Cardiovascular risk profile in patients with myelopathy associated with HTLV-1

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w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Cardiovascular

risk

proﬁle

in

patients

with

myelopathy

associated

with

HTLV-1

夽

Fabio

Luís

Silva

do

Prado

a,b,∗

_,

_Renata

_Prado

c

_,

_Ana

_Marice

_Teixeira

_Ladeia

a

a_Escola_Bahiana_de_Medicina_e_Saúde_Pública,_Salvador,_BA,_Brazil b_Rede_Sarah_de_Hospitais_de_{Reabilitac¸ão,}_Salvador,_BA,_Brazil c_Vanguard_Skin_Specialists,_Colorado_Springs,_CO,_United_States

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received1June2016 Accepted4January2017 Availableonline7March2017

Keywords: HTLV-1 HAM/TSP Cardiovascularrisk Creactiveprotein Interleukin-6

a

b

s

t

r

a

c

t

HAM/TSP(HTLV-1-associatedmyelopathy/tropicalspasticparaparesis)isaslowly progres-sivedisease,characterizedbyachronicspasticparaparesis.Itisnotknownifthedisease carriesanindependentriskforcardiovasculardisease.Theobjectiveofthisstudywasto evaluatethecardiovascularriskproﬁlerelatedtoHAM/TSPandcompareitwiththegeneral population.

Methods:Thiswasacross-sectionalstudy,withacontrolgroup.HAM/TSPpatientswere evaluated usingcardiovascularrisk scores(ASCVDRISK,SCOREandFramingham) and inﬂammatorymarkers(ultrasensitiveCRPandIL-6),andcomparedwithacontrolgroup ofhealthyindividuals.Wealsoevaluatedthecorrelationbetweencardiovascularriskand thefunctionalstatusofpatientswithHAM/TSPevaluatedbytheFIMscale.

Results:Eightypercentofpatientsinthisstudywerefemales,meanageof51years(11.3). Thecontrolgroupshowedanincreasedcardiovasculareventriskin10yearswhenASCVD wasanalyzed(cardiovascularrisk≥7.5%in10yearsseenin43%ofpatientsinthecontrol groupvs.23%ofpatientswithHAM/TSP;p=0.037).Therewasnodifferenceinultrasensitive CRPorIL-6valuesbetweenthegroups,evenwhengroupswerestratiﬁedintolowandhigh risk.TherewasnocorrelationbetweenthefunctionalstatusofHAM/TSPpatientsandthe cardiovascularrisk.

Conclusions:Inthisstudy,thecardiovascularriskproﬁleofpatientswithHAM/TSPwasbetter thantheriskofthecontrolgroup.

夽_This_article_is_part_of_Fabio_Prado_MSc_Thesis_of_Bahiana_School_of_Medicine_and_Public_Health_Post_Graduate_Course. ∗ _{Corresponding}_author.

E-mailaddress:[email protected](F.L.Prado).

http://dx.doi.org/10.1016/j.bjid.2017.01.007

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Introduction

HumanT-lymphotropic virus type 1 (HTLV-1) was the ﬁrst knownhumanretrovirus,describedin1979byPoiesz.1_It_is

estimatedthat15–20millionpeopleareaffectedworldwide.2

TheincidenceofHTLV-1infectionishigherinJapan,Africa, andCaribbeanIslands,whereitmayaffect5%ormoreofthe population.3_The_virus_was_initially_associated_with_adult

T-cellleukemia;subsequently,myelopathy(HTLV-1-associated myelopathy/tropicalspasticparaparesis–HAM/TSP),uveitis, andinfectivedermatitiswerealsoassociatedwiththevirus.4–7

Only5–10%ofpatients,however,developclinical manifesta-tions.

HAM/TSPisaslowlyprogressivedisease.Itischaracterized byachronicspasticparaparesis,neurogenicbladder, neuro-genicbowel,spasticityandneuropathicpain.Becausethese symptomsaresimilartothosefoundinpatientswithother spinalcorddiseases(traumaticornon-traumatic),their treat-mentoverlaps,consistingmostlyofsupportivemeasuresand rehabilitation.Thereiscurrentlynoantiviraltreatmentforthe disease.OnceHAM/TSPdevelops,itisusuallyprogressiveand irreversible.

Inthepast,pulmonaryandrenalcomplicationswerethe maincausesofmorbidityandmortalityofpatientswith trau-maticspinalcordinjury.8,9_However,_{cardiovascular}_disease_is

nowoneoftheleadingcausesofdeath.8,10,11_Risk_factors_such

asdiabetes,lowHDL-cholesterol(HDL-C),sedentarylife-style, andsmokinghaveahigherprevalenceamongpatientswith spinalcordinjury.8,10,12–14

Few studies describe the cardiovascular involvement relatedtoHTLV-1.In2014,Layeghetal.,15_in_a_{cross-sectional}

studyassessedatherosclerosisinpatientswithHTLV-1.The authors found that HTLV -1 infected patients had greater carotid intima-media thickness than age-mached healthy controls. In 1996, Stuver et al. found increased incidence of cardiovascular diseases and EKG changes in patients infected with HTLV-1.16 _In _2013, _Shabestari _et _al. _found

increasedprevalenceofHTLV-1amongpatientsundergoing angiography.17

TheHumanImmunodeﬁciencyVirus(HIV),another retro-virus,isassociatedtoincreasedcardiovascularrisk.Freinberg etal.studied82,459patientswithHIVduring5.9years.After adjusting for comorbiditiesand cardiovascular risk scores, theyfoundthatHIVwasanindependentcardiovascularrisk factor, raising the risk of a myocardial infarction by 50%. ThemechanismbywhichHIVincreasestheriskof myocar-dialinfarctionisnotknown;itisthoughtthatviralinduced inﬂammationandendothelialdysfunctionmayplayarole.18

Anti-retroviral therapies, especially protease inhibitors are alsorelatedtohighercardiovascularrisk.19_As_HIV_and_HTLV-1

arebothretrovirusandsharesimilarreplicationenzymessuch asretroviralproteases,20 _one_could_hypothesize _that

HTLV-1infectioncouldalsobeanindependentcardiovascularrisk factor.

Theobjectiveofthepresentstudywastoevaluatethe car-diovascularriskproﬁleofpatientswithHAM/TSPandcompare itwiththegeneralpopulation.

Methods

Studydesign

Thiswasacross-sectionalstudy,withacontrolgroup.

Patientsandsettings

The study group was comprised of HAM/TSP patients fol-lowedinarehabilitationHospitalinthecityofSalvador,Brazil fromJuly2014toOctober2015.Allpatientshadthediagnosis ofHAM/TSPdeﬁnedaccordingtotheCastro–Costacriteria.21

Patients with other possible causes for spinalcord lesions wereexcluded.Patientswithpossiblecausesforchangesin inflammatorytestssuchasacute infections,rheumatologic diseases, inflammatorybowel disease,and use of corticos-teroids or nonsteroidal anti-inflammatory drugs were also excluded.

MidlevelemployeesofHospitalSarahSalvadorconstituted thecontrolgroup.Theywerepairedina1:1proportion, match-ingforsexandage±5years.

Socio-demographicdata,physicalexaminationand laboratorytests

Data werecollected duringindividualizedinterviews,using a standardizedquestionnaire. Socio-demographic data and informationaboutHAM/TSPdisease(suchasdurationofthe diseaseandcomorbiditiesassociatedtothemyelopathy)were collected.

Weightwas obtainedinacalibrated scale withpatients usinglightclothing.Forwalkingpatientsandinthecontrol group, heightwasobtainedusing themetric measurement barattachedtoananthropometricscale.Inwheelchairbound patients,heightwasobtainedwiththepatientinthesupine position,usingaﬂexibleinelastictape,measuringsegments ofthebodyfromtheheeltohead.Bodymassindex(BMI)was calculatedbytheQueteletformula(weight/height2_).

Aninelasticﬂexibletapewasusedtomeasurewaist cir-cumference.Themeasurementwasobtainedwiththepatient standingupright,witharmsoutstretched,afteranormal expi-ration,atthemidpointbetweenthelastribandtheanterior superioriliaccrest.22_Wheelchair_bound_patients_were_assisted

toastandingpositionwiththeuseofawalker,parallelbars orastandingtableforthismeasurement,wheneverpossible. Thewaistcircumferencewasnotmeasuredifastanding posi-tionwasnotattainable.Twomeasurementswereperformed, andtheaverageofthevalueswasrecorded.

Blood pressure was measured with aneroid sphygmo-manometer with patients seated with supported upper extremity at the heart level. Patients were at rest for at least 10min and had not smoked or drank coffee 30min priortothemeasurement.23_Patients_with_neurogenic

blad-derunderwentbladdercatheterizationbeforebloodpressure measurement.Twomeasurementswereperformed,the sec-ondoneminuteaftertheﬁrst,andtheaverageofthevalues wasrecorded.23

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Presenceof metabolicsyndrome was assessedbyusing the International DiabetesFederation criteriaas previously described.24_Metabolic_syndrome_refers_to_a_cluster_of

asso-ciated symptoms composed of impaired fasting glucose, abdominalobesity,hypertension,anddyslipidemia.Itis asso-ciatedwithanincreasedriskofcardiovascularmorbidityand mortality.Theincreasedamountofvisceralfattogetherwith achronicinﬂammatorystatepredisposestothedevelopment ofarteriosclerosis.

IntheHAM/TSPgroup, thefunctional statuswas evalu-atedusingtheFunctionalIndependenceMeasure(FIM)scale,a highlyacceptedandutilizedtoolforneurologicalpatientsthat hasbeenvalidatedinBrazil.25_It_is_used_primarily_in_patients

withneurologicalsequelaeandevaluates18categoriesthat arescoredfrom1to7determinantsofthelevelofdependency toperformatask.Thesumofthepointsobtainedwillclassify thepatientintofoursubscores:completedependency, modi-ﬁeddependency(assistanceofupto50%ofthetask),modiﬁed independence(assistanceofupto25%ofthetask),andtotal independence.

Bloodsamplescollected aftera12-hourfastingincluded glucose, total cholesterol, LDL cholesterol (LDL-C), HDL cholesterol(HDL-C),triglycerides(spectrophotometry), com-plete blood count (Flow Cytometry, impedanceand optical microscopy),creatinine(Jaffé),ultrasensitiveCreactive pro-tein(CRP) (nephelometry,BNProspec®), interleukin-6(IL-6) (chemiluminescence, Simens Imullite thousand®), proviral load(PolymeraseChainReaction)fortheHAM/TSPpatients andHTLV-1testdetection(ELISA)forthecontrolgroup.All testswereperformedinhospital’slaboratoriesattheSarah Network.

Cardiovascularriskevaluation

Three different cardiovascular risk scores were used: AtheroscleroticCardiovascularDiseaseRisk(ASCVDRisk),the Framingham score,and the EuropeanSystematicCoronary RiskEvaluation(SCORE).Wecomparedtheabsolutevalueof 10-yearcardiovascularriskofeachscore.Themainoutcome ofthisstudy,however,wasthecardiovascularriskassessedby ASCVDRISK.TheASCVDRISKwaschosensinceitisascore developedfromalargenumberofpatientsincludingpatients with different racial background, and it predicts the risk forfatal and non-fatal events. Patients were dichotomized intotwogroups: lowrisk/noneedfortherapeutic interven-tion, and intermediate and high risk/need for therapeutic intervention.

The ASCVD RISK was created in 2013 in a partnership betweentheAmericanHeartAssociation,AmericanCollegeof CardiologyandtheNationalHeart,LungandBloodInstitute. ItusesdatafromCohortssuchastheARICstudy (Atheroscle-rosisRiskinCommunities),CARDIAstudy (CoronaryArtery Risk Development in Young Adults) and the Framingham study.Thesepatientswerefollowedforatleast12years,and were mainly white non-Hispanics and African Americans. Thescorewascreatedtocalculatethecardiovascularriskof adultsbetween40and79yearsofage.Itestimatestherisk ofdevelopingfatalornon-fatal acutemyocardialinfarction or stroke in 10 years based on the variables gender, age,

race, total cholesterol and HDL-C, systolic blood pressure, smoking,anddiabetes.26_Patients_with_diabetes,_symptomatic

cardiovascular disease, or a cardiovascular risk ≥7.5% are consideredhighriskpatients.

The Framingham Risk Score was created from data obtained in the Framingham Heart Study. This cohort study started in 1948 in the city of Framingham, Mas-sachusetts, withabout 5000participants.27 _In₂₀₀₈ _a_score

for assessment ofcardiovascular risk in primary care was establishedbyestimatingtheprobabilityofmyocardial infarc-tion, stroke, peripheral arterial disease, and heart failure in the next 10 years. This score uses as variables gen-der, age, smoking,diabetes, systolic blood pressure,use of medications for high blood pressure,total cholesterol, and HDL-C.28_The_Framingham_Risk_Score_classiﬁes_patients_into

three groups: low risk (<5% risk of cardiovascular event in 10 years), intermediate risk (5–20% for men and 5–10% for women), and high risk (>20% for men and >10% for women).

TheEuropeanSCOREisatoolcreatedin2003withdata from12Europeancohorts,including205,178patientsfollowed between1970and1988.Itestimatestheriskoffatal cardiovas-culareventsin10years,suchasmyocardialinfarction,stroke, andaorticaneurysmbasedonthevariablesgender,age,total cholesterol,systolicbloodpressure,andsmokingstatus.29_The

EuropeanSCOREalsoclassiﬁespatientsintothreegroups:low risk(<1%riskofcardiovasculareventin10years), intermedi-aterisk(1–5%),andhighrisk(>5%).Patientswithdiabetesare consideredhighrisk.

Thecardiovascularriskwasalsoevaluatedusing ultrasen-sitiveCRPandIL-6,inﬂammatorymarkersthatareelevatedin patientswithincreasedcardiovascularrisk.30,31_Patients_were

consideredtohaveahighcardiovascularriskifIL-6>3.4pg/ml and/orCRP>2mg/l.

Statisticalanalysis

All analyses were performed by the statistical package SPSS (Statistical Package for Social Sciences) version 21.0.

Categorical variables were comparedusing a chi-square test with Yates’s correction for continuity, as appropriate. Continuous variables were assessed for signiﬁcant depar-tures from normality. Normally distributed variables were summarized usingmean and standarddeviationand com-paredusingattest.Skewedvariablesweresummarizedusing medianandinterquartilerange(IQR)andcomparedusinga Mann–Whitneytest.

We conducteda multivariate analysisby binary logistic regression.Weincludedinthemultivariatemodelfactorswith

p<0.20inunivariateanalysis,whichhadbiological plausibil-ity and werenotusedinthe riskscore.Thefinal outcome was dichotomous (lowcardiovascular riskprofile RCV/high cardiovascularriskprofile),andthefinalmodelobtainedby theBackwardmethod.

InHAM/TSPgroup,thecorrelationbetweenFIMscale val-uesandcardiovascularriskwasevaluatedusingSpearman’s rho.

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Samplesizecalculation

Thesamplesize wascalculated toconfer statistical power tothepresetanalysis.Fifty-sixpatientswereneededineach grouptoprovidean80%powertodetectadifferenceof28%of patientswithintermediate/highcardiovascularriskbetween thegroups.Usingdatafrompreviousstudies10,14,32_we

esti-matedthat65%ofthepatientswithHAM/TSPwouldhavean intermediate/highcardiovascularrisk,whiletheprevalencein thecomparativegroupwouldbe37%.

Ethicalaspects

Thestudywasincompliancewiththeguidelinesonhuman researchoftheHelsinkiDeclarationandtheNationalHealth CouncilResolution466/2012.Thestudywassubmittedtothe EthicsCommitteeoftheSarahNetworkandapprovedinJune, 2014(CAAE 31338914.2.0000.0022). All participantsreceived detailedinformationinwritingandverballyaboutthestudy objectives,risksandbeneﬁtsinvolvedintheprocedures,and signedinformedconsentbeforebeingsubmittedtothe proce-duresdescribedinmethods.

Results

The social and clinical characteristics of the patients are presentedinTable1. Inbothgroups, 80% ofpatients were

female with a mean age ofapproximately 51 years (11.3). There was no difference between groups with respect to race(p=0.081).Thegroupsdifferedintheeducationalstatus (p<0.001)andfamilyincome(p<0.001),withthecontrolgroup presentingwithmoreyearsofformaleducationandhigher income.

Thecontrolgrouphad ahigherprevalenceof hyperten-sion(46%versus18%ofpatientsinHAM/TSPgroup,p=0.002). Thewaist circumferenceofwomen ofthis group wasalso signiﬁcantlyhigher(95cm(13)versus88cm(13)ofHAM/TSP group,p=0.019).Theincidenceofdiabetesmellituswashigher in the HAM/TSP group (16% versus 4% of control group,

p=0.026);however,themedianfastingbloodglucosewas simi-larbetweenthegroups(90mg/dlintheHAM/TSPgroupversus 92mg/dlinthecontrolgroup,p=0.239).Thecontrolgrouphad signiﬁcantlyhighertotalcholesterollevel(200mg/dl(42) ver-sus179mg/dl(33),p=0.007),andtriglyceride levels(median of 134mg/dl versus 102mg/dl in HAM/TSPgroup, p=0.012, Mann–Whitney). HDL-C level was also higher in HAM/TSP group(46mg/dl(10)versus39mg/dl(9)p<0.001).

Thecontrolgrouphad higherBMI(29kg/m2 (4.7) versus 26kg/m2 _(5), _p_<_0.001). _The _prevalence _of _obese _patients

(BMI>30kg/m2₎_was_{signiﬁcantly}_higher_in_the_control_group

thanintheHAM/TSPgroup(43%versus16%,p=0.001).There wasnosigniﬁcantdifferenceintheprevalenceofmetabolic syndrome, although we observed a trend toward higher

Table1–Characteristicsofthestudysamples.

Variables HAM/TSPn=56 Controln=56 p-Valuea

Women 45(80%) 45(80%) >0.999

Age(years)(meanSD) 52(12) 51(11) 0.790

Race White 18(32%) 10(18%) 0.081 Non-white 38(68%) 46(82%) Education Noformaleducation 2(4%) 0 1–3years 11(20%) 3(5%) <0.001 4–7years 22(39%) 6(11%) 8–10years 7(12%) 13(23%) >10years 14(25%) 34(61%) Income

<3minimumwagesalaries 34(61%) 8(14%) <0.001 ≥3minimumwagesalaries 22(39%) 48(86%)

Bodymassindex(BMI)(kg/m2₎

Waistcircumference(cm) 26(5) 29(4.7) <0.001 Women(n=45) 88(13) 95(13) 0.019 Men(n=11) 93(17) 98(10) 0.389 Hypertension 10(18%) 26(46%) 0.002 Smoking 4(7%) 5(9%) 0.728 Diabetes 9(16%) 2(4%) 0.026

Familyhistoryofcardiovasculardiseaseb ₄_(7%) ₁₁_(20%) _0.096

Metabolicsyndrome 24(44%) 33(60%) 0.127

Totalcholesterol(mg/dl) 179(33) 200(42) 0.005

LDLcholesterol(mg/dl) 118(30) 127(38) 0.167

HDLcholesterol(mg/dl) 39(9) 47(10) 0.000

Triglycerides(mg/dl)(median,IQR) 101(71–152) 132(95–177) 0.011 Fastingglucose(mg/dl) 90(83–96) 92(87–100) 0.200

a _Used_t_test_and_{Mann–Whitney}_for_continuous_variables_and_x2_or_Yate’s_correction_for_continuity_when_appropriate_for_categorical_variables.

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Table2–HAM/TSPpatientscharacteristics(n=56). Ageofonsetofsymptoms(years)(mean±SD) 41(12,7) Durationofdisease(years)(median,IQR) 10(5,14)

Neurogenicbladder 55(98%)

Neurogenicbowel 52(93%)

Lumbarpain 47(84%)

Uveitis 4(7%)

FIM*_scale_score_(n₌₃₂₎ ₁₁₁_(109–117)

Proviralload(HTLV-1copies/105_cells_copies/ml) ₂₅₁₁_(286–3518)

FIM,functionalindependencemeasure.

prevalenceinthecontrolgroup(60%versus44%ofHAM/TSP group,p=0.127).

Inthe HAM/TSPgroup,themeanageofonsetof myelo-pathysymptomswas41years(12.7).ThemedianFIMscale scorewas111(IQR109–117).Themedianprovirusloadwas 2510HTLV-1copies/105_cells_copies/ml_(IQR_286–3518)._Table₂ showsthecharacteristicsofthesepatients.

The ASCVD, Framinghan, and SCORE risk scores were calculated for each patient in the HAM/TSP and control groups(Table3).BothgroupshadsimilarASCVDandSCORE risk scores; however, the control group showed a statis-tically signiﬁcant higher Framingham risk score than the HAM/TSPgroup(medianof7.3%riskofcardiovasculareventin 10 years inthe controlgroup versus4.8% inthe HAM/TSP group,p=0.024).

UsingtheASCVDRISKscore,morepatientsinthecontrol groupwerefoundtohaveanintermediate/highcardiovascular

Table5–Multivariateanalysisfortheassociation betweeneducation,HAM/TSP,abdominalcircumference andBMI,andcardiovascularriskassessedbyASCVD RISK(n=92).

Variable Firstmodel

OR(IC95%) Finalmodel OR(IC95%) HAM/TSP 0.4(0.13–1.01) 0.4(0.18–1.11) Education 1.6(0.60–4.58) – Waistcircumference 3.6(0.70–19.03) 3.8(0.80–18.48) IMC 1.1(0.40–2.85) –

riskthanintheHAM/TSPgroup(43%ofpatientsinthecontrol groupversus23%ofpatientswithHAM/TSP,p=0.037). Simi-larly,whenusingFraminghamandSCORE,morepatientsin the control groupwere classiﬁed as intermediate/highrisk thanintheHAM/TSPgroup,althoughthisdifferencewasnot statisticallysigniﬁcant(Table3).

TherewasnodifferencebetweenultrasensitiveCRPand IL-6inbothgroupswhenweusedeithertheabsolutevalue orwhenthegroupswerecategorizedintolowandhighrisk patientsaccordingtotheirlabvalues(Table4).

Inmultivariateanalysis,noneoftheevaluatedfactorswere associatedwithabetterorworsecardiovascularriskproﬁle. Raceandincomewerenotincludedinthemodel,sinceraceis avariableusedinASCVDRISK.Incomeshowedastrong rela-tionshipwitheducation,whichcouldleadtoaninteractionin themodel(Table5).

Table3–CardiovascularriskscoresinHAM/TSPpatientsandcontrolgroup.

Variables HAM/TSP n=56 Control n=56 Prevalenceratio (IC95%) p-Valued

%Patientswithintermediate/highriska

ASCVDb _23% _43% _0.54_{(0.29–0.98)} _0.04

Framingham 46% 63% 0.74(0.53–1.05) 0.09

SCORE 52% 59% 0.88(0.63–1.23) 0.45

Absolutevaluec

ASCVDb_(median,_IQR) _3.3_(1.6–7.3) _4.8_(1.9–14.3) _0.11

Framingham 4.8(2.3–9.9) 7.3(2.9–16.7) 0.02

Score 0.0(0–1.75) 1.0(0–2.00) 0.09

a _Patients_with_{cardiovascular}_risk_≥5%_evaluated_by_Framingham_Score,_≥1%_evaluated_by_SCORE_and_≥7.5%_evaluated_by_ASCVD. b _ASCVD_RISK_evaluates₁₀_risk_of_{cardiovascular}_event_in_patients_with_age_from₄₀_to₇₉_years._n₌_49.

c _%_risk_of_a_{cardiovascular}_event_in₁₀_years.

d_Used_{Mann–Whitney}_for_continuous_variables_and_x2_for_categorical_variables_or_Yate’s_correction_for_continuity_when_appropriate.

Table4–InﬂammatorymarkersinHAM/TSPpatientsandcontrolgroup.

Variables HAM/TSP n=56 Control n=56 p-Valuea Absolutevalues CRPb_(mg/l)_(median,_IQR) _2.6_(1,_5.5) _1.7_(0.8,₅₎ _0.510 IL-6b_(pg/ml)_(media,IQR) _2.4_(0,_3.3) _2.4_(0,_3.3) _0.858

Patientswithelevatedvalues(%)

CPRb_>₃_mg/l ₂₇_(48%) ₂₃_(41%) _0.569

IL-6b_>_3.4_pg/ml ₁₂_(23%) ₉_(17%) _0.661

a _Used_{Mann–Whitney}_for_continuous_variables_and_x2_or_Yate’s_correction_for_continuity_when_appropriate_for_categorical_variables.

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Table6–Correlationbetweencardiovascularriskscore andFIMscalescore.

Variable FIMa_scale_score

Spearmen’srho p-Value

Framingham 0.098 0.595

SCORE 0.048 0.792

ASCVD 0.033 0.869

a _FIM,_Functional_independence_measure.

Ofthe56patientsinthisgroup,32wereevaluatedbythe FIMscale.TherewasnocorrelationbetweentheFIMscaleand thecardiovascularriskofthesepatients(Table6).

Discussion

Toourknowledge,thisisthefirststudyevaluatingthe cardio-vascularriskprofileofpatientswithHAM/TSP.Althoughwe initiallypostulated thatpatientswithHAM/TSPcould have aworsecardiovascularriskprofilethanthenormal popula-tion,thiswasnotseeninourstudy.Infact,morepatientsin thecontrolgrouphadhighercardiovascularscoresas mea-suredbyASCVD.ThemedianscoremeasuredbyFraminghan cardiovascularriskscorewasalsohigherinthisgroup.

Thisresultcanbepartiallyexplainedbythefactthatthe prevalenceofhighbloodpressure,totalcholesterol, triglyce-rides,andwaistcircumferencewassigniﬁcantlyhigherinthe controlgroup.However,itisimportanttonotethatHAM/TSP patients presented some characteristics that may actually lowertheircardiovascularrisk,suchaslowtotalcholesterol andlowbloodpressure.Althoughspinalcordinjurypatients usuallyhavehighprevalenceofdyslipidemia,thismaynotbe trueforHAM/TSPpatients.Doriaetal.,33_evaluated₅₄_HTLV-1

patientsforatherosclerosisusingcarotidarteryDoppler.The authorsfoundthatonly35%ofthepatientshad atherosclero-sisandattributedthisfacttothelowdyslipidemiaprevalence amongthestudiedpatients.Furthermore,bloodpressure is alsoanimportantriskfactorforcardiovasculardiseaseandfor thisreasonitisconsideredinallscoresthatassess cardiovas-cularrisk.Changesinautonomiccontrolmechanismswere alsodescribedinthesepatientswithdysfunctioninthe sym-patheticnervoussystem.Ohishietal.,34_showed_that_HTLV_-1

patientshadloweraveragebloodpressurein24handhigher averagesleepheartratewhencomparedtoacontrolgroup. Thisstudy tookplaceintheJapanesecityofNagasaki,and compared23 HTLV patients with 23 age and sex matched healthycontrols.Asbloodpressureandcholesterolare impor-tantcardiovascularriskfactors,thiscanmeanthatHAM/TSP patientsmayactuallyhave,infact,abettercardiovascularrisk proﬁlethanapparentlyhealthyindividuals.35,36

There are other possible explanations for our results, includingtheapplicationofthecardiovascularscoresinthe HAM/TSPpopulation. Finnieet al.,10 _evaluated _the

cardio-vascularriskof75patientswithspinalcordinjury.Nineteen percentofthepatientshadanintermediate/high cardiovas-cularrisk when Framingham score was used, against37% whentheyevaluatedCRP.Theauthorsarguedthatthe Fram-inghamriskscoremayunderestimatethecardiovascularrisk ofspinalcordinjurypatients, because itmay notconsider

somespeciﬁccharacteristicsofthispopulation.Thisﬁnding mayalsobetruefortheothertwoscoresusedinthisstudy.

Anotherfactorthatmayhaveplayedaroleinourﬁndingsis thatthepatientsinourHAM/TSPgrouparecloselymonitored inaspecializedrehabilitationcenterand receivehigh level medicalcare.Theyare evaluatedatleastannuallyor semi-annually by a specialized, multidisciplinary medicalteam, withemphasisnotonlyinrehabilitation,butalsoinpreventive medicine.Thefactthatthesepatientshadahigherprevalence ofhistoryofdiabetesthanthecontrolgroup,but their fas-tingbloodglucoselevelsweresimilar,demonstratestheclose monitoringandcontrolofcomorbiditiesinthisgroup. Consid-eringthattheyaresostrictlymonitored,theirriskfactorsmay beminimized.

Thecontrolgroupwasfoundtohaveahigherlevelof edu-cationandfamilyincome,whichisusuallyassociatedwith lower cardiovascular risk.37–39 _Although _one_may _postulate

thatifthegroupsweresimilarintheirsocialeconomicstatus, thedifferencebetweenthecardiovascularriskcouldhadbeen evengreater (withHAM/TSPpatients showingwithamore signiﬁcantlowercardiovascularrisk),inourmultivariate anal-ysis,educationlevelwasnotassociatedwithcardiovascular risk.

Despite the fact that HAM/TSP is considered a chronic inﬂammatorydisease,wedidnotﬁnddifferenceswhen eval-uatingultrasensitiveCRPandIL-6betweenthegroups.About 45%ofpatientsinthisstudyhadelevatedlevelsof ultrasen-sitiveCRP,andabout20%hadelevatedlevelsofIL-6,withno differencebetweentheHAM/TSPandthecontrolgroup. Ele-vatedlevelsofCRPandIL-6weredescribedbypreviousstudies inHTLV-1patients.40,41_One_possible_explanation_for_our

ﬁnd-ingisthehigherprevalenceinthecontrolgroupoffactorsalso associatedtoelevatedlevelsofinﬂammatorymarkers,suchas obesityandhypertension.42,43

ThefunctionalcapacityofpatientswithHAM/TSPinthis studyvariedwidely,withthescorebyFIMscalerangingfrom 72to121.Aworsefunctionalperformancecouldberelatedto ahighercardiovascularriskusingthehypothesisthatmost compromised patientsare more sedentary.44 _However, _this

studydidnotdemonstrateapositivecorrelationbetween car-diovascularriskandtheresultoftheFIMscale.

Ourstudyhadlimitations.Itwasacrosssectionalstudy and the number ofpatients was small.Itwas designedto detect a difference of28% prevalenceofintermediate/high cardiovascular risk amongpatientswith HAM/TSPand the controlgroup.Ifthedifferencebetweenthetwogroupswas smaller than this,we would need a bigger samplesize to detectthisdifference.Althoughouranalysisdidnotﬁndan important impact ofthe socio-demographic characteristics ontheresults,similarbaselinecharacteristicswouldprovide morereliableresults.Sincewedidnotevaluateasymptomatic HTLV-1patients, wecannottelliftheresultsfoundinthe studywereduetothemyelopathyortothevirusitself.

Conclusion

Inthisstudy,thecardiovascularriskproﬁleofpatientswith HAM/TSP followed in arehabilitation hospital inSalvador, Brazil was betterthan the riskproﬁleofthe controlgroup

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ofhealthy individuals.Furtherstudiesare neededtobetter clarifythisissue.

Funding

SARAH Network of Rehabilitation Hospitals. The funding sourcehad noinvolvementduringthe researchand prepa-rationofthearticle.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

Acknowledgements

WethankGabrielaModestoforhelpingwiththeFIMscore col-lectingdataandAlfredoSilva forhelping withthestatistic review.SupportedbySARAHNetworkofRehabilitation Hospi-tals,

This article ispart ofFábio Prado’s MSc Thesis for the BahianaSchoolofMedicineandPublicHealthPostGraduate Course.

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