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SRAA y Ateroesclerosis                                                                                                           SRAA y Ateroesclerosis




                                                                                    drpp 2009                                                                                                                             drpp 2009




                  Mecanismos de Inhibición del                                                                                                     Bloqueo del SRAA y Stress Oxidativo
                  SRAA                                                                                                                             comparado con otros antihipertensivos

                                                                                                                                                          Valsartan    Ramipril   Doxazosin      Metoprolol      Amlodipine
                                                                                                                                                          80 mg od     5 mg od     4 mg od       100 mg od        10 mg od
                                                                                                                                                           (n = 20)    (n = 20)    (n = 20)       (n = 22)         (n = 20)
                                                                                                                                                     0

                                                                                                                                                   –10                                             –2.7% *          –2.4% *

                                                                                                                                                   –20                            –15.9% *
                                                           Aldosterone                           ! in MDA
                                                           blockers
                                                                                                 Formation                                         –30
                                                                                                    (%)                                            –40                                     *P <0.001 vs baseline.

                                                                                                                                                   –50

                                                                                                                                                   –60                  –57.6%
                                                                                                                                                   –70
                                                                                                                                                           –67.2%*

                                                                                                         Change from baseline in formation of malondialdehyde (MDA), a marker of lipid peroxidation, after 3
                                                                                                         months treatment (N = 102).

                                                                                    drpp 2009   Baykal Y et al. J Hypertens. 2003;21:1207-1211.                                                                           drpp 2009




                Bloqueo de Receptor AT1                                                                                                            Efectos del Ramipril en la
                Vasodilatación mediada por flujo                                                                                                   Ateroesclerosis Carotídea
                                                                                                         N=732 patients with vascular disease or diabetes
122 Hypertensive patients treated for 2 months
                                                                                                                                           0.025                                    Mean Changes in BP:
                   2.0                                                                                                                                   RR -37 (P=0.028)           Baseline to Study End
                                                                                                   Mean Max. Carotid IMT Slope (mm/year)




                                                            1.66*
                                                                                                                                           0.020                                    Systolic BP (mmHg)
                   1.5                                                      1.32*                                                                                                   Placebo:            0.1 ± 12.2
          !                                     1.14*                                                                                      0.015                                    Ramipril 2.5 mg/d: -4.6 ± 13.5*
        FMD        1.0                                                                                                                                                              Ramipril 10 mg/d:  -4.1 ± 12.4*
        (%)
                                                                                                                                           0.010                                    Diastolic BP (mmHg)
                   0.5                                                                                                                                                              Placebo:           -0.4 ± 7.3
                                  0.15                                                                                                     0.005                                    Ramipril 2.5 mg/d: -2.9 ± 7.9*
                                                                                                                                                                                    Ramipril 10 mg/d:  -2.8 ± 7.6*
                   0.0
                               Placebo         Losartan   Irbesartan     Candesartan                                                          0
                               (n = 44)         100 mg      300 mg          16 mg                                                                                                   Values are mean ± SD.
                                                                                                                                                                                    *P<0.001 for mean BP changes compared with
                                               (n = 31)     (n = 30)       (n = 30)                                                                 Placebo Ramipril Ramipril       placebo. There were no significant differences in
*P < 0.05 vs baseline and vs placebo                                                                                                                         2.5 mg   10 mg         BP changes between the two active ramipril groups.


Referencia al. Am J Cardiol. 2004;93:1432-5.
   Koh KK et                                                                        drpp 2009   Lonn EM, et al. Circulation 2001; 103:919–25.                                                                             drpp 2009
Val-PREST: Re-estenosis intra-Stent                                                                   Mortalidad in SAVE,
                      y Reintervención a 6 meses                                                                            TRACE, AIRE, y VALIANT
                                                                          Valsartan 80 mg (n = 99)
                                                                                                                                                       Hazard Ratio for Mortality
                                                                          Placebo (n = 101)
                     50
                                                                                                                                 SAVE
                                50% reduction
                          with valsartan vs placebo
                     40
                                                                  58% reduction
                                                                                                                               TRACE
                                                            with valsartan vs placebo
    Restenosis (%)
     Patients with




                     30
                                                                                                                                 AIRE
                              *
                     20
                                                                 *                                                          Combined

                     10
                                                                                                                       VALIANT
                                                                                                                (imputed placebo)
                      0
                                                                                                                                          0.5                            1                           2
                            Restenosis                      Reintervention
                                                                                  *P <0.005 vs placebo.
                                                                                                                                                   Favors                           Favors
                                                                                                                                                 Active Drug                        Placebo
Adapted with permission from Peters S et al. J Invasive Cardiol. 2001;13:93-97.           drpp 2009       Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349                                     drpp 2009




                                                                                                                            MICRO-HOPE: IECAs Mejoran
                                                                                                                            Metas CV y Renales en Diabetes

                                                                                                                                         N=3577 patients with diabetes

      (SRAA) Sistema                                                                                                                               Overt
                                                                                                                                              CV nephro-


    Renina-Angiotensina-
                                                                                                                               MI     Stroke death pathy         Mean albumin:
                                                                                                                        0                                        creatinine ratio
                                                                                                                                                                   3.0                     Placebo
                                                                                                                     –10
                                                                                                                                                                   2.5

        Aldosterona:
                                                                                                            Risk                                                   2.0
                                                                                                          Reduction –20                                                                                 P=0.02
                                                                                                             (%)                                                   1.5                        Ramipril 10 mg
                                                                                                                                                                   1.0


      Efectos Renales
                                                                                                                     –30                                                         P=0.001
                                                                                                                             P=0.01
                                                                                                                                                   P=0.027         0.5
                                                                                                                     –40                                                     0      1        2           3     4.5
                                                                                                                                      P=0.007                                              Years
                                                                                                                                            P=0.0001



                                                                                          drpp 2009       HOPE Study Investigators. Lancet. 2000;355:253–259.                                            drpp 2009




                                                                                                                (SRAA) Sistema
                                                                                                              Renina-Angiotensina-
                                                                                                                  Aldosterona:
                                                                                                                    Diabetes
N Engl J Med.
                                                                                                            www.mechanismsincardiology.com
2001;345:851-860.                                                                         drpp 2009                                                                                                      drpp 2009
Bloqueo del SRAA y metabolismo de                                                                                                                                                                  Bloqueo del SRAA: Mejoría del
                     glucosa: Insulina y mediadores                                                                                                                                                                     Metabolismo de glucosa

                                                      BK
                                                                             NO
                                                                                                                                                                                                                    Angiotensin I                                                       Bradykinin
                                            BK2                     +
                                          Receptor                           "NO           Glucose                                                                                                                                                ACE/Kininase II
                                                                                          Transport
                                                                   Akt1                                                                                                                                                                                                               Degradation
                                                                                              +                                                                                                                     Angiotensin II
                                Insulin                                                                                                                                                                                                                                                products
                               Receptor      +             +
                                                                                      +                GLUT-4
               Insulin                       IRS-1                 PI3-K
                                                                                          +             Trans-
                                                                                                       location
                                                                                                                                                                                                                                           SRAA Blockage
                                                               -                GLUT-4
                                                                             Biosynthesis                                                                                                                          $Angiotensin II                                                      "Bradykinin
                                                                         -                        GLUT-4
                                            AT1
                                          Receptor
                                                                                                                                                                                                                                            !Skeletal muscle                         "Nitric oxide
                                                                                                                                                                                                                                               blood flow
                                                     Ang II                                                                                                                                                                               !Glucose metabolism


Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9.                                                    drpp 2009     Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9.                                                                                                             drpp 2009




                     Efecto de los IECA’s en Diabetes                                                                                                                                                                  Metas de PA diastólica:
                     Estudio HOPE                                                                                                                                                                                      Estudio HOT


                         Reducción relativa del riesgo con Ramipril vs
                             Placebo en pacientes con Diabetes                                                                                                                                                     30
                                                                                                                                                                                                                                           -2.1 mmHg =                   -2.1 mmHg =
                                                                                                                                          CV Events /1,000 Patient-Years in
                                                                                                                                                                              Patients with Diabetes at Baseline




                                                                                                                                                                                                                                       - 5.8 events/1000 py          - 6.7 events/1000 py
                                                                                                                                                                                                                   25

              22% de Infarto de Miocardio                                                                       p = 0.01                                                                                           20
              33% de EVC                                                                                        p = 0.0074                                                                                         15
              37% de muerte cardiovascular                                                                      p = 0.0001
              24% de nefropatía                                                                                 p = 0.027                                                                                          10
              17% de revascularización                                                                          p = 0.031
                                                                                                                                                                                                                   5
              20% de Insuficiencia Cardíaca                                                                     p = 0.019
                                                                                                                                                                           0
                                                                                                                                                                         Target: # 90 mmHg DBP                                                       # 85 mmHg DBP              #80 mmHg DBP
                                                                                                                                                                     (Achieved): (mean 85.2 mmHg)                                                    (mean 83.2 mmHg)          (mean 81.1 mmHg)


                                                                                                                                     p for trend = 0.005
HOPE investigators. Lancet 2000;355:253-259.                                                                           drpp 2009       Referencia
                                                                                                                                     Adapted from Hansson et al. Lancet 1998;351(9118):1755-1762.                                                                                                       drpp 2009




                     Antihipertensivos:                                                                                                                                                                             Prevención de Nuevos Casos de
                     Sensibilidad a la Insulina                                                                                                                                                                     Diabetes tipo 2

                                                                                                                                                                                                                                                                 Mejor Nuevo            Mejor convencional
                                                                                                                                      Estudio                                                                                        Seguimiento                           RR (IC 95%)

                                                                                                           18                   20     CAPPP (IECA vs Diu-BB)                                                                                  6,1
                                                                                                                       16                                                                                                                                                               0,86 (0,74-0,99); p= 0,03
                                                                                      12                                               HOPE (IECA vs Placebo)*                                                                                5,0                                       0,66 (0,51-0,85); p= 0,001
 Cambio (%)




                                                                                                                            10
                                                                                                                                       NORDIL (CA vs Diu-BB)                                                                                  4,5                                       0,87 (0,73-1,04); p= 0,14
                                                                                                                            0          INVEST (CA vs BB)                                                                                      2,7                                       0,85 (0,77-0,95); p= 0,01
                                                                    -4
                                                                                                                                       ALLHAT (IECA vs Diu)                                                                                   4,6
                                                                                                                        -10                                                                                                                                                             0,77 (0,66-0,89); p= 0,001
                                      -15                                                                                              LIFE (ARA II vs BB)                                                                                    4,8
                               -22               -18                                                                                                                                                                                                                                    0,75 (0,63-0,88); p= 0,001
               -30   -27                                                                                               -20             CHARM (ARA II vs Placebo) 3,1
                                                                                                                                                                                                                                                                                        0,78 (0,64-0,96); p= 0,01
               PRO
                         MET
                                                                                                                      -30
                                                                                                                                       VALUE (ARA II vs CA)                                                                                   4,2                                       0,77 (0,69-0,86); p= 0,0001
                               ATEN
                                      HCTZ
                                                 NIF
                                                                   VER
                                                                               DOXA                                   -40                                                                                                                                     0,50     0,75         1         1,25
                                                                                              IECA
                                                                                                            ARA II
                                                                                                                       drpp 2009                                                                                                                                                                        drpp 2009
ARA II en Nefropatía Diabética




Referencia                   drpp 2009   Referencia   drpp 2009

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Riesgo Cardiometabolico: Papel de la Hipertension (3)

  • 1. SRAA y Ateroesclerosis SRAA y Ateroesclerosis drpp 2009 drpp 2009 Mecanismos de Inhibición del Bloqueo del SRAA y Stress Oxidativo SRAA comparado con otros antihipertensivos Valsartan Ramipril Doxazosin Metoprolol Amlodipine 80 mg od 5 mg od 4 mg od 100 mg od 10 mg od (n = 20) (n = 20) (n = 20) (n = 22) (n = 20) 0 –10 –2.7% * –2.4% * –20 –15.9% * Aldosterone ! in MDA blockers Formation –30 (%) –40 *P <0.001 vs baseline. –50 –60 –57.6% –70 –67.2%* Change from baseline in formation of malondialdehyde (MDA), a marker of lipid peroxidation, after 3 months treatment (N = 102). drpp 2009 Baykal Y et al. J Hypertens. 2003;21:1207-1211. drpp 2009 Bloqueo de Receptor AT1 Efectos del Ramipril en la Vasodilatación mediada por flujo Ateroesclerosis Carotídea N=732 patients with vascular disease or diabetes 122 Hypertensive patients treated for 2 months 0.025 Mean Changes in BP: 2.0 RR -37 (P=0.028) Baseline to Study End Mean Max. Carotid IMT Slope (mm/year) 1.66* 0.020 Systolic BP (mmHg) 1.5 1.32* Placebo: 0.1 ± 12.2 ! 1.14* 0.015 Ramipril 2.5 mg/d: -4.6 ± 13.5* FMD 1.0 Ramipril 10 mg/d: -4.1 ± 12.4* (%) 0.010 Diastolic BP (mmHg) 0.5 Placebo: -0.4 ± 7.3 0.15 0.005 Ramipril 2.5 mg/d: -2.9 ± 7.9* Ramipril 10 mg/d: -2.8 ± 7.6* 0.0 Placebo Losartan Irbesartan Candesartan 0 (n = 44) 100 mg 300 mg 16 mg Values are mean ± SD. *P<0.001 for mean BP changes compared with (n = 31) (n = 30) (n = 30) Placebo Ramipril Ramipril placebo. There were no significant differences in *P < 0.05 vs baseline and vs placebo 2.5 mg 10 mg BP changes between the two active ramipril groups. Referencia al. Am J Cardiol. 2004;93:1432-5. Koh KK et drpp 2009 Lonn EM, et al. Circulation 2001; 103:919–25. drpp 2009
  • 2. Val-PREST: Re-estenosis intra-Stent Mortalidad in SAVE, y Reintervención a 6 meses TRACE, AIRE, y VALIANT Valsartan 80 mg (n = 99) Hazard Ratio for Mortality Placebo (n = 101) 50 SAVE 50% reduction with valsartan vs placebo 40 58% reduction TRACE with valsartan vs placebo Restenosis (%) Patients with 30 AIRE * 20 * Combined 10 VALIANT (imputed placebo) 0 0.5 1 2 Restenosis Reintervention *P <0.005 vs placebo. Favors Favors Active Drug Placebo Adapted with permission from Peters S et al. J Invasive Cardiol. 2001;13:93-97. drpp 2009 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 drpp 2009 MICRO-HOPE: IECAs Mejoran Metas CV y Renales en Diabetes N=3577 patients with diabetes (SRAA) Sistema Overt CV nephro- Renina-Angiotensina- MI Stroke death pathy Mean albumin: 0 creatinine ratio 3.0 Placebo –10 2.5 Aldosterona: Risk 2.0 Reduction –20 P=0.02 (%) 1.5 Ramipril 10 mg 1.0 Efectos Renales –30 P=0.001 P=0.01 P=0.027 0.5 –40 0 1 2 3 4.5 P=0.007 Years P=0.0001 drpp 2009 HOPE Study Investigators. Lancet. 2000;355:253–259. drpp 2009 (SRAA) Sistema Renina-Angiotensina- Aldosterona: Diabetes N Engl J Med. www.mechanismsincardiology.com 2001;345:851-860. drpp 2009 drpp 2009
  • 3. Bloqueo del SRAA y metabolismo de Bloqueo del SRAA: Mejoría del glucosa: Insulina y mediadores Metabolismo de glucosa BK NO Angiotensin I Bradykinin BK2 + Receptor "NO Glucose ACE/Kininase II Transport Akt1 Degradation + Angiotensin II Insulin products Receptor + + + GLUT-4 Insulin IRS-1 PI3-K + Trans- location SRAA Blockage - GLUT-4 Biosynthesis $Angiotensin II "Bradykinin - GLUT-4 AT1 Receptor !Skeletal muscle "Nitric oxide blood flow Ang II !Glucose metabolism Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9. drpp 2009 Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171–9. drpp 2009 Efecto de los IECA’s en Diabetes Metas de PA diastólica: Estudio HOPE Estudio HOT Reducción relativa del riesgo con Ramipril vs Placebo en pacientes con Diabetes 30 -2.1 mmHg = -2.1 mmHg = CV Events /1,000 Patient-Years in Patients with Diabetes at Baseline - 5.8 events/1000 py - 6.7 events/1000 py 25 22% de Infarto de Miocardio p = 0.01 20 33% de EVC p = 0.0074 15 37% de muerte cardiovascular p = 0.0001 24% de nefropatía p = 0.027 10 17% de revascularización p = 0.031 5 20% de Insuficiencia Cardíaca p = 0.019 0 Target: # 90 mmHg DBP # 85 mmHg DBP #80 mmHg DBP (Achieved): (mean 85.2 mmHg) (mean 83.2 mmHg) (mean 81.1 mmHg) p for trend = 0.005 HOPE investigators. Lancet 2000;355:253-259. drpp 2009 Referencia Adapted from Hansson et al. Lancet 1998;351(9118):1755-1762. drpp 2009 Antihipertensivos: Prevención de Nuevos Casos de Sensibilidad a la Insulina Diabetes tipo 2 Mejor Nuevo Mejor convencional Estudio Seguimiento RR (IC 95%) 18 20 CAPPP (IECA vs Diu-BB) 6,1 16 0,86 (0,74-0,99); p= 0,03 12 HOPE (IECA vs Placebo)* 5,0 0,66 (0,51-0,85); p= 0,001 Cambio (%) 10 NORDIL (CA vs Diu-BB) 4,5 0,87 (0,73-1,04); p= 0,14 0 INVEST (CA vs BB) 2,7 0,85 (0,77-0,95); p= 0,01 -4 ALLHAT (IECA vs Diu) 4,6 -10 0,77 (0,66-0,89); p= 0,001 -15 LIFE (ARA II vs BB) 4,8 -22 -18 0,75 (0,63-0,88); p= 0,001 -30 -27 -20 CHARM (ARA II vs Placebo) 3,1 0,78 (0,64-0,96); p= 0,01 PRO MET -30 VALUE (ARA II vs CA) 4,2 0,77 (0,69-0,86); p= 0,0001 ATEN HCTZ NIF VER DOXA -40 0,50 0,75 1 1,25 IECA ARA II drpp 2009 drpp 2009
  • 4. ARA II en Nefropatía Diabética Referencia drpp 2009 Referencia drpp 2009