Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘High-sensitivity cardiac troponin and natriuretic peptide with risk of lower-extremity peripheral artery disease: the Atherosclerosis Risk in Communities (ARIC) Study’†, by K. Matsushita et al., on page 2412. Atherosclerotic disease is a pan-vascular process involving the coronary, cerebral, and peripheral arteries. Peripheral artery disease (PAD) is under-recognized by patients and health care providers alike, affects greater than 200 million people worldwide, and is strongly associated with incident coronary and cerebrovascular morbidity and mortality.1–5 Though classical descriptions of PAD symptoms invoke exertional extremity pain relieved by rest, accounts of claudication by the patient are in reality an exception. Instead, most patients are asymptomatic, present with atypical pain, and an additional unfortunate minority present with a threatened limb. Nonetheless, for those diagnosed with PAD, a range of evidence-based treatment options, including cardiovascular preventive measures, supervised exercise, antithrombotic medications, and catheter interventions or surgery to restore circulation are available.6 These treatments can improve quality of life, functional status, alleviate symptoms, and reduce mortality. The asymmetry between the recognition of PAD and the ability to offer meaningful treatments to patients suggests that tools that aid in the early identification of patients with or at risk of PAD may support efforts toward preventive, medical, and, when appropriate, interventional treatment strategies. To this end, there has been escalating interest in the potential role of cardiovascular biomarkers to improve the identification of patients with PAD. In this issue of the European Heart Journal, Matsushita and colleagues present their study exploring the utility of high-sensitivity cardiac troponin (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) as predictors of incident PAD and critical limb ischaemia (CLI).7 These candidate biomarkers, which have demonstrated utility in predicting cardiovascular risk in stable settings and beyond the coronary bed in prior studies, were evaluated in a diverse cohort of 12 288 patients without prevalent PAD from the Atherosclerotic Risk in Communities (ARIC) Study.8–10 The mean age of study patients was nearly 57 years, 55.7% were women, and 24.7% were black patients. The hs-cTnT and NT-proBNP levels were measured using prospectively collected serum samples, and clinical PAD and CLI were identified using previously validated ICD-9 discharge codes. The association between each cardiac biomarker with incident PAD and CLI was quantified according to five assay level categories, and adjusted for potential confounders using three different models incorporating cardiovascular risk factors. An independent dose-response association of hs-cTnT and NT-proBNP with incident PAD was discovered, with an approximately eight-fold higher risk among patients in the highest biomarker level groups (corresponding to the 99th percentile of healthy subjects) with consistently higher hazard ratios for NT-proBNP compared with hs-cTnT. Among patients who were identified as having CLI, the highest category of hs-cTnT was associated with ∼24-fold risk, and NT-proBNP was associated with a ∼10-fold risk of CLI. Overall, both biomarkers were found to be more strongly correlated with CLI than PAD without CLI. The analysis was then repeated with stratification by demographic and clinical subgroups of particular interest, demonstrating consistent associations between biomarker levels and incident disease. Overall, this is a rigorously conducted observational study, using prospectively collected serum samples from a large historical cohort identifying significant associations between hs-cTnT and NT-proBNP levels and incident PAD and CLI. Among patients in the highest category of biomarker levels, after adjustment for some demographic factors, the association with incident disease was very strong. However, it should be noted that incorporating an adjustment model accounting for many traditional cardiovascular risk factors attenuated the final magnitude of association. Additionally, while the authors should be commended for formally evaluating the incremental change in risk discrimination utilizing these biomarkers, despite the strong association between hs-cTnT and CLI, hs-cTnT was unable to improve risk discrimination of CLI, and NT pro-BNP or both biomarkers together moved the needle only slightly. No combination of biomarkers led to significant changes in discrimination for PAD. This is likely because a model comprised of standard cardiovascular risk factors has relatively good discrimination for PAD and CLI, as evidenced by the high baseline c-statistic. In the context of clinical practice, broad application of these biomarkers for risk prediction will likely require additional validation in external data sets to determine their full potential. As with many other biomarkers, whether utilizing them to guide therapy can ultimately improve clinical outcomes or reduce incident PAD or CLI will require additional study. Matsushita and colleagues have shed light upon an emerging and particularly suitable arena for biomarker research with this important study. Early identification of PAD and subsequent treatment may in fact have the potential to improve quality of life, reduce devastating morbidities such as major limb-related events, and extend longevity. After a period of relative quiescence, novel therapies for PAD are again emerging. In the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) study, a large multicenter, randomized placebo-controlled trial comparing combination low-dose rivaroxaban and aspirin with aspirin alone for prevention of cardiovascular events among patients with coronary artery disease or PAD on optimal medical therapy, among 7470 with PAD, combination therapy reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke by 28%, and reduced major adverse limb events including amputation by 46%, without a significant increase in fatal or critical organ bleeding.11 In a substudy of the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 54) study evaluating long-term use of ticagrelor in patients with prior myocardial infarction, placebo-treated patients with PAD experienced a 1.6 times greater likelihood of major adverse cardiovascular events.12 Among the 1143 patients with known PAD in the study, ticagrelor in addition to aspirin reduced the risk of major adverse limb events by 35%, and achieved greater absolute risk reduction of major adverse cardiovascular events compared with those without PAD. Finally, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolucumab was shown in the FOURIER (Further Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial to markedly reduce low-density lipoprotein cholesterol and cardiovascular events in patients with atherosclerotic disease on a background of moderate- or high-intensity statin therapy. Among 3542 patients in the study with PAD and no history of myocardial infarction or stroke, evolocumab reduced the composite cardiovascular endpoint with greater absolute risk reduction among patients with PAD and additionally reduced the risk of major adverse limb events in all patients.13 These studies underscore PAD as a modifiable disease process, and should serve as encouragement that identifying patients, using all the tools at our disposal, could have great impact. Biomarkers have been used widely across cardiovascular medicine to aid in diagnosis, inform risk models, and alter pharmacotherapuetic and procedural choices. Yet, biomarkers exist in various states of maturity in different disciplines (Take home figure). While one can no longer imagine triaging coronary disease patients without using cardiac troponins, biomarkers in PAD remain largely exploratory at this time. Whether biomarkers in PAD are simply risk markers or may serve as modifiable surrogate endpoints remains to be seen. Deciding whether a biomarker should be directly targeted likely depends to an extent on whether it is on the causal pathway to disease. For example, while hs-CRP has been linked to vascular risk, a causal role in atherogenesis is yet unproven. Still, in the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) study, hs-CRP was used to identify patients for treatment with the fully humanized antibody canakinumab, which targets IL-1B, the product of the macrophage NLRP3 inflammasome, a receptor of the immune system through which LDL is linked to atherogenesis.14,15 Certainly, strategies that lower troponin and BNP levels may reduce all sorts of cardiovascular endpoints, including PAD-related ones, but further studies will need to establish what role these and other more comprehensive biomarker panels may have not only in more precise risk prognostication, but in altering therapies. With this study, Matsushita and colleagues have laid the foundation for this essential future work. Take home figure View largeDownload slide Evolving use of biomarkers in cardiovascular disease. Cardiac biomarkers have been widely adopted across cardiovascular medicine and continue to evolve. Currently available biomarkers exist in various states of clinical maturity. Biomarkers coded in red represent those that are no longer commonly used or have been replaced by other biomarkers. Biomarkers coded in yellow represent those that are occasionally used or have as yet uncertain clinical value. Biomarkers coded in green represent those that are commonly used in clinical practice. AF, atrial fibrillation; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; CAD, coronary artery disease; CHF, congestive heart failure; CK-MB, creatine kinase-MB; CRP, c-reactive protein; hs-CRP, high sensitivity c-reactive protein; hs-troponin, high sensitivity troponin; IL-6, interleukin 6; LAD, lactate dehydrogenase; NT-proBNP, n-terminal prohormone of brain natriuretic peptide; PAD, peripheral artery disease. Take home figure View largeDownload slide Evolving use of biomarkers in cardiovascular disease. Cardiac biomarkers have been widely adopted across cardiovascular medicine and continue to evolve. Currently available biomarkers exist in various states of clinical maturity. Biomarkers coded in red represent those that are no longer commonly used or have been replaced by other biomarkers. Biomarkers coded in yellow represent those that are occasionally used or have as yet uncertain clinical value. Biomarkers coded in green represent those that are commonly used in clinical practice. AF, atrial fibrillation; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; CAD, coronary artery disease; CHF, congestive heart failure; CK-MB, creatine kinase-MB; CRP, c-reactive protein; hs-CRP, high sensitivity c-reactive protein; hs-troponin, high sensitivity troponin; IL-6, interleukin 6; LAD, lactate dehydrogenase; NT-proBNP, n-terminal prohormone of brain natriuretic peptide; PAD, peripheral artery disease. Finally, we must comment on the senior author of this paper, the late Dr Alan T. Hirsch, a pioneer in the world of PAD. In one of the marvels of academic life, this paper will live on and help commemorate his immense contributions to the field and his enduring legacy. Conflict of interest: A.M. has nothing to disclose. D.L.B discloses the following relationships. Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; Board of Directors: Boston VA Research Institute and Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); Trustee: American College of Cardiology; and Unfunded Research: FlowCo, Merck, PLx Pharma, and Takeda. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. doi:10.1093/eurheartj/ehy106. References 1 Bhatt DL , Steg PG , Ohman EM , Hirsch AT , Ikeda Y , Mas JL , Goto S , Liau CS , Richard AJ , Rother J , Wilson PW , REACH Registry Investigators . International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis . JAMA 2006 ; 295 : 180 – 189 . Google Scholar CrossRef Search ADS PubMed 2 Steg PG , Bhatt DL , Wilson PW , D'Agostino R Sr , Ohman EM , Rother J , Liau CS , Hirsch AT , Mas JL , Ikeda Y , Pencina MJ , Goto S , REACH Registry Investigators . One-year cardiovascular event rates in outpatients with atherothrombosis . JAMA 2007 ; 297 : 1197 – 1206 . Google Scholar CrossRef Search ADS PubMed 3 Bhatt DL , Eagle KA , Ohman EM , Hirsch AT , Goto S , Mahoney EM , Wilson PW , Alberts MJ , D'Agostino R , Liau CS , Mas JL , Rother J , Smith SC Jr , Salette G , Contant CF , Massaro JM , Steg PG , REACH Registry Investigators . Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis . JAMA 2010 ; 304 : 1350 – 1357 . Google Scholar CrossRef Search ADS PubMed 4 Alberts MJ , Bhatt DL , Mas JL , Ohman EM , Hirsch AT , Rother J , Salette G , Goto S , Smith SC Jr , Liau CS , Wilson PW , Steg PG , REduction of Atherothrombosis for Continued Health Registry Investigators . Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry . Eur Heart J 2009 ; 30 : 2318 – 2326 . Google Scholar CrossRef Search ADS PubMed 5 Criqui MH , Aboyans V. Epidemiology of peripheral artery disease . Circ Res 2015 ; 116 : 1509 – 1526 . Google Scholar CrossRef Search ADS PubMed 6 Aboyans V , Ricco JB , Bartelink MEL , Bjorck M , Brodmann M , Cohnert T , Collet JP , Czerny M , De Carlo M , Debus S , Espinola-Klein C , Kahan T , Kownator S , Mazzolai L , Naylor AR , Roffi M , Rother J , Sprynger M , Tendera M , Tepe G , Venermo M , Vlachopoulos C , Desormais I ; ESC Scientific Document Group . 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by: the European Stroke Organization (ESO). The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS) . Eur Heart J 2018 ; 39 : 763 – 816 . Google Scholar CrossRef Search ADS PubMed 7 Matsushita K , Kwak L , Yang C , Pang Y , Ballew SH , Sang Y , Hoogeveen RC , Jaar B , Selvin E , Ballantyne CM , Sharrett AR , Folsom AR , Heiss G , Coresh J , Hirsch AT . High-sensitivity cardiac troponin and natriuretic peptide with risk of lower-extremity peripheral artery disease: the Atherosclerosis Risk in Communities (ARIC) Study . Eur Heart J 2018 ; 39 : 2412 – 2419 . 8 Bhatt DL. Troponin and the J-curve of diastolic blood pressure: when lower is not better . J Am Coll Cardiol 2016 ; 68 : 1723 – 1726 . Google Scholar CrossRef Search ADS PubMed 9 McEvoy JW , Chen Y , Rawlings A , Hoogeveen RC , Ballantyne CM , Blumenthal RS , Coresh J , Selvin E. Diastolic blood pressure, subclinical myocardial damage, and cardiac events: implications for blood pressure control . J Am Coll Cardiol 2016 ; 68 : 1713 – 1722 . Google Scholar CrossRef Search ADS PubMed 10 Everett BM , Brooks MM , Vlachos HE , Chaitman BR , Frye RL , Bhatt DL ; BARI 2D Study Group . Troponin and cardiac events in stable ischemic heart disease and diabetes . N Engl J Med 2015 ; 373 : 610 – 620 . Google Scholar CrossRef Search ADS PubMed 11 Anand SS , Bosch J , Eikelboom JW , Connolly SJ , Diaz R , Widimsky P , Aboyans V , Alings M , Kakkar AK , Keltai K , Maggioni AP , Lewis BS , Stork S , Zhu J , Lopez-Jaramillo P , O'Donnell M , Commerford PJ , Vinereanu D , Pogosova N , Ryden L , Fox KAA , Bhatt DL , Misselwitz F , Varigos JD , Vanassche T , Avezum AA , Chen E , Branch K , Leong DP , Bangdiwala SI , Hart RG , Yusuf S , COMPASS Investigators . Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial . Lancet 2017 ;doi: 10.1016/S0140-6736(17)32409-1. Published online ahead of print 10 November 2017. 12 Bonaca MP , Bhatt DL , Storey RF , Steg PG , Cohen M , Kuder J , Goodrich E , Nicolau JC , Parkhomenko A , Lopez-Sendon J , Dellborg M , Dalby A , Spinar J , Aylward P , Corbalan R , Abola MTB , Jensen EC , Held P , Braunwald E , Sabatine MS. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease . J Am Coll Cardiol 2016 ; 67 : 2719 – 2728 . Google Scholar CrossRef Search ADS PubMed 13 Bonaca MP , Nault P , Giugliano RP , Keech AC , Pineda AL , Kanevsky E , Kuder J , Murphy SA , Jukema JW , Lewis BS , Tokgozoglu L , Somaratne R , Sever PS , Pedersen TR , Sabatine MS. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) . Circulation 2018 ; 137 : 338 – 350 . Google Scholar CrossRef Search ADS PubMed 14 Verma S , Leiter LA , Bhatt DL. CANTOS ushers in a new calculus of inflammasome targeting for vascular protection-and maybe more . Cell Metab 2017 ; 26 : 703 – 705 . Google Scholar CrossRef Search ADS PubMed 15 Ridker PM , Everett BM , Thuren T , MacFadyen JG , Chang WH , Ballantyne C , Fonseca F , Nicolau J , Koenig W , Anker SD , Kastelein JJP , Cornel JH , Pais P , Pella D , Genest J , Cifkova R , Lorenzatti A , Forster T , Kobalava Z , Vida-Simiti L , Flather M , Shimokawa H , Ogawa H , Dellborg M , Rossi PRF , Troquay RPT , Libby P , Glynn RJ , CANTOS Trial Group . Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med 2017 ; 377 : 1119 – 1131 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Mar 22, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera