Systolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence

HomeHypertensionVol. 80, No. 3Systolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSystolic Blood Pressure and Cardiovascular Risk: Straightening the Evidence Cian P. McCarthy and Pradeep Natarajan Cian P. McCarthyCian P. McCarthy Correspondence to: Cian McCarthy, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5013-6112 Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (C.P.M., P.N.). Search for more papers by this author and Pradeep NatarajanPradeep Natarajan https://orcid.org/0000-0001-8402-7435 Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (C.P.M., P.N.). Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston (P.N.). Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston (P.N.). Search for more papers by this author Originally published15 Feb 2023https://doi.org/10.1161/HYPERTENSIONAHA.123.20788Hypertension. 2023;80:577–579This article is a commentary on the followingGenetically Predicted Differences in Systolic Blood Pressure and Risk of Cardiovascular and Noncardiovascular Diseases: A Mendelian Randomization Study in Chinese AdultsFor the past several decades, hypertension has been defined as the blood pressure (BP) threshold at, or above, which the benefits of treating BP outweigh the harms of treatment as determined by randomized clinical trials.1 However, while this notion of hypertension remains unchanged, the systolic BP (SBP) and diastolic BP thresholds at which hypertension is diagnosed have gradually been reduced as clinical trials demonstrated the efficacy of antihypertensive medications on reducing cardiovascular events at increasingly lower BP cut-offs.2 The BP level at which treatment is no longer efficacious remains uncertain.See related article, pp 566–576Epidemiology studies play a major role in examining the associations between SBP and diastolic BP and cardiovascular disease to inform the design of clinical trials, and BP thresholds and targets for treatment recommended by clinical guidelines. Observational studies found that the cardiovascular risk associated with BP may begin and rise in a linear manner at BP levels within ranges categorized by guidelines as normal or even optimal.3,4 Furthermore, observational data suggest that the relative risk associated with a fixed increase in BP may be higher for younger individuals than older individuals,3 and also reported conflicting data regarding sex differences in the relative risk of cardiovascular disease associated with hypertension.5,6 Nevertheless, interpretation of observational studies is tempered by the possibilities of residual confounding or reverse causation.Bolstered by the contemporary expansion of human genetic datasets, Mendelian randomization (MR) analyses have gained popularity for prioritizing causal relationships with less risk for confounding. These analyses use naturally occurring genetic variations, randomly allocated and fixed at conception, as instrumental variables for the specific risk factor of interest and examine their potential causal effects on the desired outcome. MR analyses to date have found linear relationships between both physiologic SBP and diastolic BP values and cardiovascular events among persons of largely European ancestry in the United States and United Kingdom.7,8 However, the epidemiology of hypertension is varied by geography and ancestry. As a result, the generalizability of these findings is not well understood but are important in the context of hypertension’s global importance as a cardiovascular disease risk factor.In this issue of Hypertension, Clarke and colleagues9 solidify and expand on the results from these prior analyses using the China Kadoorie Biobank. The investigators identified 489 495 adults living in China between 40 and 79 years of age without prior cardiovascular disease of whom 86 060 had available genetic data. Utilizing the larger observational cohort, the investigators first examined the association between SBP and cardiovascular and noncardiovascular diseases using Cox proportional hazards models stratifying by age-at-risk, sex, and region and adjusting for education, tobacco use, alcohol consumption, and body mass index. Among those with available genetic data, the investigators then constructed genetic risk scores to examine the association between genetically predicted SBP and cardiovascular and noncardiovascular outcomes. Beginning at an SBP of 120 mm Hg, the investigators found a log-linear relationship between SBP and each of their cardiovascular outcomes of interest including ischemic stroke, intracerebral hemorrhage, major coronary events, and major vascular events in both the observational and MR analyses. Notably, a 10 mm Hg increase in SBP was associated with a 2-fold higher relative risk of intracerebral hemorrhage than for ischemic stroke or major coronary events. The investigators found that the hazard ratios for major vascular events for a fixed SBP increase were 2-fold higher for younger individuals (age, 40–54 years) compared to older individuals (age, 70–79 years) in both observational and MR analyses with statistically significant interaction tests. Although the observational analysis found that men had higher relative risk of major vascular events than women, there was no statistically significant interaction for sex in the MR analysis. Lastly, the investigators found no association between SBP and diabetes or chronic kidney disease in the genetic analysis.The findings from this study add to the growing amount of epidemiological evidence demonstrating that the risk of cardiovascular events increases in a linear pattern at least at a SBP beginning at 120 mm Hg.3,7,8 Combined with a large meta-analysis of individual patient-level data from 48 randomized clinical trials, demonstrating that a fixed absolute reduction in SBP reduced cardiovascular events with no evidence of effect modification down to a SBP of 120 mm Hg,10 there is now accumulating evidence to suggest that treating BP above a SBP of 120 mm Hg may prevent cardiovascular events. Accordingly, one might ask, should all individuals with an SBP >120 mm Hg be treated with antihypertensive medications? And as the present genetic and prior epidemiologic studies demonstrate even greater relative risks for younger individuals, should we implement such thresholds earlier in life? To answer this question, it is important to recognize that the decision to initiate any medical treatment is determined by the net benefit or harm and the cost-effectiveness of that treatment. This tradeoff is determined by the difference between the absolute reduction in the outcome the therapy is preventing (which is proportional to the absolute risk of that outcome for an individual) and the absolute risk of harm caused by the treatment. For many people with an SBP between 120 mm Hg and 140 mm Hg, including younger individuals, their absolute risk of cardiovascular events in the short to intermediate future may not be sufficiently high to exceed this net benefit/harm threshold. Yet, for certain individuals with an SBP within this range who have additional cardiovascular risk factors treating their blood pressure is likely to be beneficial. How can we identify these individuals? Prediction models of 10-year absolute cardiovascular risk have gained popularity in recent international guidelines. Additional risk factors not captured by the prediction models may also be considered to reclassify risk. For younger individuals, polygenic risk scores may be helpful in identifying high-risk individuals meriting antihypertensives earlier.11This study by Clarke and colleagues also provides important insights regarding the influence of sex on the cardiovascular risk associated with SBP. Observational studies have yielded conflicting results as to whether men and women have the same cardiovascular risk for a given SBP range with uncertainty over residual confounding.5,6 As MR largely mitigates this concern, the results of this study suggest that the cardiovascular risk associated with SBP may be similar for men and women. Further studies are needed to understand the mechanisms leading to the empiric discrepancies in observational analyses.Elevated SBP remains the foremost modifiable risk factor for attributable cardiovascular mortality globally.12 A substantial proportion of western populations have a SBP between 120 mm Hg and 140 mm Hg contributing a large burden of excess cardiovascular events.13 The results of MR studies including this study by Clarke and colleagues,9 combined with a recent meta-analysis of clinical trial data,10 highlight further opportunities to prevent cardiovascular events with lower BP treatment thresholds for high-risk individuals (Figure 1).Download figureDownload PowerPointFigure 1. The unmet need for cardiovascular risk reduction at blood pressure levels below hypertension diagnostic threshold. MVE indicates major vascular events; and SBP, systolic blood pressure.Article InformationSources of FundingC.P. McCarthy is supported by the NHLBI T32 postdoctoral training grant (5T32HL094301-12). P. Natarajan is supported by grants from the National Heart Lung and Blood Institute (R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), National Human Genetics Research Institute (U01HG011719), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125782), Foundation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine).Disclosures C.P. McCarthy has received consulting fees from Abbott Laboratories unrelated to the present work. P. Natarajan reports prior or current grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Genentech, GV, Blackstone Life Sciences, Foresite Labs, and Novartis; scientific advisory board membership at Esperion Therapeutics, Preciseli, and TenSixteen Bio; a patent issued for helical synthetic peptides that stimulates cellular cholesterol efflux licensed to Artery Therapeutics; and spousal employment at Vertex, all unrelated to the present work.FootnotesFor Sources of Funding and Disclosures, see page 579.The opinions expressed in this article are not necessarily those of the editors nor the American Heart Association.Correspondence to: Cian McCarthy, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA. Email CMCCARTHY37@PARTNERS.ORGReferences1. Rose G. Sick individuals and sick populations.Int J Epidemiol. 1985; 14:32–38. doi: 10.1093/ije/14.1.32CrossrefMedlineGoogle Scholar2. 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Relationship between blood pressure and incident cardiovascular disease: linear and nonlinear Mendelian randomization analyses.Hypertension. 2021; 77:2004–2013. doi: 10.1161/hypertensionaha.120.16534LinkGoogle Scholar9. Clarke R, Wright N, Walters R, Gan W, Guo Y, Millwood IY, Yang L, Chen Y, Lewington S, Lv J, et al. Genetically-predicted differences in systolic blood pressure and risk of cardiovascular and non-cardiovascular diseases: a Mendelian randomization study in Chinese adults.Hypertension. 2023; 80:566–576. doi: 10.1161/HYPERTENSIONAHA.122.20120LinkGoogle Scholar10. Blood Pressure Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis.Lancet. 2021; 397:1625–1636doi: 10.1016/S0140-6736(21)00590-0CrossrefMedlineGoogle Scholar11. Cho SMJ, Koyama S, Ruan Y, Lannery K, Wong M, Ajufo E, Lee H, Khera AV, Honigberg MC, Natarajan P. Measured blood pressure, genetically predicted blood pressure, and cardiovascular disease risk in the UK biobank.JAMA Cardiol. 2022; 7:1129–1137. doi: 10.1001/jamacardio.2022.3191CrossrefMedlineGoogle Scholar12. Vaduganathan M, Mensah GA, Turco Justine V, Fuster V, Roth GA. The global burden of cardiovascular diseases and risk.J Am Coll Cardiol. 2022; 80:2361–2371. doi: 10.1016/j.jacc.2022.11.005CrossrefMedlineGoogle Scholar13. Karmali KN, Ning H, Goff DC, Lloyd-Jones DM. Identifying individuals at risk for cardiovascular events across the spectrum of blood pressure levels.J Am Heart Assoc. 2015; 4:e002126doi: 10.1161/JAHA.115.002126LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. 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Hypertension. 2023;80:566-576 March 2023Vol 80, Issue 3 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.123.20788PMID: 36791225 Originally publishedFebruary 15, 2023 KeywordsEditorialsMendelian randomizationsystolic blood pressurecardiovascular riskPDF download Advertisement SubjectsEpidemiologyHigh Blood PressurePrimary Prevention