Pulmonary hypertension: diagnostic method to test the true curative efficacy of a drug

Beyond PVR: A New Hemodynamic Law Integrating Intrapulmonary Arteriovenous Anastomoses and Gas Exchange | 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 Beyond PVR: A New Hemodynamic Law Integrating Intrapulmonary Arteriovenous Anastomoses and Gas Exchange Rosalba Vanni This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7706035/v4 This work is licensed under a CC BY 4.0 License Status: Posted Version 4 posted You are reading this latest preprint version Show more versions Abstract The evaluation of drug efficacy in pulmonary hypertension (PH) relies on decreased pulmonary vascular resistance (PVR). However, PVR may provide a misleading interpretation of pulmonary hemodynamics if the role of intrapulmonary arteriovenous anastomoses (IPAVA) is neglected. We coupled the hemodynamic/metabolic data to develop a new hemodynamic law. The pulmonary circuit, with open IPAVA, was modelled like an electrical circuit with two resistances in parallel: arteriolar resistance (R \(\dot{\text{Q}}\) p ) and IPAVA resistance (R \(\dot{\text{Q}}\) IPAVA ). This model was applied to healthy subjects under acetazolamide (ACZ) and placebo during acute hypoxia ( F IO 2 = 0.125) at rest and during exercise in normoxia. Under resting hypoxia, ACZ decreased PVR (-0.25 WU vs. placebo), but there was a contemporary drastic decrease in R \(\dot{\text{Q}}\) IPAVA (-24.05 WU), which masked a reduction in effective capillary flow ( \(\dot{\text{Q}}\) p = -1.08 L/min) and \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) . During heavy exercise in normoxia/placebo, the blood flow through IPAVA ( \(\dot{\text{Q}}\) IPAVA ) was 2.4% of cardiac output ( \(\dot{\text{Q}}\) T ), whereas ACZ increased \(\dot{\text{Q}}\) IPAVA to ~ 15% of \(\dot{\text{Q}}\) T , reducing \(\dot{\text{Q}}\) p by ~ 11% and \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) by ~ 9%. Crucially, the gas exchange extraction efficiency ( \(\text{ϵ}\) = \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) / \(\dot{\text{Q}}\) p) remained stable ( \(\text{ϵ}\) : 0.199 placebo vs. 0.205 ACZ), indicating that the \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) impairment was mechanistically driven solely by flow redistribution rather than by carbonic anhydrase inhibition. These results suggest that therapeutic efficacy based solely on PVR may be a “hemodynamic illusion” with potential iatrogenic risks for the patient. A new paradigm coupling hemodynamic/metabolic parameters (Lavoisier's mass law) is needed to enable precision medicine, more accurate pharmacovigilance and the development of new therapeutic targets for pulmonary vascular diseases. Biophysics Cardiac & Cardiovascular Systems Physiology Clinical Pharmacology Pulmonary vascular resistance Intrapulmonary arteriovenous anastomoses Pulmonary hemodynamics Acetazolamide Pulmonary gas exchange Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 4 posted You are reading this latest preprint version Show more versions 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7706035","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585260197,"identity":"23ac3d81-56fb-4dca-b982-cea79adb068d","order_by":0,"name":"Rosalba Vanni","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3577-9128","institution":"E.S.C.O.T.- Europe","correspondingAuthor":true,"prefix":"","firstName":"Rosalba","middleName":"","lastName":"Vanni","suffix":""}],"badges":[],"createdAt":"2025-09-24 17:28:04","currentVersionCode":4,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7706035/v4","doiUrl":"https://doi.org/10.21203/rs.3.rs-7706035/v4","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104397887,"identity":"f7e2a8b8-590f-443e-bb15-121cea1c7620","added_by":"auto","created_at":"2026-03-11 11:58:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":857740,"visible":true,"origin":"","legend":"","description":"","filename":"BeyondPVRNEW.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7706035/v4_covered_b9cb1610-4e2c-4fa9-acf0-9365a97ae149.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eBeyond PVR: A New Hemodynamic Law Integrating Intrapulmonary Arteriovenous Anastomoses and Gas Exchange\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"E.S.C.O.T.-Europe","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"Pulmonary vascular resistance, Intrapulmonary arteriovenous anastomoses, Pulmonary hemodynamics, Acetazolamide, Pulmonary gas exchange","lastPublishedDoi":"10.21203/rs.3.rs-7706035/v4","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7706035/v4","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe evaluation of drug efficacy in pulmonary hypertension (PH) relies on decreased pulmonary vascular resistance (PVR). However, PVR may provide a misleading interpretation of pulmonary hemodynamics if the role of intrapulmonary arteriovenous anastomoses (IPAVA) is neglected.\u003c/p\u003e \u003cp\u003eWe coupled the hemodynamic/metabolic data to develop a new hemodynamic law. The pulmonary circuit, with open IPAVA, was modelled like an electrical circuit with two resistances in parallel: arteriolar resistance (R\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003ep\u003c/sub\u003e) and IPAVA resistance (R\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eIPAVA\u003c/sub\u003e). This model was applied to healthy subjects under acetazolamide (ACZ) and placebo during acute hypoxia (\u003cem\u003eF\u003c/em\u003eIO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.125) at rest and during exercise in normoxia.\u003c/p\u003e \u003cp\u003eUnder resting hypoxia, ACZ decreased PVR (-0.25 WU vs. placebo), but there was a contemporary drastic decrease in R\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eIPAVA\u003c/sub\u003e (-24.05 WU), which masked a reduction in effective capillary flow (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003ep = -1.08 L/min) and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{V}}\\text{C}{\\text{O}}_{2}\\)\u003c/span\u003e\u003c/span\u003e. During heavy exercise in normoxia/placebo, the blood flow through IPAVA (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eIPAVA\u003c/sub\u003e) was 2.4% of cardiac output (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eT\u003c/sub\u003e), whereas ACZ increased \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eIPAVA\u003c/sub\u003e to ~\u0026thinsp;15% of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003e\u003csub\u003eT\u003c/sub\u003e, reducing \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003ep by ~\u0026thinsp;11% and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{V}}\\text{C}{\\text{O}}_{2}\\)\u003c/span\u003e\u003c/span\u003e by ~\u0026thinsp;9%. Crucially, the gas exchange extraction efficiency (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{ϵ}\\)\u003c/span\u003e\u003c/span\u003e = \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{V}}\\text{C}{\\text{O}}_{2}\\)\u003c/span\u003e\u003c/span\u003e/\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{Q}}\\)\u003c/span\u003e\u003c/span\u003ep) remained stable (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{ϵ}\\)\u003c/span\u003e\u003c/span\u003e: 0.199 placebo vs. 0.205 ACZ), indicating that the \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\dot{\\text{V}}\\text{C}{\\text{O}}_{2}\\)\u003c/span\u003e\u003c/span\u003e impairment was mechanistically driven solely by flow redistribution rather than by carbonic anhydrase inhibition.\u003c/p\u003e \u003cp\u003eThese results suggest that therapeutic efficacy based solely on PVR may be a \u0026ldquo;hemodynamic illusion\u0026rdquo; with potential iatrogenic risks for the patient.\u003c/p\u003e \u003cp\u003eA new paradigm coupling hemodynamic/metabolic parameters (Lavoisier's mass law) is needed to enable precision medicine, more accurate pharmacovigilance and the development of new therapeutic targets for pulmonary vascular diseases.\u003c/p\u003e \u003cp\u003e \u003cdiv description=\"\" class=\"Drawing\" id=\"777909638\" name=\"Immagine 1\"\u003e\u003c/div\u003e \u003c/p\u003e","manuscriptTitle":"Beyond PVR: A New Hemodynamic Law Integrating Intrapulmonary Arteriovenous Anastomoses and Gas Exchange","msid":"","msnumber":"","nonDraftVersions":[{"code":4,"date":"2026-02-26 18:00:30","doi":"10.21203/rs.3.rs-7706035/v4","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}},{"code":3,"date":"2026-02-03 19:44:56","doi":"10.21203/rs.3.rs-7706035/v3","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}},{"code":2,"date":"2026-01-20 19:58:03","doi":"10.21203/rs.3.rs-7706035/v2","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}},{"code":1,"date":"2025-09-26 03:14:14","doi":"10.21203/rs.3.rs-7706035/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":"03a5bbd1-d9f8-4cae-b084-1f39e989b04b","owner":[],"postedDate":"February 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63582329,"name":"Biophysics"},{"id":63582330,"name":"Cardiac \u0026 Cardiovascular Systems"},{"id":63582331,"name":"Physiology"},{"id":63582332,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2025-09-26T03:14:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-26 18:00:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v4","identity":"rs-7706035","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7706035","identity":"rs-7706035","version":["v4"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}