The diagonal ear lobe crease (Frank's sign) as a marker of cardiovascular disease. A systematic review

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The diagonal ear lobe crease (Frank's sign) as a marker of cardiovascular disease. A systematic review
  calculate other important markers of cardiovascular risk like barore 󿬂 exsensitivity, at no extra cost and with considerable time saving.Supplementary data to this article can be found online at Groop has gained lecture fees from Eli Lilly, BoehringerIngelheim, Novartis, Genzyme, MSD, and Novo Nordisk, and he is anadvisory board member of Boehringer Ingelheim (global), Novartis(global), Abbott (local), and Cebix (global). He has received grantsfrom Eli Lilly, and Roche. The other authors declare that there is noduality of interest associated with this manuscript.The skilled assistance of Anna Sandelin is gratefully acknowledged.The study was supported by the Folkhälsan Research Foundation,Helsinki University Central Hospital Research Funds (EVO), theWilhelm and Else Stockmann Foundation, the Waldemar von FrenckellFoundation,theLivochHälsaFoundation,theSigneandAneGyllenbergFoundation, the Finnish Medical Society (Finska Läkaresällskapet), theNovo Nordisk Foundation and the Academy of Finland.LB.researcheddata,performedstatisticalanalyses,wrotepartof theanalysis software and wrote the manuscript. D.G. researched data,performed statistical analyses, contributed to discussion, and reviewedand edited the manuscript. V-P.M.performed statisticalanalyses,wrotepart of the analysis software, contributed to discussion, and reviewedandeditedthemanuscript.RMandAdTresearcheddata,contributedtodiscussion, and reviewed and edited the manuscript. M.R-B. and P.-H.G. contributed to discussion and reviewed and edited themanuscript. P.-H.G. is the guarantor of the study. References [1] Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C.Prediction of cardiovascular events and all-cause mortality with central haemo-dynamics: a systematic review and meta-analysis. Eur Heart J 2010;31:1865 – 71.[2] Chirinos JA, Zambrano JP, Chakko S, et al. Aortic pressure augmentation predictsadversecardiovasculareventsinpatientswithestablishedcoronaryarterydisease.Hypertension 2005;45:980 – 5.[3] Gordin D, Wadén J, Forsblom C, et al. Arterial stiffness and vascular complicationsin patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane)Study. Ann Med 2012;44:196 – 204.[4] Prince CT, Secrest AM, Mackey RH, Arena VC, Kingsley LA, Orchard TJ.Cardiovascular autonomic neuropathy, HDL cholesterol, and smoking correlatewith arterial stiffness markers determined 18 years later in type 1 diabetes.Diabetes Care 2010;33:652 – 7.[5] Millasseau SC, Kelly RP, Ritter JM, Chowienczyk PJ. Determination of age-relatedincreases in large artery stiffness by digital pulse contour analysis. Clin Sci2002;103:371 – 7.[6] Karamanoglu M, Feneley MP. On-line synthesis of the human ascending aorticpressure pulse from the  󿬁 nger pulse. Hypertension 1997;30:1416 – 24.[7] Chen CH, Nevo E, Fetics B, et al. Estimation of central aortic pressure waveformby mathematical transformation of radial tonometry pressure. Validation of generalized transfer function. Circulation 1997;95:1827 – 36.[8] Bland JM, Altman DG. Statistical methods for assessing agreement between twomethods of clinical measurement. Lancet 1986;1:307 – 10.[9] Wilkinson IB, Fuchs SA, Jansen IM, et al. Reproducibility of pulse wave velocityand augmentation index measured by pulse wave analysis. J Hypertens1998;16:2079 – 84.[10] Frimodt-Møller M, Nielsen AH, Kamper AL, Strandgaard S. Reproducibility of pulse-wave analysis and pulse-wave velocity determination in chronic kidneydisease. Nephrol Dial Transplant 2008;23:594 – 600.© 2014 Published by Elsevier Ireland Ltd. Ear lobe crease as a marker of coronary artery disease: A meta-analysis Ersilia Lucenteforte a , Marco Romoli b , Giovanni Zagli c , Gian Franco Gensini d ,Alessandro Mugelli a , Alfredo Vannacci a, ⁎ a NEUROFARBA, Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, Center for Integrative Medicine, Florence University,Careggi General Hospital, Florence, Italy b Florence University, Careggi General Hospital, Florence, Italy c  Anaesthesiology Unit, Florence University, Careggi General Hospital, Florence, Italy d Department of Critical Care Medicine and Surgery, Florence University, Careggi General Hospital, Florence, Italy a r t i c l e i n f o  Article history: Received 25 March 2014Accepted 2 April 2014Available online 13 April 2014 Keywords: Coronary artery diseaseEar lobe creaseMeta-analysis The possible relation between ear lobe crease (ELC) and coronaryartery disease (CAD) was described for the  󿬁 rst time by Frank in 1973inalettertotheeditoroftheNewEnglandJournalofMedicine[1].Theauthorobservedthat 19 outof 20 patientswithELC had1 ormore riskfactors for CAD, and he suggested that the presumptive relationshould have been tested.Since Frank's  󿬁 rst publication several trials and necropsy studieshave been debating the association between ELC and CAD. Since thenseveralarticles were published con 󿬁 rmingor denying this relationship.A recent review addressing the issue of cutaneous markers associatedwithatherosclerosis, concluded thatit appears prudentto examineELCin a suspected case of CAD as additional indirect evidence of atherosclerosis [2]. Two reviews also addressed the relationshipbetweendiagonalear-lobecreaseandatherosclerosisfocusingondental[3] and maxillofacial [4] implications, and concluded that ELC in combination with patient's medical history, vital signs and panoramicradiograph should be considered in atherosclerosis risk assessment.Despitethenotablenumberofpublicationsavailableonthissubject,acomprehensivereviewandameta-analysisofpublishedstudiesisstilllacking. The aim of our study was to provide a thorough evaluation andmeta-analysisofexistingevidenceregardingthepossibleroleofELCasamarker of CAD, providing also statistical indexes potentially useful forclinicians such as sensitivity, speci 󿬁 city and diagnostic odds ratios.The PUBMED database was searched for published reports, using thefollowingterms:( “ earlobe ” [tiab]OR  “ earlobe ” [tiab])AND “ crease* ” [tiab].Three investigators (EL, MR, and AV) independently reviewed titles andabstracts for relevance. Disagreements were resolved by discussion andconsensus.Mostreportswereretrievedforfull-textreview.Referencelistfrom these reports were hand searched and relevant articles were alsoretrieved for full-text review. Original articles published in Chinese,English, French, German, Italian, and Spanish and including number of  ⁎  Corresponding author at: NEUROFARBA, Department of Neurosciences, Psychology,Drug Research and Child Health, University of Florence, viale G. Pieraccini 6, 50139Florence, Italy. Tel.: +39 055 4271270; fax: +39 055 4271280. E-mail address:  alfredo.vannacci@uni 󿬁 .it (A. Vannacci).171 Letters to the Editor   subjects with and without CAD and with and without ELC wereconsidered. The search strategy yielded 120 papers, 36 papers wereincludedinthepresentwork[5 – 40].Onepaper[18]showedresultsoftwo different studies, thus 󿬁 nal sample included 37 different studies.For each study, patients with CAD were considered as cases andpatients without CAD as controls. Depending on the de 󿬁 nition of CADused in the different studies, cases were categorized as angiographicallyde 󿬁 ned (Ang cases), autoptically de 󿬁 ned (Aut cases), and clinicallyde 󿬁 ned(Clincases).Controlswerecategorizedascardiovascularcontrols(i.e. patients undergoing cardiovascular examinations for some medicalreason but not satisfying diagnostic criteria for CAD – CV controls) andnon-cardiovascular controls (i.e. healthy subjects with no symptom orhistory of cardiovascular disease – NonCV controls). Cases with ELC wereconsidered as true-positives, controls with ELC as false-positives, caseswithoutELCasfalse-negatives,andcontrolswithoutELCastrue-negatives.Sensitivities and speci 󿬁 cities with corresponding 95% con 󿬁 denceintervals(CIs)foreachstudywerecalculatedfromthecontingencytablesof true-positives, false-positives, false-negatives, and true negatives. Therandom-effectbivariatemodels[41],whichtakeintoaccountthenegativecorrelation between sensitivity and speci 󿬁 city, were used to calculatesummary estimates of sensitivity, speci 󿬁 city, and diagnostic odds ratio(DOR) with corresponding 95% con 󿬁 dence interval (CI). Heterogeneitywithin studies was assessed by Cochran's Q test. Potential sources of heterogeneity were investigated by carrying out several prede 󿬁 nedsubgroupanalyses:location,yearofpublication,samplesize,de 󿬁 nitionof patientwithCADandwithoutCAD,andselectedpatients'characteristics.Becausebivariatemodelsdonotconvergewithlessthanfourstudies,fewsubgroup analyses were performed by the use of univariate models [42].Heterogeneity across stratawas tested using the χ  2 statistic.All analyses were performed using Midas [43], Metandi [44], and Metan [45] commands in STATA 11.Eleven studies (5239 subjects, Inline Supplementary Table) wereconducted in USA, 14 (19,931 subjects) in Europe, and 12 (6018subjects)inothercountries(Argentina,Australia,Brazil,Canada,Israel, Japan, and Mexico). Twenty-three studies (9599 subjects) werepublishedbefore1989,and14after(21,598subjects).Nineteenstudies(3414 subjects) included less than 340 subjects, and 18 more (27,774subjects) (Table 1). With regard to de 󿬁 nition of cases and controls,16studies (6135 subjects) and two sub-studies (312 patients) usedangiographically or autoptically de 󿬁 ned cases, while 20 (24,053subjects) used clinically de 󿬁 ned cases. Twenty- 󿬁 ve studies (27,399subjects) used non-cardiovascular controls, while 12 (2789 subjects)and 1 sub-study (200 patients) used cardiovascular controls notsatisfying case criteria. One study (1000 patients) included mixedcasesandmixedcontrols,andalsoperformedasubgroupanalysis(112subjects) on angiographycally de 󿬁 ned cases and mixed controls. Thenumber of patients refers to all participants included in the presentanalysis, and in some cases marginally differs from those in thepublishedreports,generallyduetomissingdataforrelevantvariables.The sensitivities ranged between .21 (95% CI: .07 – .42) and .88 (95%CI:.76 – .95),whilespeci 󿬁 citiesrangedbetween.13(95%CI:.03 – .34)and.95(95%CI: .93 – .97)(Fig.1).Therewasheterogeneity betweenstudies.  Table 1 Pooled sensitivity, speci 󿬁 city, and diagnostic odds ratio (DOR) with corresponding 95% con 󿬁 dence interval (95% CI) overall and in strata of selected studies and patients'characteristics.No. of studies(no. of subjects)Sensitivity(95% CI)Speci 󿬁 city(95% CI)DOR (95% CI) p-Value forinteractionAll studies 37 (31,188) 0.62 (0.56 – 0.67) 0.67 (0.61 – 0.73) 3.27 (2.47 – 4.32) Stratum according to study characteristics LocationUSA 11 (5239) 0.64 (0.53 – 0.73) 0.64 (0.53 – 0.74) 3.18 (1.77 – 5.71) 0.589Europe 14 (19,931) 0.62 (0.54 – 0.69) 0.64 (0.52 – 0.74) 2.80 (1.86 – 4.22)Other countries 12 (6018) 0.60 (0.49 – 0.70) 0.72 (0.62 – 0.81) 4.03 (2.48 – 6.54)Year of paper publication ≤ 1989 23 (9599) 0.63 (0.57 – 0.70) 0.67 (0.58 – 0.74) 3.48 (2.43 – 4.99) 0.567 N 1989 14 (21,589) 0.59 (0.51 – 0.67) 0.67 (0.58 – 0.75) 2.94 (1.89 – 4.56)Sample size ≤ 340 subjects 19 (3414) 0.66 (0.60 – 0.71) 0.61 (0.52 – 0.68) 2.97 (2.00 – 4.41) 0.456 N 340 subjects 18 (27,774) 0.58 (0.50 – 0.65) 0.73 (0.65 – 0.79) 3.67 (2.53 – 5.31)De 󿬁 nition of cases a Angiography/autopsy cases 18 (6447) 0.64 (0.57 – 0.69) 0.66 (0.55 – 0.76) 3.44 (2.34 – 5.06) 0.653Clinical cases 20 (24,053) 0.59 (0.49 – 0.68) 0.68 (0.59 – 0.75) 3.02 (2.03 – 4.48)Type of controls a Non-cardiovascular controls (healthy subjects) 25 (27,399) 0.62 (0.55 – 0.69) 0.66 (0.58 – 0.73) 3.20 (2.35 – 4.37) 0.992Cardiovascular controls not satisfying case criteria 12 (2989) 0.57 (0.48 – 0.66) 0.71 (0.57 – 0.81) 3.21 (1.89 – 5.44)Type of study  a,b Studies comparing Ang/Aut cases versus NonCV controls 6 (3558) 0.68 (0.60 – 0.74) 0.62 (0.45 – 0.76) 3.38 (2.20 – 5.20) 0.978Studies comparing Ang/Aut cases versus CV controls 11 (2777) 0.59 (0.51 – 0.67) 0.71 (0.56 – 0.82) 3.56 (2.07 – 6.13)Studies comparing Clin cases versus NonCV controls 19 (24,053) 0.61 (0.51 – 0.69) 0.67 (0.58 – 0.75) 3.20 (2.16 – 4.73) Stratum according to patients characteristics GenderMale 8 (4770) 0.60 (0.53 – 0.68) 0.60 (0.49 – 0.71) 2.31 (1.40 – 3.82) 0.337Female 4 (425) 0.57 (0.48 – 0.66) 0.78 (0.55 – 0.91) 4.66 (1.22 – 17.91)Age ≤ 60 years 8 (3013) 0.58 (0.47 – 0.68) 0.81 (0.71 – 0.89) 5.99 (2.48 – 14.48) 0.264 N 60 years 8 (2221) 0.68 (0.54 – 0.78) 0.60 (0.48 – 0.70) 3.14 (1.54 – 6.40)History of diabetes c No 2 (1170) 0.52 (0.48 – 0.56) 0.74 (0.70 – 0.77) 3.79 (1.17 – 12.25) 0.520Yes 3 (1197) 0.61 (0.52 – 0.69) 0.60 (0.44 – 0.74) 2.35 (0.99 – 5.57)History of hypertension c No 2 (563) 0.54 (0.47 – 0.60) 0.71 (0.60 – 0.80) 3.01 (0.47 – 19.33) 0.810Yes 2 (1027) 0.53 (0.49 – 0.58) 0.73 (0.69 – 0.77) 3.92 (1.31 – 11.75) a The sum does not add up to the total because two studies included mixed patients or performed subgroup analyses. b Only one study compared Clin cases versus CV controls. c Because bivariate models do not converge with less than four studies, subgroup studies were combined by using univariate models.172  Letters to the Editor   The 37 studies showed an overall pooled sensitivity of .62 (95% CI:.56 – .67), speci 󿬁 city of .67 (95% CI: .61 – .73), and DOR of 3.27 (95% CI:2.47 – 4.32) (Table 1).DOR reached 4.03 (95% CI: 2.48 – 6.54) in studies conducted incountries other than USA and Europe, 3.48 (95% CI: 2.43 – 4.99), inthose published before 1989, and 3.67 (95% CI: 2.53 – 5.31) in studiesincluding more than 340 subjects (Table 1, Fig. 2a). With regard to de 󿬁 nition of cases and controls, DOR was higher in studies includingangiography or autopsy cases (3.44; 95% CI: 2.34 – 5.06), in thoseincluding cardiovascular controls not satisfying case criteria (3.21;95% CI: 1.89 – 5.44), and in those comparing angiography or autopsycases versus cardiovascular controls (3.56; 95% CI: 2.07 – 6.13). More-over, DOR seemed to be stronger among females (4.66; 95% CI: 1.22 – 17.91), in patients with less than 60 years (5.99; 95% CI: 2.48 – 14.48),without diabetes (3.79; 96% CI: 1.17 – 12.25), and with hypertension(3.92; 95% CI: 1.31 – 11.75) (Table 1, Fig. 2b). However, the overlap of  95% CIs and the high p-values for interaction demonstrated that allthese differences were not statistically signi 󿬁 cant.Basedonourlargemeta-analysis,coveringmorethan31,100subjects,itwouldbeexpectedthat 62% ofpatients withCADhaveELC, while67%ofthosewithoutCADwouldnothaveanyELC.Moreover,theriskofCADis 3.3-fold higher in patients with ELC compared to those without ELC.Therewasatrendtowardahigherriskinfemales,insubjectsunder60,insubjects without diabetes and in hypertensive patients, although thesedifferences were not statistically signi 󿬁 cant. No heterogeneity wasfound in different strata of selected study characteristics, showing asubstantial consistency among them.A minority of the studies included in the present meta-analysislooked at ELC as a marker of CAD calculating sensitivity and speci 󿬁 city[9,11,13,17,22,23,28,34,37,40]. In particular, the lowest sensitivity (51%)was reported in a study on 415 consecutive patients admitted to acardiology department for coronary angiography [13]; the same studyalsoreportedthehighestspeci 󿬁 city(85%).Thehighestsensitivity(85%)was instead found in an investigation on 530 patients undergoingelective surgery [22]; it is worth nothing that the study reporting thelowest speci 󿬁 city (43%), also registered a high sensitivity (78%) [40].Overall, sensitivity and speci 󿬁 city both ranged from 45 to 50% to85% in the different studies, with ELC being presented as a sensitivebut not speci 󿬁 c marker for CAD by some authors, as well as just theopposite from other authors; most investigations reported inter-mediate values for both indexes. These data are quite consistent withsensitivity and speci 󿬁 city values calculated by us for all 37 studiesincluded in our meta-analysis. In fact, as shown in Fig. 1, sensitivity ranged from 0.21 to 0.88, with a combined value of 0.62, andspeci 󿬁 city ranged from 0.13 to 0.95, with a combined value of 0.67.With regard to underlying mechanisms, although the link betweenELC and CAD was suggested by many studies and con 󿬁 rmed by thepresent meta-analysis, a pathophysiologic explanation for this associa-tionisstilllackingandonlyhypothesescanbeforwarded.Isunadoetal.have shown that both earlobe and myocardium are supplied by  “ endarteries ”  without the possibility for collateral circulation [46] andShoenfeld et al. found pre-arteriolar wall thickening and elastic- 󿬁 bertears on biopsysectionsfrom theearlobes atthe site of thecrease [30].Wemightthereforehypothesizethatinchronicpathologicalconditionscharacterized by atherosclerosis, ear lobe tissues might undergo adiminishedbloodsupplysimilartothatofmyocardium,determiningthepremature destruction of elastic  󿬁 bers which becomes manifest as theearly creasing and folding seen by the naked eye. Fig.1. Forestplotshowingstudy-speci 󿬁 c(box)andoverall(diamond)sensitivitiesandspeci 󿬁 citiesofthestudiesincludedinthemeta-analysis,withcorresponding95%CIs(inbrackets).173 Letters to the Editor   In conclusion, data from our meta-analysis strongly support thehypothesisthatELCcouldbeamarkerforCAD,withasensitivityof0.62,aspeci 󿬁 city of 0.67 and a diagnostic odd ratio of 3.3. Nevertheless, furtherstudies are needed to better de 󿬁 ne histological, cellular and molecularmechanisms leading to the development of ELC during the course of CAD, as well as prospective population-based studies aimed atde 󿬁 ning time of onset and evolution of ELC presence and character-istics with regard to cardiovascular risk factors and CAD development.  Appendix A. Supplementary data Supplementary data to this article can be found online at http:// References [1] Frank ST. Aural sign of coronary-artery disease. 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Incidence of sudden cardiac death in congestive heart failure:Chagas disease versus systemic arterial hypertension Henrique Horta Veloso ⁎ Department of Cardiology (Cardioteam), Hospital do Rio, Rio de Janeiro, Brazil a r t i c l e i n f o  Article history: Received 11 March 2014Accepted 2 April 2014Available online 5 May 2014 Keywords: Chagas diseaseHeart failureSystemic arterial hypertensionSudden cardiac death In a recent article, Bestetti et al. [1] compared the outcome of patients with congestive heart failure (CHF) secondary to Chagascardiomyopathy (n = 244) with those with CHF secondary tosystemic arterial hypertension (n = 130). In this interesting research,patients were followed for 33 months and the probability of survivalfor Chagas disease at 12, 24, 36, 48, and 60 months was 76%, 56%, 45%,37%, and 29%, respectively; nonetheless, the probability of survival forhypertensive cardiomyopathy at 12, 24, 36, 48, and 60 months was96%, 92%, 82%, 77%, and 73%, respectively (p  b  0.05). Thus, the authorsconcluded that patients with Chagas heart disease have a pooreroutcome in comparison to those with CHF secondary to hypertensivecardiomyopathy. Unfortunately, in this article, the authors did notmention the mechanism of death in the studied population.The conceptof apoorer prognosisof patientswith CHFdue toChagasdisease in comparison to those with hypertensive cardiomyopathy wasalready demonstrated in a Brazilian cohort of outpatients followed for26 months[2]. Inthisstudy,themortalityratewasof45%inthechagasicgroup (110 of 242 patients) versus 26% in the hypertensive group (45 of 170 patients) (p  b  0.0001; relative risk 2.73, 95% con 󿬁 dence interval 1.82to 4.07).Bestetti et al. [1] discussed that the worse prognosis of patientswith CHF secondary to Chagas disease in comparison to thosesecondary to hypertensive cardiomyopathy could be the consequenceof a less aggressive ventricular remodeling process observed in thelatter, and also to the lower proportion of patients on, and the lowerdose of, beta-blocker therapy in the Chagas group. Both of theseexplanationscanberelatedtoahigherpropensitytofatalarrhythmiasand sudden cardiac death (SCD) in Chagas cardiomyopathy, but thismechanism of death was not explored.SCD is the main mechanism of death in patients with Chagasdisease (62%), followed by progressive heart failure (15%) [3,4]. Inchagasic patients with non-sustained ventricular tachycardia, thisdifferenceisstillmoreevident(73%ofSCDand9%ofheartfailure)[5].In opposition, it is well established that SCD is not a common event inpatients with CHF secondary to hypertension. Among patients withSCD and nonischemic dilated cardiomyopathy of several etiologies, ⁎  Rua Conde de Bon 󿬁 m 255/505, Tijuca, Rio de Janeiro, RJ, ZIP 20520-051, Brazil.175 Letters to the Editor  View publication statsView publication stats
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