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Inflammation and Hypertension

2019; Lippincott Williams & Wilkins; Volume: 75; Issue: 2 Linguagem: Inglês

10.1161/hypertensionaha.119.14195

1524-4563

Dave L. Dixon, George F. Wohlford, Antonio Abbate,

Stress Responses and Cortisol

HomeHypertensionVol. 75, No. 2Inflammation and Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBInflammation and HypertensionCausal or Not? Dave L. Dixon, George F. Wohlford IV and Antonio Abbate Dave L. DixonDave L. Dixon Correspondence to Dave Dixon, Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, 1112 E Clay St, Box 980533, Richmond, VA 23298. Email E-mail Address: [email protected] From the Department of Pharmacotherapy and Outcomes Science, VCU School of Pharmacy, Richmond, VA (D.L.D., G.F.W.) , George F. Wohlford IVGeorge F. Wohlford IV From the Department of Pharmacotherapy and Outcomes Science, VCU School of Pharmacy, Richmond, VA (D.L.D., G.F.W.) and Antonio AbbateAntonio Abbate VCU Pauley Heart Center, Richmond, VA (A.A.). Originally published30 Dec 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.14195Hypertension. 2020;75:297–298This article is a commentary on the followingEffects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory RiskOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 30, 2019: Ahead of Print See related article, pp 477–482In recent years, significant progress has been made in understanding the role of innate and adaptive immunity in the pathogenesis of cardiovascular disease.1 There has also been intense research towards better understanding the link between inflammation and hypertension with a specific focus on the role inflammation plays in the development of hypertension in hopes of identifying novel drug therapy targets to treat hypertension.2,3 Both animal and human studies support that inflammation may lead to the development of hypertension; however, there remains a lack of robust clinical data to support causality. It has also been proposed that anti-inflammatory therapies may be effective to treat, and possibly, prevent hypertension but this has yet to be demonstrated in a clinical trial.3In this post hoc analysis performed by Rothman et al,4 the authors explored the relationship of hypertension and inflammatory biomarkers in the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial. Briefly, the CANTOS trial evaluated IL (interleukin)-1β blockade using the fully human monoclonal antibody canakinumab in patients with a history of myocardial infarction and residual systemic inflammation as shown by elevated serum levels of hsCRP (high-sensitivity C-reactive protein).5 Canakinumab reduced major adverse cardiovascular events by ≈15% after a median follow-up of 3.7 years, paralleled by a robust reduction in hsCRP as early as 3 months. In the current analysis, the authors sought to use the reported blood pressure data from the CANTOS trial to determine if treatment with canakinumab reduced incident hypertension or affected blood pressure values to shed light on the relationship between inflammation and hypertension.4 Patient-level data were used to compare baseline characteristics and inflammatory markers by quartile of systolic blood pressure at baseline. Statistical analyses used adjusted Cox proportional-hazard models to assess if increases in hsCRP for the 20% of trial participants without a reported history of hypertension before randomization were associated with new-onset hypertension. Additionally, the primary study analysis was completed in this subgroup with respect to major adverse cardiovascular events.The authors concluded that treatment with canakinumab was not associated with a reduced rate of incident hypertension or lower systolic blood pressure in the overall cohort.4 Additionally, a greater hsCRP response at 3 months was not associated with lower blood pressure despite being associated with lower cardiovascular event rates. Collectively, these observations suggest that the cardiovascular event reduction observed in CANTOS with canakinumab was not mediated through blood pressure lowering and that in this relatively homogenous group of patients, inhibition of IL-1β may not be sufficient to prevent incident hypertension.The authors appropriately pointed out that the CANTOS trial was not designed to determine whether or not inflammation played a causative role in the development of hypertension or if canakinumab reduced blood pressure.4 There are additional limitations and points of clarification regarding this analysis. Blood pressure data were available for 9549 of the 10 061 participants for both baseline and at 3 months. Nearly 80% of these patients had hypertension reported at baseline. Incident hypertension was defined as having a blood pressure >140/90 mm Hg recorded without having a history of hypertension reported by the investigator before randomization. Per the study protocol, a seated blood pressure was measured in triplicate following at least 5 minutes of rest and investigators were allowed to choose between using a validated automated device or a manual sphygmomanometer. It should be noted that standardized oscillometric devices for measuring blood pressure are more accurate than auscultatory methods and now preferred in clinical practice and research.6 Notably, blood pressure varies beat-to-beat and reproducibility is often prone to a large variability around measurements, especially when the auscultatory technique is used.6 This is an important limitation of the analysis given reliability issues with office blood pressure measurements.More importantly, CANTOS was a secondary prevention study which may make it difficult to observe a causal relationship with respect to incident hypertension given that hypertension was found to be highly prevalent in this population at baseline.4,5 Many enrolled patients were also receiving evidence-based therapies that may have masked a prior diagnosis of hypertension and led to misclassification of some patients at baseline. Thus, making it difficult to truly ascertain the effects of canakinumab on incident hypertension.Despite the aforementioned limitations, this analysis does provide several important insights. Canakinumab does not appear to reduce or increase systolic or diastolic blood pressure.4 This statement deserves highlighting as it is not unusual for anti-inflammatory drugs to be limited by a negative impact on blood pressure.7 Likewise, canakinumab has no clinically appreciable effects on low-density lipoprotein cholesterol.5 Together, these data broadly support the observation that the decrease in cardiovascular risk with canakinumab is via modulation of inflammation and not through the modulations of other traditional cardiovascular risk factors (Figure).Download figureDownload PowerPointFigure. Primary and secondary findings of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial. Canakinumab significantly decreased hsCRP (high-sensitivity C-reactive protein) and 3-point major adverse cardiovascular events (MACE) in the CANTOS trial without a clinically significant effect on LDL (low-density lipoprotein)-Cholesterol. A subgroup analysis of CANTOS showed canakinumab has no effect on blood pressure and does not reduce incident hypertension (HTN). Thus, the cardiovascular benefit observed with canakinumab is likely IL (interleukin)-1 mediated and not due to modification of traditional cardiovascular risk factors.In closing, the findings of this post hoc analysis showing that targeted inhibition of IL-1β does not alter blood pressure in a secondary prevention cohort does not prove that IL-1β is not involved in blood pressure control or incident hypertension. It is possible that canakinumab, or a similar strategy, could be efficacious in a different population as there are well-defined mechanisms by which inflammation may contribute to the development of hypertension.3 For example, inflammation downregulates nitric oxide synthase activity and causes an overproduction of reactive oxygen species, both of which contribute to endothelial dysfunction and oxidative stress, respectively, and are established factors in the development of hypertension.3 However, it is also possible that IL-1-independent inflammatory processes, yet to be identified, play a role in the development of hypertension, or that IL-1-mediated inflammation is not associated with hypertension at all. It remains unknown if IL-1-targeted treatment earlier in the hypertension etiopathogenesis would reduce blood pressure and incident hypertension, therefore, additional targeted studies are needed to address this question.Sources of FundingNone.DisclosuresA. Abbate has received research grants from Novartis and Swedish Orphan Biovitrum. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the American Heart Association.Correspondence to Dave Dixon, Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, 1112 E Clay St, Box 980533, Richmond, VA 23298. Email [email protected]eduReferences1. Buckley LF, Abbate A. Interleukin-1 blockade in cardiovascular diseases: a clinical update.Eur Heart J. 2018; 39:2063–2069. doi: 10.1093/eurheartj/ehy128CrossrefMedlineGoogle Scholar2. Solak Y, Afsar B, Vaziri ND, Aslan G, Yalcin CE, Covic A, Kanbay M. Hypertension as an autoimmune and inflammatory disease.Hypertens Res. 2016; 39:567–573. doi: 10.1038/hr.2016.35CrossrefMedlineGoogle Scholar3. Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension.Biomed Res Int. 2014; 2014:406960. doi: 10.1155/2014/406960CrossrefMedlineGoogle Scholar4. Rothman AMK, MacFadyen J, Thuren T, Webb A, Harrison DG, Guzik TJ, Libby P, Glynn RJ, Ridker PM. Effects of interleukin-1β inhibition on blood pressure, incident hypertension, and residual inflammatory risk: a secondary analysis of CANTOS.Hypertension. 2020; 75:477–482. doi: 10.1161/HYPERTENSIONAHA.119.13642LinkGoogle Scholar5. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377:1119–1131. doi: 10.1056/NEJMoa1707914CrossrefMedlineGoogle Scholar6. Muntner P, Shimbo D, Carey RM, Charleston JB, Gaillard T, Misra S, Myers MG, Ogedegbe G, Schwartz JE, Townsend RR, et al. Measurement of blood pressure in humans: a scientific statement from the American Heart Association.Hypertension. 2019; 73:e35–e66. doi: 10.1161/HYP.0000000000000087LinkGoogle Scholar7. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure.Arch Intern Med. 2005; 165:490–496. doi: 10.1001/archinte.165.5.IOI50013CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Chaudhari S, Pham G, Brooks C, Dinh V, Young-Stubbs C, Shimoura C and Mathis K (2022) Should Renal Inflammation Be Targeted While Treating Hypertension?, Frontiers in Physiology, 10.3389/fphys.2022.886779, 13 dos Santos R, de C. Oliveira L, Sena E, de Sousa D, Maia Filho A, Soriano R, da S. Lopes L, Branco L, de Oliveira A, Salgado H and Sabino J (2021) Acute autonomic effects of rose oxide on cardiovascular parameters of Wistar and spontaneously hypertensive rats, Life Sciences, 10.1016/j.lfs.2021.120107, 287, (120107), Online publication date: 1-Dec-2021. Myhre P, Selvaraj S and Solomon S (2021) Management of hypertension in heart failure with preserved ejection fraction: is there a blood pressure goal?, Current Opinion in Cardiology, 10.1097/HCO.0000000000000852, 36:4, (413-419), Online publication date: 1-Jul-2021. Rodilla E, López-Carmona M, Cortes X, Cobos-Palacios L, Canales S, Sáez M, Campos Escudero S, Rubio-Rivas M, Díez Manglano J, Freire Castro S, Vázquez Piqueras N, Mateo Sanchis E, Pesqueira Fontan P, Magallanes Gamboa J, González García A, Madrid Romero V, Tamargo Chamorro L, González Moraleja J, Villanueva Martínez J, González Noya A, Suárez-Lombraña A, Gracia Gutiérrez A, López Reboiro M, Ramos Rincón J and Gómez Huelgas R (2020) Impact of Arterial Stiffness on All-Cause Mortality in Patients Hospitalized With COVID-19 in Spain, Hypertension, 77:3, (856-867), Online publication date: 3-Mar-2021. Zhao X and Bie M (2020) Predictors for the development of preoperative oxygenation impairment in acute aortic dissection in hypertensive patients, BMC Cardiovascular Disorders, 10.1186/s12872-020-01652-5, 20:1, Online publication date: 1-Dec-2020. Shen Z, Han Y, Wang Y and Xie H (2020) LncRNA and mRNA expression profiles and functional networks of hyposalivation of the submandibular gland in hypertension, Scientific Reports, 10.1038/s41598-020-70853-x, 10:1, Online publication date: 1-Dec-2020. Lu X and Crowley S (2020) Actions of immune cells in the hypertensive kidney, Current Opinion in Nephrology & Hypertension, 10.1097/MNH.0000000000000635, 29:5, (515-522), Online publication date: 1-Sep-2020. Related articlesEffects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory RiskAlexander MK Rothman, et al. Hypertension. 2020;75:477-482 February 2020Vol 75, Issue 2 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.119.14195PMID: 31884858 Originally publishedDecember 30, 2019 PDF download Advertisement SubjectsHigh Blood PressureHypertension