HTA Si Sindromul Metabolic

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  • HTA si sindromul metabolicProf. Doina Dimulescu, MD, PhD, FESCClinica de Cardiologie Elias Bucuresti

  • Obesity in USA during 1995-2005

  • Mortalitatea prin boala cerebrovasculara in diferite regiuni ale Europei(barbati,femei 45-74 ani)Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326; doi:10.1093/eurheartj/ehm604

  • Mortality by Ischemic Heart Disease in Different Regions of Europe(Males, Females, 45-74y)Copyright restrictions may apply.Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326;

  • Mortality by Ischemic and Cerebrovascular Disease in Different Regions of Europe(Males, Females, 45-74 y)Muller-Nordhorn, J. et al. Eur Heart J 2008 29:1316-1326; doi:10.1093/eurheartj/ehm604

  • Components of cardiovascular dysmetabolic syndromeBraunwald 2008

  • Inflamation and obesity

  • Plasma renin and epinephrine activity variation during treadmill test in lean vs obese patientsAntman 2007

  • Metabolic syndrome and diabetes mellitusMetabolic syndrome min. two of the following conditions:- abdominal obesity- insulin resistance (FG)- hypertension- dyslipidemia (TG, HDL-C)- microalbuminuriaCo-existance of MS and DM prevalence of coronary disease reaches 19,2% of population (in the absence of MS the prevalence of CD in pts with DM is low -7,5%, similar to the population without DM (8,7%)

    Alexander CM et al, Diabetes 2003; 52:1210-4

  • Global projections for the diabetes epidemic:1995-2010


  • CV RISK FACTORS CLUSTER TOGETHERTHE DIABETIC POPULATION2%3%1%3%1%0%1%DYSLIPIDEMIA9 % of US popln has diabetes and dyslipidemiaOBESITY7 % of US popln has diabetes and obesityHYPERTENSION6% of US popln has diabetes and HBP11% of the US adult population has diabetes, but only 0.1% has no co-morbidity.NHANE Survey, 1988 - 94

  • Cardiovascular mortality and the risk factors DIABETICS vs NONDIABETICS* MRFITMRFIT = Multiple Risk Factor Intervention Trial*Serum cholesterol >200 mg/dl, smoking, systolic blood pressure >120 mmHgAdapted from Stamler J et al Diabetes Care 1993;16(2):434-444.140120100806040200Non diabetes DiabetesNo risk factorsOne risk factorTwo risk factorsThree risk factorsn=25,517n=216n=99,896n=1470n=155,338n=2530n=62,114n=947Cardiovasc. Mort. Rate adjusted per 10000 pts.x year

  • Hypertension and diabetes systemic diseaseCommon comorbid diseasesPowerful predisposing for cardiovascular and renal disease, synergic deletorious effect on large and small vessels Two-fold increase of the risk of stroke, cardiovascular diseaseFive to six fold increase of risk for end-stage renal disease

    Crawford 2004

  • Hypertension and diabetesEndothelial dysfunction, impaired NOIncreased salt sensitivityVolume expansionIsolated systolic hypertensionLoss of nocturnal dipping of blood pressure and pulseIncreased propensity to proteinuria and orthostatic hypotensionAtherosclerosis, microvascular impairement

  • Diabetes dyslipidemiaLow HDL-CHigh trigliceridesIncreased oxidized LDL-C

    Endothelial dysfunctionProthrombotic statusInflamation Crawford 2004

  • Diabetes and atherosclerosisFruchard CJ 2003

  • Diabetic atherosclerosis Increased MMP expressionPlaque composition: increased macrophage infiltration, thrombus formationAdventiceal inflamation and rupture of internal elastic laminaVasa vasorum neovascularization of media and plaque cerebrovasc. diseaseElevated concentration of procoagulant factors (TF, ) coronary thrombosis

    Moreno PR, Fuster V, JACC 2004, Dec

  • ObesityAssociation with hypertensionWight gain +5 kg over the age of 18 y increases with 60% the risk ofdevelopping hypertension+10Kg increases 2,2 fold the risk of hypertensionFramingham Study: 70% of hypertension in men and61% in women attribuable to excess adiposityObesity- accompanied by hypertension-related outcomes: stroke, heart failureKaplan 2006

  • Mechanisms of hypertension in METSVolume-expansion due to obesityIncreased cardiac outputFailure of systemic vascular resistances to decrease for balancing the high outputHyperinsulinemia ( endothelial dysfunction, endogenous AT II production, activation of sympathetic nervous system)Impaired normal vasodilatatory effect of insulin by impaired NO synthesis

    Kaplan 2006

  • Mechanisms of hypertension in METS (II)InsulinresistanceIncreased RAAS activityIncreased leptinIncreased ET-1More intense inflamationIncreased renal sodium retention Most of these reflect insulin-resistance and hyperinsulinemia

    Kapalan 2006

  • Leptin resistance and cardiovascular riskLeptin regulatory key of energy balanceIncreased circulating Leptin marker of Leptin resistance common in obesityLeptin has structural and functional resemblance to proinflamatory cytokines (IL-6) and may modulate CRPLeptin regulates components of innate and adaptive immunity (T lymfocites and monocytes)Convergence of increased levels of leptin and inflamation markers in CVD

    JACC, Oct 2008

  • Leptin resiatance Pathways to cardiovascular risk (I)Immunity, inflamation, atherosclerosis (direct atherogenic effect, leptin receptors in plaques; activation of T cells, pro-inflamatory immune response)The relation of leptin ans subclinical atherosclerosis in obese humans requires further studyPositive CV prediction (acute events sroke, MI) for both inflamatory markers and leptin

  • Leptin resiatance Pathways to cardiovascular risk (II)Insulin resistance and diabetes leptin as an insulin- sensitising hormone ?Basal plasma leptin and insulin parallel each otherInsulin and glucose appear to stimulate leptin secretion in adipocytesIncreased leptin is associated with hyperinsulinemia and insulin-resistance, independent of BMIJACC 2008

  • Leptin resiatance Pathways to cardiovascular risk (III)In response leptin decreases insulin secretion by direct effect on pancreatic -cells, might reduce lipotoxicity of TG and improve whole body insulin sensitivityLeptin therapy-dissapointing in obesity trials (leptin resistance?), but improved diabetic measures in patients with familial leptin defficiency and lipoatrophic diabetes

  • Copyright 2008 American College of Cardiology Foundation. Restrictions may apply.Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210Cellular and molecular Leptin pathophysiology

  • Leptin resiatance Pathways to cardiovascular risk (IV)HypertensionIncreasing leptin levels with increased BP levels (especially in hypertensive, obese woman)Chronic leptin-mediated central (hypotalamus) sympathetic activation pressor effects role in obesity-mediated hypertension

  • Leptin resistance Pathways to cardiovascular risk (V)ThrombosisLeptin enhances platelet aggregation and may promote arterial thrombosis (might be limited to obese patients)Leptin levels-possible correlation with PAI-1, VWFactor, Fg, F VIIa

  • Leptin resistance Pathways to cardiovascular risk (VI)Myocardial injuryDecreased myocyte contractilityIncreased O2 reactive speciesReduced NOProinflamatory factorsCardyomyocites hypertrophy, prolipheration, apoptosis maladaptive cardiac remodelling in obese patients

  • Copyright 2008 American College of Cardiology Foundation. Restrictions may apply.Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210Overview of Leptin Resistance and Hyperleptinemia in Obesity-Related Cardiovascular Disease

  • Copyright 2008 American College of Cardiology Foundation. Restrictions may apply.Martin, S. S. et al. J Am Coll Cardiol 2008;52:1201-1210Overview of Leptin Resistance and Hyperleptinemia in Obesity-Related Cardiovascular Disease

  • Does the METS predict CV risk beyond its components?6 definitions of METS: WHO, NCEP updated, EGIR, ACE, IDFImprecise definitions, uncertain pathogenesis, ambiguous value as CV risk factorA prospective population-based study , 13 y follow-up, 1025 nondiabetic subjects (65-74Y/o) that met criteria for METS; Eur Heart J 2007

  • Does the METS predict CV risk beyond its components?METS defined by all 6 criteria predicted CVD mortality in elderly population (1,32-1,56 fold risk)METS cefinition by WHO, ACE, IDF predicted CHD mortality (1,42-1,58 fold risk)METS did not predict CVD mortality byond and above of 4 of his single components (IFG, IGT, low HDL C, HRs for CVD mortalityEur Heart J 2007JACC 2006

  • Does the METS predict CV risk beyond its components?IGT and microalbuminuria predicted most consistently CVD and CHD mortalityWHO and ACE criteria predicted most consistently CVD and CHD mortalityMETS defined by NCEP crit was not associated with a greater risk of early-onset coronary disease than individual components (HDL, HTA, IFG)

    Eur Heart J 2007JACC 2006

  • 2007 Guidelines for the Management of Arterial HypertensionJournal of Hypertension 2007;25:1105-1187European Society of Hypertension European Society of Cardiology

  • Goals of TreatmentIn hypertensive patients, the primary goal of treatment is to achieve maximum reduction in the long-term total risk of cardiovascular diseaseThis requires treatment of the raised BP per se as well as of all associated reversible risk factorsBP should be reduces to at least below 140/90 mmHg (systolic/diastolic) and to lower values, if tolerated, in all hypertensive patients

  • Goals of TreatmentTarget BP should be at least
  • Choice of Antihypertensive Drugs The main benefits of antihypertensive therapy are due to lowering of BP per se

  • Bood Pressure Lowering Treatment Trialists CollaborationThe Lancet 2003

  • Trials comparing the effect on primary endpoint of tratments based on different antihypertensive drugsBraunwald 2008

  • Antihypertensive therapy in diabetic patientsACEI (HOPE)ARBs (LIFE, RENAAL)Calcium channel blockers (HOT, Syst-Eur)Betablockers (UKPDS)Diuretics (ALLHAT)

    ESC/EHS Guidelines 2007JNC -7 Guidelines for recommended drugs for patients with compelling indications

  • ALLHAT: Serum glucose JAMA 2002; 288:2981-2997

  • ALLHAT: De Novo DM JAMA 2002; 288:2981-2997

  • Comparatia BB vs ARB in terapia antihipertensiva asupra riscului de evenimente CV


    Lancet 2002; 359: 995-1003.


    Results BP by 30.2/16.2 in losartan arm and 29.1/16.8 in atenolol arm (p=0.017 for SBP; p=0.37 for DBP) Primary composite endpoint in losartan arm (Figure), as was stroke and new onset diabetes but no difference in CV mortality (Figure)Conclusions Unlike CAPPP, NORDIL and STOP-HTN2 trials which compared ACE inhibitors or calcium channel blockers with beta blockers and diuretics for treatment of hypertension, LIFE showed a significant treatment effect with use of the angiotensin II type 1-receptor antagonist losartanLimitations High risk HTN patients selected for study; generalizability to lower risk patients cannot be made No comparison of losartan to diuretic

    Trial Design: LIFE was a multi-center randomized trial of losartan (an ARB) compared with atenolol alone in prevention of coronary events in patients with hypertension (HTN) and LVH. Mean follow-up was 4.8 yrs. Primary endpoint was a composite of death, MI and stroke.



    Primary Composite

    HR 0.87p=0.021

    CV Mortality

    HR 0.89p=0.206


    HR 0.75p=0.001

    New onset DM

    HR 0.75p=0.001


  • DZ nou aparut in studii clinice de terapie antihipertensiva

    Williams JACC 2005

  • Evenimente CV la pacienti hipertensivi tratati, fara DZ, cu DZ nou aparut si cu DZ vechiPreviously known diabetesVerdecchia et al Hypertension 2004Probability of event-free survival%10090807060504030Time to event (years)03691215No diabetesNew-onset diabetesACBp
  • Diabetul nou aparut sub terapie antihipertensivaEfecte diabetogene ale diureticelor si betablocantelor care se translateaza in alterarea prognosticului- cresterea glicemiei indusa de tratament la pacienti in varsta de 50 de ani a fost un predictor major pentru IM la 60 aniDunder K et al, BMJ 2003; 326:681-8

  • Choice of Antihypertensive Drugs-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetesESC/ISH Guidelines 2007

  • Antihypertensive Treatment in DiabeticsA blocker of the renin-angiotensin system should be a regular component of combination treatment and the one preferred when monotherapy is sufficientESC/ISH Guidelines 2007

  • Mortalitate CV + IM + AVC0. PRESTARIUMl(Nr. de evenimente = 796)Atenolol tiazida(Nr. de evenimente = 937)HR = 0.84 (0.760.92)p < 0.0003Numar la riscAmlodipina PRESTARIUM 96399415 9228 90078778 7655Atenolol tiazida 96189400 9152 88918629 7500%-16%

  • Betablocantele la diabetici sant sigure?Sant toate BB la fel?

    Results Mean change in HbA1c from baseline in metoprolol group vs carvedilol (Figure) Study drug discontinuation due to worsening glycemic control in metoprolol group (2.2% vs 0.6%, p=0.04) Reduction in HOMA-IR from baseline greater in carvedilol group (Figure) Triglyceride greater in metoprolol group (13.2% vs 2.2%, p





    Fatal heart disease or MIRR A vs C = 0.98, p=0.65RR L vs C = 0.99, p=0.81


    Trial Design: ALLHAT was a NHLBI sponsored, 623 site, blinded randomized trial of the diuretic chlorthalidone vs the calcium channel blocker amlodipine and the ACE inhibitor lisinopril in patients with hypertension. Patients were followed for a mean of 4.9 yrs. Primary endpoint (EP) was fatal heart disease or nonfatal MI.

    All Cause MortalityRR A vs C = 0.96, p=0.20RR L vs C = 1.00, p=0.90

    JAMA 2002;288:2981-2997

    Results No difference in prespecified 1 endpoint Lower heart failure rate (2 EP) with chlorthalidone vs amlodipine or lisinopril Lower stroke rate (2 EP) with chlorthalidone vs lisinopril(RR 1.15 p=0.02) Higher glucose levels with chlorthalidone vs amlodipine or lisinopril All 3 drugs reduced blood pressure from baseline, but SBP reduction greater with chlorthalidone Conclusions No difference in fatal heart disease or MI Benefit for chlorthalidone in heart failureEP Limitations Important side effect in the chlorthalidone arm was higher fasting glucose levels Impact of chlorthalidone on diabetes and CV disease may not be fully manifested in the relatively short follow-up of 4 years ACE-I arm may be disadvantaged since the 1st add-on therapy specified was beta-blocker rather than diuretic or Ca blocker Relatively large crossover rate

    Chlorthalidone (C)

    Amlodipine (A)

    Lisinopril (L)



    Heart FailureRR A vs C = 1.38, p

  • Role of HDL -CHDL-C is responsible for removal of free cholesterole from the blood

    HDL- C is associated with cardiovascular risk

    Nissen SE et al JAMA 2003

  • HDL:an anti-atherogenic lipoproteinFruchard J 2003

  • 246810121416TelmisartanFold activation5 micromolarAbility of Different ARBs To Activate PPAR (S.C. Benson et al., Hypertension, 43:993-1002, 2004)

  • ONTARGETTelmisartan (16.7%) noninferior; combination (16.3%) not superior to ramipril (16.5%) for primary endpoint (CV death, MI, stroke, heart failure)Greater incidence of hypotension in combination (4.8%) and telmisartan (2.7%) groups, compared with ramipril group (1.7%) (p < 0.001) Trial design: Patients at high risk for cardiovascular events, but without heart failure, were randomized to telmisartan, ramipril, or the combi...