [cited 2021 Mar 31]; 62: 1660–1670Available from: https://pubmed.ncbi.nlm.nih.gov/23916933/. De Schutter A, Lavie CJ, Kachur S, Patel DA, Milani R V. Body composition and mortality in a large cohort with preserved ejection fraction: Untangling the obesity paradox. Mayo Clin. Proc. [Internet] Elsevier Ltd; 2014 [cited 2021 Apr 1]; 89: 1072–1079Available from: https://pubmed-ncbi-nlm-nih-gov.liboff.ohsu.edu/25039037/. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-540969","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":28431597,"identity":"6c18beae-f9e6-489d-a0b7-6ca214f3e76b","order_by":0,"name":"Raju M 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Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yazan","middleName":"","lastName":"Zayed","suffix":""}],"badges":[],"createdAt":"2021-05-20 04:23:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-540969/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-540969/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":9624676,"identity":"0ef91235-37ef-4104-91e3-1326af71ad4f","added_by":"auto","created_at":"2021-05-26 19:34:49","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":114080,"visible":true,"origin":"","legend":"Forest plot for mortality amongst obese versus non-obese subjects in combined pre- and post- capillary pulmonary hypertension and pre-capillary pulmonary hypertension only.","description":"","filename":"FINALForestplotforobesityandPHTN.jpg","url":"https://assets-eu.researchsquare.com/files/rs-540969/v1/e79a349cfdcbb6f865a44212.jpg"},{"id":17145118,"identity":"8244b4ec-f0d5-4257-84f5-7d98e36b906a","added_by":"auto","created_at":"2022-01-10 02:42:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":249531,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-540969/v1/c750c562-feb7-4473-bf5a-e5d4f280bbf6.pdf"}],"financialInterests":"","formattedTitle":"Effect of Obesity on Mortality in Pulmonary Hypertension, Does Obesity Paradox Exist?","fulltext":[{"header":"Introduction","content":" \u003cp\u003eObese patients with left sided heart failure have higher survival rates compared to their non-obese counterparts, a phenomena known as obesity paradox [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Similar findings have been reported in patients with pre-capillary pulmonary hypertension (PH) also but the association of obesity paradox with mortality in PH remains controversial. This relationship, if any, is not well understood clinically or physiologically.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eTo further examine this association, we sought to examine the effect of obesity on PH mortality by performing a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) 2015 Statement guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A literature search utilizing major electronic databases including PubMed, Cochrane library, and Embase was performed using the MeSH term \u0026ldquo;obesity AND pulmonary hypertension\u0026rdquo;. Only studies with hemodynamic data obtained by right heart catheterization and reported mortality outcomes were included. We used the generic inverse variance to calculate the pooled hazards ratio of mortality using random effects model.\u003c/p\u003e \u003cp\u003eAfter the final review by two authors (RR, YZ), seven studies met inclusion criteria for the analysis of which four were prospective observational studies and three were retrospective registry-based studies. Two studies included subjects with pre-capillary PH, post-capillary PH and combined pre and post-capillary PH [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], while the other five studies included only subjects with pre-capillary PH [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. All studies classified obese individuals as those with body mass index (BMI)\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e. Five studies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] compared obese (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e) versus non-obese subjects while two studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] compared obese (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e) versus normal weight subjects (BMI 18-24.9 kg/m\u003csup\u003e2\u003c/sup\u003e). We performed a sensitivity analysis by including only studies that included patients with pre-capillary PH. The main outcome was all-cause mortality.\u003c/p\u003e "},{"header":"Results","content":" \u003cp\u003eThe final analysis included seven studies totaling 79,577 patients; 49,607 (62.3%) were obese subjects defined as BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e, and 29,970 (37.7%) non-obese or normal weight subjects. Obese subjects had significantly reduced mortality when compared to non-obese subjects in the mixed PH patient population (Hazard ratio 0.67, 95% CI 0.51\u0026ndash;0.87, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) as well as in subjects with pre-capillary PH (Hazard ratio 0.74; 95% CI 0.58\u0026ndash;0.96; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (Figure A).\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eOur study showed that obesity is present in 62.3% of subjects with PH and was associated with a significant reduction in mortality among subjects with both precapillary PH as well as combined pre and postcapillary PH when compared with non-obese subjects. This finding was consistent in all included studies except the study by Weatherald et al., who found no effect of obesity on mortality [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe mechanism of the protective effect of obesity on mortality in cardiovascular disease is unknown but a few hypotheses have been explored. Adiponectin, a hormone derived from adipocytes, is thought to play a protective role in cardiovascular diseases by decreasing inflammatory cytokines such as tumor necrosis factor \u0026alpha; levels and inhibition of NF-\u0026kappa;\u0026beta; activity [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. In a study by Kumada et al., low levels of adiponectin were associated with the development of coronary artery disease and myocardial infarction in humans [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. Similarly, in animal models of PH, it has been shown that adiponectin is associated with reduced smooth muscle cell proliferation and decreasing levels of inflammatory cytokines [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Thus, patients who are normal or underweight may lose the protective effect of adiponectin. In addition, adipose tissue secretes apelin, an adipokine, which is known to promote vasodilation by activating nitric oxide synthase [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Whether the vasodilatory effect of apelin exits in obese PH patients remains unknown and is an area for further research.\u003c/p\u003e\n\u003cp\u003eWhile these findings are interesting, they should be interpreted with caution for several reasons. First, the hemodynamic variables between the two patient groups were different. In the three of the included studies [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e], obese patients tended to have higher pulmonary artery wedge pressures suggesting that they may have occult left ventricular diastolic dysfunction despite meeting criteria for pre-capillary PH at the time of right heart catheterization [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, obese patients in the same studies had higher cardiac output [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e] and lower PVR [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e] which could also contribute to improved outcomes in these patients[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Second, rather than obesity conferring a protective effect, it is also possible that low BMI may simply be a manifestation of declining health due to right ventricular dysfunction. This decline in right ventricular failure may manifest as cardiac cachexia; characterized by congestion of hepatic and splanchnic beds, intestinal dysmotility and protein malabsorption [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. Third, BMI does not capture body composition accurately. The implication that higher BMI is related to higher fat mass is not necessarily true. Thus, a better predictor of mortality could be the total fat mass or the pattern of distribution of fat (central vs. peripheral). In a study of heart failure patients by Sutter et al., a J-shaped mortality curve was seen where patients with the lowest BMI and higher BMI (BMI\u0026thinsp;\u0026gt;\u0026thinsp;35 kg/m\u003csup\u003e2\u003c/sup\u003e) had higher mortality compared to the overweight BMI 25\u0026ndash;35 kg/m\u003csup\u003e2\u003c/sup\u003e group [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. On further analysis, it was found that having a higher lean body mass despite being overweight conferred a protective effect and that higher body fat percentage in the obese population was detrimental. A similar J-shaped mortality curve was also observed in patients with pre-capillary PH [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. While these studies did not examine the body mass composition, it is possible that the morbidly obese PH patients who had a higher mortality had a higher fat mass percentage.\u003c/p\u003e\n\u003cp\u003eOur analysis is limited by its heterogeneity. Many potential reasons account for this. First, studies included used various definitions of PH. To minimize the impact of the variation, we only included studies that reported hemodynamics obtained by right heart catheterization and also performed a sub-group analysis for patients with pre-capillary PH. Second, three of the seven included studies were retrospective. Given that PH is a rare disease, data gathering is often limited to retrospective data from registries. Third, the confounding variables used in studies differed which could have affected the hazard ratios obtained when studying the impact of obesity in PH patients.\u003c/p\u003e\n\u003cp\u003eIn summary, we found that obese PH patients had lower mortality compared to non-obese patients. This \u0026lsquo;obesity paradox\u0026rsquo; in PH is a noteworthy finding and warrants further studies. Given the pathobiologic complexities of PH, it is possible that there are different phenotypes of obesity that confer either protective or pathologic effects on pulmonary vascular disease. Future studies examining the association between BMI and PH may help better define this relationship by studying the effect of body composition and body fat distribution on outcomes in PH. With the precise causal effects of obesity in PH being unknown, future registry-based studies could increase long term follow up of patients and closely track body composition to more precisely determine the effect of obesity in PH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003enone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no conflicts of interests to declare related to this work\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eData available on request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eRaju Reddy (data curation, conceptualization, methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Akram Khan (methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Saminder Singh (data curation, conceptualization, methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Bashar Alzghoul (methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Sherri Gause (methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Nalini Colaco (methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Jeffrey Robinson (data curation, conceptualization, methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing); Yazan Zayed (data curation, conceptualization, methodology, investigation, writing \u0026ndash; original draft, writing \u0026ndash; reviewing and editing)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSharma A, Lavie CJ, Borer JS, Vallakati A, Goel S, Lopez-Jimenez F, Arbab-Zadeh A, Mukherjee D, Lazar JM. 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Proc.\u003c/em\u003e [Internet] Elsevier Ltd; 2014 [cited 2021 Apr 1]; 89: 1072\u0026ndash;1079Available from: https://pubmed-ncbi-nlm-nih-gov.liboff.ohsu.edu/25039037/.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"obesity, pulmonary hypertension, mortality, body mass index","lastPublishedDoi":"10.21203/rs.3.rs-540969/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-540969/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObesity is reported to have a protective effect on mortality in pulmonary hypertension (PH), a phenomenon known as obesity paradox. However, the data is conflicting with some studies showing decreased mortality while other studies found no effect of obesity on mortality. Therefore, we performed a meta-analysis to examine the effect of obesity on mortality in PH. Only patients with PH diagnosed by right heart catheterization were included. We also performed a sub-group analysis of subjects with pre-capillary PH only. A total of seven studies met the inclusion criteria with a sample size of 79,577 patients. Obese subjects had lower mortality compared to non-obese subjects in the mixed PH group (hazard ratio 0.67, 95% CI 0.51-0.87, P\u0026lt;0.00001) and in the pre-capillary PH group (hazard ratio 0.74; 95% CI 0.58-0.96; P\u0026lt;0.00001). Body mass index ≥ 30 kg/m\u003csup\u003e2\u003c/sup\u003e may be associated with reduced mortality but these results must be interpreted with caution.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Effect of Obesity on Mortality in Pulmonary Hypertension, Does Obesity Paradox Exist?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-26 19:34:48","doi":"10.21203/rs.3.rs-540969/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e61029d0-8707-48af-a7ba-25740ec47cc5","owner":[],"postedDate":"May 26th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":4578589,"name":"Pulmonology"}],"tags":[],"updatedAt":"2022-01-10T02:42:00+00:00","versionOfRecord":[],"versionCreatedAt":"2021-05-26 19:34:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-540969","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-540969","identity":"rs-540969","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}