colloque du service de cardiologie 2πrcardiology-geneva.com/colloque/colloques...

22ππrrDr. Dr. FranFranççois Mach, MD,ois Mach, MD,Division de CardiologieDivision de Cardiologie

Hôpital Universitaire de GenHôpital Universitaire de Genèè[email protected]@medecine.unige.ch

www.cardiologywww.cardiology--geneva.chgeneva.ch

GenGenèèveve, HUG le 2 mars 20, HUG le 2 mars 200066

Colloque du Service de CardiologieColloque du Service de Cardiologie

Despite therapeutic advances, cardiovascular Despite therapeutic advances, cardiovascular disease remains the leading cause of death (USA)disease remains the leading cause of death (USA)

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DiabetesDiabetes

Am J CardiolAm J Cardiol 19981998;82(;82(supplsuppl 10A)10A)

AthAthéérogenrogenèèsese

Physiopathologie de lPhysiopathologie de l’’athathéérosclrosclééroserose

SmokingSmoking

EndothelialEndothelial DysfunctionDysfunctionAthAtheerorogenesisgenesis

DiabDiabeetetess

Oxydative StressOxydative StressOxydative Stress

HypertensionHypertension

High LHigh LDLDL--cholcholLowLow HDLHDL--cholchol

ObesityObesitySedentaritySedentarity

CardioVascularCardioVascular RiskRisk FactorsFactors

IntraIntra--abdominal obesity (adiposity)abdominal obesity (adiposity)

and cardiovascular risk factorsand cardiovascular risk factors

115 cm115 cm

2.3 mmol/l2.3 mmol/l



•• Obesity: BMI Obesity: BMI ≥≥ 30 (kg/m30 (kg/m22))7% of the world population of adults or about 312 7% of the world population of adults or about 312 millionmillion

•• Overweight: BMI 25Overweight: BMI 25--30 30 (kg/m(kg/m22))1.1 billion adults1.1 billion adults

•• Prevalence of obesity and overweight in childrenPrevalence of obesity and overweight in childrenas high as 36%as high as 36%

The Current Obesity PandemicThe Current Obesity Pandemic

WorldwideWorldwide epidemiaepidemia of of «« diabesitydiabesity »»

CardiovascularCardiovascular RiskRisk FactorsFactors

Obesity, Body Fat Distribution and Risk of CVD Obesity, Body Fat Distribution and Risk of CVD

N Engl J MedN Engl J Med 19981998;338:1;338:1

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Quintiles of waist circumference (cm)Quintiles of waist circumference (cm)

Obesity, Body Fat Distribution and Risk of CVD Obesity, Body Fat Distribution and Risk of CVD

RR >3 foldRR >3 fold RR between 2RR between 2--3 fold3 fold RR between 1RR between 1--2 fold2 fold

Type 2 diabetesType 2 diabetes CVDCVD HPG axis abnormalitiesHPG axis abnormalities

Gallbladder diseaseGallbladder disease HypertensionHypertension CancerCancer

DyslipidemiaDyslipidemia Knee Knee osteoarthritesosteoarthrites Lower spine problemsLower spine problems

Sleep ApneaSleep Apnea GoutGout Birth defectsBirth defects

Adapted from WHO Report, Geneva Adapted from WHO Report, Geneva 19981998

Relative Risk of ObesityRelative Risk of Obesity--Associated Associated Health ProblemsHealth Problems

AbdominalAbdominalobesityobesity

DyslipidaemiaDyslipidaemiaHypertensionHypertension

Glucose intoleranceGlucose intoleranceInsulin resistanceInsulin resistance

Increased Increased CardiometabolicCardiometabolic RiskRisk

Multiple cardiovascular risk factors Multiple cardiovascular risk factors drive adverse clinical outcomesdrive adverse clinical outcomes

CARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE

Classical Risk FactorsClassical Risk Factors Novel Risk FactorsNovel Risk Factors

Major Unmet Clinical NeedMajor Unmet Clinical Need

Metabolic syndromeMetabolic syndrome

AbdominalAbdominalObesityObesity

↓↓HDLHDL--CC

↑↑TGTG

↑↑TNFTNFαα ILIL--66

↑↑PAIPAI--11

↑↑GluGlu

↑↑InsulinInsulin

T2DMT2DM↑↑SmokingSmoking↑↑ LDLLDL--CC ↑↑ BPBP

Multiple cardiovascular risk factors Multiple cardiovascular risk factors drive adverse clinical outcomesdrive adverse clinical outcomes

•• High waist circumferenceHigh waist circumference

•• Plus any two ofPlus any two of

•• Triglycerides (Triglycerides (≥≥ 1.7 mmol/L [150 mg/dL])1.7 mmol/L [150 mg/dL])‡‡

•• HDL cholesterolHDL cholesterol‡‡

•• MenMen < 1.0 mmol/L (40 mg/dL)< 1.0 mmol/L (40 mg/dL)

•• WomenWomen < 1.3 mmol/L (50 mg/dL)< 1.3 mmol/L (50 mg/dL)

•• Blood pressure Blood pressure ≥≥ 130 / 130 / >>85 mm Hg85 mm Hg‡‡

•• FPG (FPG (≥≥ 5.6 mmol/L [100 mg/dL])5.6 mmol/L [100 mg/dL]), or diabetes, or diabetes

IDF criteria of the metabolic syndrome IDF criteria of the metabolic syndrome

Abdominal obesity: required for diagnosing the Abdominal obesity: required for diagnosing the metabolic syndromemetabolic syndrome

International Diabetes Federation (International Diabetes Federation (20052005))

‡‡or specific treatment for these conditionsor specific treatment for these conditions

Metabolic syndrome has a negative impact Metabolic syndrome has a negative impact on CV health and mortalityon CV health and mortality

DiabetologiaDiabetologia 20012001;44:1148;44:1148

No metabolic syndromeNo metabolic syndrome

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Metabolic syndromeMetabolic syndrome

•• New IDF criteria:New IDF criteria:

NCEP NCEP 20022002; ; International Diabetes Federation International Diabetes Federation 20052005

•• Current NCEP ATPCurrent NCEP ATP--III criteriaIII criteria

>102 cm (>40 in) in men, >88 cm (>35 in) in women>102 cm (>40 in) in men, >88 cm (>35 in) in women

WomenWomenMenMen

>>90 cm (35.4 in)90 cm (35.4 in)

>>80 cm (31.5 in)80 cm (31.5 in)

>>80 cm (31.5 in)80 cm (31.5 in)

>>80 cm (31.5 in)80 cm (31.5 in)

>>85 cm (33.5 in)85 cm (33.5 in)

>>90 cm (35.4 in)90 cm (35.4 in)

>>90 cm (35.4 in)90 cm (35.4 in)

>>94 cm (37.0 in)94 cm (37.0 in)

JapaneseJapanese

ChineseChinese

South AsianSouth Asian

EuropidEuropid

Abdominal obesity and Abdominal obesity and waist circumference thresholdswaist circumference thresholds

Place a tape measure around the Place a tape measure around the bare abdomen, just above the hip bare abdomen, just above the hip bone bone

Be sure the tape is snug, but does Be sure the tape is snug, but does not compress the skin not compress the skin

The tape should be parallel to the The tape should be parallel to the floor floor

The patient should relax and The patient should relax and exhale while the measurement is exhale while the measurement is made made

http://http://win.niddk.nih.gov/publications/tools.htm#circumfwin.niddk.nih.gov/publications/tools.htm#circumf

Measuring waist circumference: Measuring waist circumference: a practical guide from the NIDDK/NIHa practical guide from the NIDDK/NIH

Am J CardiolAm J Cardiol 19941994;73:460;73:460

Waist circumference correlates closely Waist circumference correlates closely with intrawith intra--abdominal adiposityabdominal adiposity

IAA: the Perils of PortlinessIAA: the Perils of Portliness

Visceral fatVisceral fat

Subcutaneous fatSubcutaneous fat

J J MagnMagn ResonReson ImagingImaging 20052005;21:455;21:455

+ 18%+ 18%55.1%55.1%46.7%46.7%WomenWomen

+ 28%+ 28%36.9%36.9%29.5%29.5%MenMen

Relative Relative changechange

NHANES NHANES (1999(1999––2000)2000)

NHANES IIINHANES III(1988(1988––1994)1994)

ObesObes ResRes 20032003;11:1223;11:1223

US National Health andUS National Health andNutrition Examination Survey (NHANES)Nutrition Examination Survey (NHANES)

Abdominal obesity defined as waist circumference: >102 cm (>40 iAbdominal obesity defined as waist circumference: >102 cm (>40 in)n)in men or >88 cm (>35 in) in women in men or >88 cm (>35 in) in women

Growing prevalence of abdominal obesityGrowing prevalence of abdominal obesity

USUS 36.936.9 55.155.1 46.046.0

Spain Spain 30.530.5 37.837.8 34.734.7

ItalyItaly 24.024.0 37.037.0 31.531.5

UKUK 29.029.0 26.026.0 27.527.5

FranceFrance –– –– 26.326.3

NetherlandsNetherlands 14.814.8 21.121.1 18.218.2

Germany Germany 20.020.0 20.520.5 20.320.3

Men (%)Men (%) WomenWomen (%)(%) TotalTotal (%)(%)

High waist circumference: High waist circumference: >>102 cm (102 cm (>>40 in) in men or 40 in) in men or >>88 cm (88 cm (>>35 in) in women35 in) in womenexcept in Germany (>103 cm [41 in] and >92 cm [36 in], respectivexcept in Germany (>103 cm [41 in] and >92 cm [36 in], respectively)ely)

Abdominal obesity Abdominal obesity has reached epidemic has reached epidemic proportions worldwideproportions worldwide

Swiss Statistical Federal Office 2003 Swiss Statistical Federal Office 2003 Percentage of obesityPercentage of obesity

Obesity Obesity in Switzerlandin Switzerland

Patients with abdominal Patients with abdominal obesity (high waist obesity (high waist circumference) often circumference) often present with one or more present with one or more additional additional CV risk factors CV risk factors

CV risk factors in a typical patient with abdominal obesityCV risk factors in a typical patient with abdominal obesity

High waist circumference is associated with High waist circumference is associated with multiple cardio vascular risk factorsmultiple cardio vascular risk factors

115 cm115 cm




Adverse Adverse cardiometaboliccardiometabolic effects of effects of products of products of adipocytesadipocytes

AdiposeAdiposetissuetissue

↑↑ ILIL--66

↓↓ AdiponectinAdiponectin

↑↑ LeptinLeptin

↑↑ TNFTNFαα

↑↑ AdipsinAdipsin(Complement D)(Complement D)

↑↑ PlasminogenPlasminogenactivator inhibitoractivator inhibitor--11

(PAI(PAI--1)1)

↑↑ ResistinResistin

↑↑ FFAFFA

↑↑ InsulinInsulin

↑↑ AgiotensinogenAgiotensinogen

↑↑ Lipoprotein lipaseLipoprotein lipase

↑↑ LactateLactate

InflammationInflammation

TypeType2 diabetes2 diabetes

HypertensionHypertension

AtherogenicAtherogenicdyslipidaemiadyslipidaemia

ThrombosisThrombosisAtherosclerosisAtherosclerosis

BrBr J J NutrNutr 20042004;92:347;92:347

<71<71 7171––75.975.9 7676––8181 81.181.1––8686 86.186.1––9191 91.191.1––96.396.3 >96.3>96.3

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Am J Am J EpidemiolEpidemiol 19971997;145:614;145:614

Abdominal obesity increases the risk of Abdominal obesity increases the risk of developing type 2 diabetesdeveloping type 2 diabetes

WomenWomen

Intra abdominal adiposity impairs pancreatic Intra abdominal adiposity impairs pancreatic ββ--cell functioncell function

Long-term damageto β-cellsDecreased insulinsecretion

Short-termstimulationof insulinsecretion

Intra abdominal Intra abdominal adiposityadiposity

FFA: Free fatty acidsFFA: Free fatty acids

SplanchnicSplanchnic & systemic& systemiccirculationcirculation

DiabetesDiabetes 19921992;41:826;41:826

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LeanLean

HDLHDL--cholesterolcholesterol

Visceral fatVisceral fat(obese subjects)(obese subjects)

LowLow HighHigh LeanLean

Visceral fatVisceral fat(obese subjects)(obese subjects)

LowLow HighHigh

IntraIntra--abdominal adiposity and abdominal adiposity and dyslipidaemiadyslipidaemia

LancetLancet 20042004;364:937;364:937

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aaProportionProportion of MI in the total population attributable to a specific risk fof MI in the total population attributable to a specific risk factoractor

Abdominal obesity predicts the Abdominal obesity predicts the risk of CVD beyond BMIrisk of CVD beyond BMI

Cardiometabolic risk factors in the Cardiometabolic risk factors in the InterHeartInterHeart StudyStudy

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Abdominal obesity: a major underlying Abdominal obesity: a major underlying cause of acute myocardial infarctioncause of acute myocardial infarction

LancetLancet 20020044;;364364::937937

CardiovascularCardiovascular RiskRisk FactorsFactors

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Tertile 1Tertile 1Tertile 2Tertile 2

Tertile 3Tertile 3

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>103>103

<87<878787––9898

>98>98

Waist circ. (cm):Waist circ. (cm):

Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDLAdjusted for BMI, age, smoking, sex, CVD disease, DM, HDL--C, totalC, total--CC

The HOPE StudyThe HOPE Study

Abdominal obesity and increased Abdominal obesity and increased risk of cardiovascular eventsrisk of cardiovascular events

•• Abdominal obesity (visceral)Abdominal obesity (visceral)

•• is often associated with other CV risk factorsis often associated with other CV risk factors

•• is an independent CV risk factoris an independent CV risk factor

•• AdipocytesAdipocytes are metabolically active endocrine are metabolically active endocrine organs, not simply inert fat storageorgans, not simply inert fat storage

Why is abdominal obesity harmful ?Why is abdominal obesity harmful ?

IntraIntra--AbdominalAbdominalAdiposityAdiposity

CVCVdiseasedisease

CardiovascularCardiovascularrisk factorsrisk factors

DirectDirect

IndirectIndirect

IntraIntra--abdominal adiposity is abdominal adiposity is characterisedcharacterised by accumulation ofby accumulation offat around and inside abdominal organsfat around and inside abdominal organs

ObesObes ResRes 20032003;11:1278;11:1278

Abdominal obesityAbdominal obesity(High waist circumference)(High waist circumference)

IntraIntra--abdominal adiposity: abdominal adiposity: a a rootroot cause of cause of cardiometaboliccardiometabolic diseasedisease

Le systLe systèème EC est un systme EC est un systèème endogme endogèène et physiologique qui joue un rne et physiologique qui joue un rôle ôle clcléé dans la rdans la réégulation de lgulation de l’’homhomééostasie ostasie éénergnergéétique et de ltique et de l’’accumulation de accumulation de graisse, aussi bien que dans le mgraisse, aussi bien que dans le méétabolisme tabolisme glucogluco--lipidiquelipidique..

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(A) (A) BlocageBlocage PharmacologiquePharmacologique des des rréécepteurscepteursCBCB11 chezchez la la sourissouris et le ratet le rat

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e.ge.g.: Rimonabant.: Rimonabant

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LL’’activation des ractivation des réécepteurs CBcepteurs CB11 par les par les EndocannabinoEndocannabinoïïdes stimule la prise alimentairedes stimule la prise alimentaire

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Mol PharmacolMol Pharmacol 2003;63:908 2003;63:908

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Souris CBSouris CB1 1 +/++/+Souris CBSouris CB11 –– //––

**

Effet du Rimonabant sur les niveaux de ARNm dEffet du Rimonabant sur les niveaux de ARNm d’’aadiponectinediponectinechez les rats maigres et obchez les rats maigres et obèèses et le souris CBses et le souris CB11--//--

*P<0.05; **P<0.01 vs V*P<0.05; **P<0.01 vs Vééhiculehicule

LL’’adiponectineadiponectine: : uneune protprotééineine sséécrcrééttééeespspéécifiquementcifiquement par les par les tissustissus adipeuxadipeux

Propriétés anti-athérogéniques:↓ Expression de molécules d’adhésion↓ Adhésion des monocytes aux cellules endothéliales↓ Captage du LDL oxydé↓ Formation de cellules spumeuses↓ Prolifération et migration des cellules musculaires lisses

PropriPropriééttéés antis anti--athathéérogrogééniquesniques::↓↓ Expression de molExpression de moléécules dcules d’’adhadhéésionsion↓↓ AdhAdhéésion des monocytes aux cellules endothsion des monocytes aux cellules endothéélialesliales↓↓ Captage du LDL oxydCaptage du LDL oxydéé↓↓ Formation de cellules spumeusesFormation de cellules spumeuses↓↓ ProlifProliféération et migration des cellules musculaires lissesration et migration des cellules musculaires lisses

Propriétés anti-diabétiques :↑ Sensibilité à l’insuline↑ Captage musculaire de glucose et oxydation des AGL↓ Production hépatique de glucose↓ Triglycérides intracellulaires

PropriPropriééttéés antis anti--diabdiabéétiques :tiques :↑↑ SensibilitSensibilitéé àà ll’’insulineinsuline↑↑ Captage musculaire de glucose et oxydation des AGLCaptage musculaire de glucose et oxydation des AGL↓↓ Production hProduction héépatique de glucosepatique de glucose↓↓ TriglycTriglycéérides intracellulairesrides intracellulaires

0 0 --

2 2 --

4 4 --

6 6 --

8 8 --

10 10 --

12 12 --

14 14 --A

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LeanLeanIAA (obese subjects)IAA (obese subjects)

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IAA IAA isis associatedassociated withwith reducedreduced adiponectinadiponectin levelslevels

J Clin J Clin EndocrinolEndocrinol MetabMetab 20052005;90:1434;90:1434

JAMAJAMA 20042004;291:1730;291:1730

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Risk of MI for highest Risk of MI for highest vsvs. lowest quintile of adiponectin. lowest quintile of adiponectin

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Relationship between Relationship between adiponectinadiponectinlevels and risk of MIlevels and risk of MI

Localisations des rLocalisations des réécepteurs CBcepteurs CB11 et effets du et effets du blocage des rblocage des réécepteurs CBcepteurs CB11

Sites dSites d’’actionaction MMéécanisme(s)canisme(s) ImplicationsImplications

Hypothalamus / Hypothalamus /

Noyau Noyau accumbensaccumbensPrise alimentairePrise alimentaire PoidsPoids

AdipositAdipositéé intra abdominaleintra abdominale

Tissus adipeuxTissus adipeuxAdiponectineAdiponectineLLipogenipogenèèsese

DyslipidDyslipidéémiemie

RRéésistance sistance àà ll’’insuline insuline

MusclesMusclesCaptation duCaptation du

glucoseglucoseRRéésistance sistance àà ll’’insulineinsuline

FoieFoieLLipogenipogenèèsese DyslipidDyslipidéémiemie

RRéésistance sistance àà ll’’insulineinsuline

Tractus GITractus GISignaux de Signaux de

satisatiééttéé

PoidsPoids

AdipositAdipositéé intraintra--abdominaleabdominale

IntraIntra--abdominal adiposity and cardiovascular riskabdominal adiposity and cardiovascular risk

BMJBMJ 20052005;322:716;322:716

LancetLancet 20052005;365:1389;365:1389

Treatment of IntraTreatment of Intra--abdominal adiposityabdominal adiposity

Treatment of IntraTreatment of Intra--abdominal adiposityabdominal adiposity

LancetLancet 20052005;365:1389;365:1389

Endocannabinoid and cardiovascular riskEndocannabinoid and cardiovascular risk

N Engl J MedN Engl J Med NovemberNovember 17, 17, 20052005;353:2121;353:2121


BMJBMJ 20052005;322:716;322:716


LancetLancet 20052005;365:1389;365:1389

Multiple Multiple secretorysecretoryproductsproductsLiverLiverPancreasPancreas

MuscleMuscle

VasculatureVasculature

Current View: Current View: secretory secretory/endocrine organ /endocrine organOld View: inert storage depot Old View: inert storage depot

Fatty acids GlucoseFatty acids Glucose

Fatty acids GlycerolF

atty acids G

lycerol

Fed Fed

Fasted Fasted

TgTg

TgTg

TgTg

The evolving view of adipose tissue:The evolving view of adipose tissue:an endocrine organ an endocrine organ

Le Le blocageblocage de CB1 de CB1 rrééduitduit de multiples de multiples facteursfacteurs de de risquerisque caridomcaridoméétaboliquestaboliques

SyndrSyndrome ome MMéétaboliquetabolique

Obésité abdominale(HWC)*

Blocage de CB1

AdipositéIntra-abdominale

Mode inflammatoireMode inflammatoire

DyslipidémieAthérogénique• Faible HDL-C • TG élevés• Petites, denses particules de LDL

Intolérance au glucoseRésistance à l’insuline• Hyperinsulinémie• Diabètes de type 2

*HWC = High waist circumference*HWC = High waist circumference

Dr. FranDr. Franççois Mach, MDois Mach, MDDivision de Division de CardiologieCardiologie

DDéépartementpartement de de MMéédecinedecine InterneInterneHôpital Universitaire de GenHôpital Universitaire de Genèèveve

[email protected]@medecine.unige.ch

www.cardiologywww.cardiology--geneva.chgeneva.ch

HUG, GenHUG, Genèève, le 2 mars 2006ve, le 2 mars 2006

MerciMerci

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