50% ICC

SHEP. 4,5 años

BENEFICIOS DE LA REDUCCIÓN DE LA PA

5-6 mmHg PA diastólica y 10-12 mmHg PA sistólica

35-40 % ACV35-40 % ACV

20-25 % IM20-25 % IM

Reducción del Riesgo de EC y ACVcon reducción de la PAD (5-6 mmHg)

Estudio(s)

HDFPMRC12 másTodos

HDFPMRC12 másTodos

Estudio(s)

HDFPMRC12 másTodos

HDFPMRC12 másTodos

Eventos

ACVACV102:15860:109127:217

ECEC275:343222:234174:194

Eventos

ACVACV102:15860:109127:217

ECEC275:343222:234174:194

Modificado de Lancet 1990;335:833Modificado de Lancet 1990;335:833

Relación de ProbabilidadesRelación de Probabilidades

ACV ECACV EC

MejorTratamiento

MejorTratamiento

PeorTratamientoPeorTratamiento

Esperados 35-40% Evitados 42%

Esperados 35-40% Evitados 42%

Esperados 20- 25%Evitados 14%

Esperados 20- 25%Evitados 14%

0.5 1.0 1.50.5 1.0 1.5

CardioproteccionHipertensión

Nicolás Jaramillo GómezInternista – CardiólogoClinica Las Americas

CEMDE

EL MOSAICO DE LA PROTECCION CARDIO VASCULAR

A PESAR DEL ENTENDIMIENTO DEL PROBLEMA Y DE LA IDENTIFICACION DE GRUPOS A RIESGO...

AÚN ESTAN FALTANDO PIEZAS EN LA OBTENCION DE LA PROTECCIÓN C.V.

LA HIPERTENSION ARTERIAL MARCA EL INICIO DEL “CONTINUUM” CARDIOVASCULAR

5487 M

Trials on “New” vs “Old” Treatments Primary Endpoints (RR + 95% CI)

Mancia G. et al., 2003

CAPPP*

STOP2*

ANBP2*

ALLHAT°

STOP2*

NORDIL*

INSIGHT*

ALLHAT°

INVEST*

ALLHAT°

SCOPE*

LIFE*

ACE-I

ACE-I

ACE-I

ACE-I

CCB

CCB

CCB

CCB

CCB

B

ARB

ARB

n = 10985

n = 4418

n = 6083

n = 9054

n = 4209

n = 10881

n = 6321

n = 9048

n = 22599

n = 24335

n = 4506

n = 9193

0.5 1.0 2.0

New better Old better

1.05 (0.90-1.22)

1.01 (0.84-1.22)

0.89 (0.79-1.00)

0.99 (0.91-1.08)

0.97 (0.80-1.17)

1.00 (0.87-1.15)

1.10 (0.91-1.34)

0.98 (0.90-1.07)

0.98 (0.90-1.06)

1.03 (0.90-1.17)

0.89 (0.75-1.06)

0.87 (0.77-0.98)

* CVD; ° CHD

Trials on “New” vs “Old” Treatments Primary Endpoints (RR + 95% CI)

ALLHAT Vs ANBP2

Diferencias marcadas aun con los mismos objetivos.

Tto de HTA es complicado: Tiempo y análisis

Trabajos de investigación: Descubren poblaciones promedio para el propósito de desarrollar guías, mientras que los MD deben enfocarse en pctes individuales con Rx clinica

Trials on “New” vs “Old” Treatments Primary Endpoints (RR + 95% CI)

ALLHAT Vs ANBP2

En Hipertensión: Únicos Fenotipos y tratamientos antihipertensivos

Viejos ttos rencauchados (tiazidas)

Tratamiento: Única Talla !!!!!!!!!!

Antioxidative protection in hypertensive patients treated with diuretics

Skalska, A.; Gasowski, J.; Stepniewski, M.; Grodzicki, T.American Journal of Hypertension 18(8):1130-1132, 8/1/2005

Background: Recently results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that a thiazide diuretic was unsurpassed by any other drug class studied in achieving the level of cardiovascular protection, a finding reflected in the recent Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC7) recommendations. Oxidative stress has been found to be one of the key players in the pathophysiology of cardiovascular disease at large. The objective of this study was to check the hypothesis that diuretics may favorably affect the oxidative status of plasma, which could account in part for the results of recent trials. Methods: In addition to the routine workup in a series of 39 medically treated hypertensive patients, we analyzed the level of antioxidative protection afforded by the ferric-reducing ability of plasma (FRAP), according to class of drug used.

Results: We found that patients taking diuretics had significantly better antioxidative protection expressed by the higher levels of FRAP. Although the limited number of patients did not allow us to exclude the influence of other variables in the multiple regression analysis, we did not observe any differences in the level of FRAP when the group was divided according to the other drug classes, gender (men versus women), smoking, diabetes mellitus, duration of treatment, concomitant therapy, or level of uric acid.

Conclusions: The use of thiazide diuretics seems to be associated with better antioxidative protection. This observation may add to the explanation of the results of recent trials in hypertension.

ANG II AND THE ATHEROTHROMBOTIC PROCESS

Endothelial activation

Wall inflammation& plaque formation

Rupture &thrombosis

Weiss D et al, Am J Cardiol 2001;87[suppl]:25C-32C

Endothelial cells Monocytes VSMCs Macrophages Platelets

AT1

ANG II

AT1

ANG II

AT1

ANG II

AT1

ANG II

AT1

ANG II

EL MOSAICO DE LA PROTECCION CARDIO VASCULAR

LOS ESTUDIOS CLINICOS HAN DEMOSTRADO QUE EL EMPLEO DE BLOQUEANTES DEL SISTEMA “RAA” PARA INTERRUMPIR

SU EXPRESION EXAGERADA REDUCE LA MORTALIDAD

* MORBILIDAD Y MORTALIDAD CARDIOVASCULAR * LA HIPERTROFIA VI * EL DETERIORO RENAL

* EL ACCIDENTE CEREBRAL ISQUEMICO * LA RESISTENCIA A LA INSULINA (DIABETES DE NOVO)

CUAL ES EL PRESENTE Y EL FUTURO EN CUAL ES EL PRESENTE Y EL FUTURO EN

LA PROTECCION DEL RIESGO GLOBAL?LA PROTECCION DEL RIESGO GLOBAL?

Especialmente en la subpoblación diabética

Sobre expresión de Receptores AT1 Causa hipertrofia/ Ratones transgenicos

Apoptosis y fibrosis miocárdica

Hipertrofia cardiacaRatones Tg-WT / Tg-i2m

Sobre expresión de Receptores AT1 Causa hipertrofia/ Ratones transgenicos

Recent Hypertension Trials With “New” Versus “Old” Drugs

Primary Endpoint (RR + 95% CI)

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

CAPPP captopril p=0.52 (n=10.985) Lancet 1999

STOP-2 ACEIs/CCBs p=0.89 (n=6.614) Lancet 1999

NORDIL diltiazem p=0.97 (n=10.948) Lancet 2000

INSIGHT nifedipine GITS p=0.34 (n=6.321) Lancet 2000

ALLHAT doxazosin p=0.71 (n=24.335) JAMA 2000

ALLHAT ACEIs/ CCBs p=0.65 (n-33,357) JAMA 2002

ANBP-2 ACEIs p=0.05 (n=6083) NEJM 2003

VALUE ARB/CCB p=0.49 (n=15,245) Lancet 2004

LIFE losartan p=0.021 (n=9.193) Lancet 2002

Old Drugs Better New Drugs Better

Hansson et al 1998

00

55

1010

1515

2020

2525

3030

105105 100100 9595 9090 8585 8080

% REDUCCIÓN DEL RIESGO

REDUCCIÓN ÓPTIMA DE TAD EN EL ESTUDIO HOT

PAD alcanzada en mm HG

Subgrupo diabéticosSi la PAD era menor

de 80 mmHg: Disminución problemas

CV en un 50%

El riesgo de un evento cardiovascular mayor se redujo en un 30% en el estudio HOT

(Felodipino y ASA)

Effect of BP on CHD Mortality MRFIT

100+ 90-99 80-89 75-79 70-74 <70

140-159120-139

<120

CHD death rateper 10,000 person-years

160+

Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

DBP (mm Hg)

SBP(mm Hg)

21

10 12 9 9 9

2417 14 13 13 12

2525252317

24

40 37 3544

38

8181

Reversión de Hipertrofia V.I con tratamiento anti-hipertensivo

Mean values and 95% confidence intervals adjusted for duration are given.

*p<0.01 between drug classes.†p<0.10 between drug classes.

Change in

LV mass

index

(%)

0

-5

-10

-15

-20

-25

Diuretics -blockers

Calcium-channelblockers

ACEinhibitors

*†

7%6%

9%

13%

Schmieder RE et al. JAMA. 1996;275:1507–1513.

1. Savage DD et al Circulation 1979;59:6236322. Devereux RB et al Hypertension 1982;4:5245313. Devereux RB et al Circulation 1983;68:4704764. Kannel WB et al Ann Intern Med 1969;71:891055. Dunn FG et al J Hypertens 1990;8:775782

6. Levy D Drugs 1988;35(suppl 5):157. Kannel WB Am J Med 1983;75(suppl 3A):4118. Bella JN et al Am J Cardiol 2001;87:1260-12659. Palmieri V et al Circulation 2001;103:102-107

Left-Ventricular Hypertrophy (LVH)

Approximately 40% of mild-to-moderate hypertensive patients have LVH1-5,8-9

LVH increases the risk of 6

stroke x 3-10

myocardial infarction (MI) x 2-5

angina pectoris x 1-6

heart failure x 6-17

Up to one-third of patients with LVH die from cardiovascular disease within 5 years of diagnosis7

LIFE: Puntos Finales del Estudio

•Riesgo ajustado para el grado de hipertrofia VI yRiesgo ajustado para el grado de hipertrofia VI ypuntaje Framingham en el momento de la randomización. puntaje Framingham en el momento de la randomización.

Dahlöf et al. Lancet. 2002;359:995-1003.

0,5 0,75 1 1,25 1,5

RR Ajustado* (CI 95%)

Favorece al Losartán

Favorece alAtenolol

Punto finalLosartán

n (%)Atenolol

n (%) P

Punto final primario compuesto

508 (11%)

588 (13%)

.021

Mortalidad CV 204 (4%) 234 (5%) .206

Accidente cerebrovascular

232 (5%) 309 (7%) .001

IM 198 (4%) 188 (4%) .491

Falla cardíaca 153 (3%) 161 (4%) .765

Diabetes de aparición reciente

241 (6%) 319 (8%) .001

Oparil et al. Ann Intern Med 139:761-76, 2003.

ANG II ANG IIDOS VIAS

How to explain the differences between renin angiotensin system modulators

(Ang II) plays important roles in the development of cardiovascular diseases including hypertension, renal diseases, cardiac hypertrophy, congestive heart failure, and ischemic heart disease. Angiotensin II exerts classic hemodynamic and renal effects, but it is also a local

biologically active mediator with direct effects on endothelial and smooth muscle cells. Two subtypes of Ang II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Their roles have been investigated in depth in vivo and in vitro, although few data are available

concerning the role of the AT(2) receptors in the adult circulation in humans. The two receptors, both of which belong to the superfamily of G-protein-coupled receptors, have different signaling pathways and different functions. The AT(1) receptor subtype is expressed

ubiquitously and is involved in most of the well-known biological functions of Ang II. The AT(1) receptor transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell

proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress. In contrast to AT(1), the physiologic role of AT(2) receptors has long remained an enigma. The AT(2) receptors are highly expressed in fetal tissues, although their expression dramatically decreases after birth, being restricted to a few organs, including the cardiovascular system. The AT(2) receptor is re-

expressed in the adult animal after cardiac and vascular injury and during wound healing, suggesting a role for this receptor in tissue remodeling, growth, or development. Recent and concordant data suggested that overstimulation of AT(2) receptors might be implied in cardiac and vascular hypertrophic processes. Both Ang II receptors are involved in hypoxia-induced neovascularization. A large set of experimental evidence suggests that activation of the AT(1) receptor results in proangiogenic effects, whereas AT(2) receptors mediate

apoptosis and thus antiangiogenic effects. Furthermore, bradykinin through its B-1 or B-2 receptors is a potent activator of experimental hypoxia-induced neovascularization.

Thus, pharmacologic blockade of the AT(1) receptor and resulting overactivation of AT(2) receptors could impair or delay neovascularization in ischemic tissues in

patients receiving chronic treatment with angiotensin receptor blockers. In contrast, increased tissue bradykinin resulting from inhibition of converting enzyme could help to

restore functional vascularization in ischemic tissues.

These basic concepts deserve a second reading and re-evaluation to discuss differences in vascular protection in large clinical trials with different classes of drugs acting on the renin-

angiotensin system.

Levy, B.I.American Journal of Hypertension 18(9 Part 2):134S-141S, 9/1/2005

Association of Atrial Natriuretic Peptide and Type A Natriuretic Peptide Receptor Gene Polymorphisms With Left Ventricular Mass in Human Essential Hypertension Speranza Rubattu, MD*,

OBJECTIVES: The goal of our study was to investigate the relationships between atrial

natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type A natriuretic peptide receptor (NPRA) gene polymorphisms and left ventricular structure in human essential hypertension.

BACKGROUND: Experimental evidence supports a key role for natriuretic peptides in the modulation of cardiac mass. This relationship has not yet been described in human disease.

METHODS: A total of 203 hypertensive patients were studied by mono-bidimensional echocardiography. Three markers of the ANP gene (–C664G, G1837A, and T2238C polymorphisms) and a microsatellite marker of both NPRA and BNP genes were characterized.

RESULTS: Patients carrying the ANP gene promoter allelic variant had increased left ventricular mass index (117.4 ± 1.7 g vs. 95.7 ± 1.7 g, p = 0.005), left ventricular posterior wall thickness (1.14 ± 0.07 cm vs. 0.96 ± 0.01 cm, p < 0.0001), left ventricular septal thickness (1.12 ± 0.10 cm vs. 1.04 ± 0.01 cm, p = 0.01), and relative wall thickening (47.5 ± 4.1% vs. 39.4 ± 5.3%, p = 0.001) as compared with the wild-type genotype. These associations were independent from anthropometric factors and major clinical features and were confirmed in a large subgroup of never-treated hypertensive patients (n = 148). Carrier status of the ANP gene promoter allelic variant was associated with significantly lower plasma proANP levels: 1,395 ± 104 fmol/ml versus 3,110 ± 141 fmol/ml in hypertensive patients carrying the wild-type genotype (p < 0.05).

A significant association for NPRA gene variants with left ventricular mass index and left ventricular septal thickness was found. The analysis of BNP did not reveal any effect on cardiac phenotypes.

CONCLUSIONS: Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.

LeptinaLeptina

SISTEMA NERVIOSO CENTRALSISTEMA NERVIOSO CENTRALSistema nervioso simpáticoSistema nervioso simpático

Sistema neuroendocrinoSistema neuroendocrino

AdipocitosAdipocitos

ResistinaResistina

TEJIDOS PERIFÉRICOSTEJIDOS PERIFÉRICOSMúsculoMúsculoHígadoHígado

Balance energético negativoBalance energético negativo

Balance energético positivoBalance energético positivo

Gasto energético incrementadoGasto energético incrementadoIngesta de alimentos disminuidaIngesta de alimentos disminuida

AdiponectinaAdiponectina

Resistencia a la insulinaResistencia a la insulina

TNF-aTNF-aPAI-1PAI-1AGLAGL

Shuldiner A.R. NEJM 2001;345:1345-46Shuldiner A.R. NEJM 2001;345:1345-46

SRAA

IL1, IL6IL1, IL6

AngiotensinógenoAngiotensinógeno

Angiotensina IIAngiotensina II

Infl

am

ació

n V

asc

ula

r y

Dis

fun

ció

n E

nd

ote

lial

Infl

am

ació

n V

asc

ula

r y

Dis

fun

ció

n E

nd

ote

lial

Infl

am

ació

n V

asc

ula

r y

Dis

fun

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n E

nd

ote

lial

Infl

am

ació

n V

asc

ula

r y

Dis

fun

ció

n E

nd

ote

lial

InflamaciónInflamaciónyy

TrombosisTrombosis

DiabetesDiabetesTipo 2Tipo 2

SíndromeSíndromeMetabólicoMetabólico

HiperglicemiaHiperglicemia

Journal of Human Hypertension Lowering of blood pressure leads to decreased circulating

interleukin - 6 in hypertensive subjects

Interleukin- 6 ( IL- 6), the major proinflammatory cytokine, has been described to be associated with the hypertensive and atherosclerotic states

.We aimed to explore whether the concentration of circulating IL- 6 and adhesion molecules could be modified by decreasing blood pressure in hypertensive subjects. A total of 30 subjects ( 18 men), aged 34 - 48 years, were enrolled in this study, 17 hypertensive never- treated patients ( HTA) and 13 normotensive subjects ( C). HTA subjects were treated with irbesartan, 150 - 300 mg/ day for 3 months, and serum IL- 6, vascular cell adhesion molecule- 1, intercellular adhesion molecule- 1, sP- selectin, sE- selectin and monocyte chemoattractant protein- 1 were measured at 0 and 12 weeks.

The two study groups were similar in age, body mass index ( BMI) and gender. At baseline, circulating IL- 6 levels, but not adhesion molecules, were significantly associated with systolic blood pressure ( r = 0.41; P = 0.03) and BMI ( r = 0.53; P = 0.005). Systolic and diastolic blood pressure decreased significantly ( P < 0.01) in parallel to serum IL- 6 levels ( from 3.72 +/- 0.82 to 3.23 +/- 0.19 pg/ ml, P = 0.02) reaching a similar concentration to normotensive patients ( 3.33 +/- 0.3 pg/ ml) after treatment with irbesartan. No significant changes were observed in any other of the tested parameters.

In conclusion : the treatment of high blood pressure lowers circulating IL- 6 in young hypertensive patients.

VazquezOliva, G.; FernandezReal, J.M.; Zamora, A.; Vilaseca, M.; Badimon, L.Vol: 19, Nro: 6, Págs. 457 - 462. Fecha: 01/06/2005

Activación Colágeno IIIFormación placa Diabéticos

Journal of Human Hypertension Further evidence for low-dose combinations in patients with

left ventricular hypertrophy

Dahlof, B. Vol: 19, Nro: Suppl. 1, Págs. S9 - S14. Fecha: 01/06/2005

Left ventricular hypertrophy (LVH) is a powerful independent risk predictor for cardiovascular disease and reversal of LVH has become a primary goal of anti-hyperensive management.

Recent evidence has confirmed that most hypertensive patients will benefit from a low-dose combination strategy to manage their hypertension, and two trials have recently examined the effect of this strategy on left ventricular mass. The REASON study (pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study) compared the low-close combination of an anglotensin-converting enzyme (ACE) inhibitor and a diuretic with beta-blocker monotherapy in hypertensive patients with LVH, and the PICXEL study (Preterax In a double-blind Controlled study versus Enalapril in LVH) compared the same low-dose combination with ACE inhibitor monotherapy in hypertensive patients with echocardiographic LVH. The REASON study demonstrated that the low-dose combination produced a significantly greater change in left ventricular mass after 1 year than the beta-blocker, despite inducing a similar change in mean blood pressure.

Additionally, perindopril/indapamide reduced central (carotid) and peripheral (brachial) systolic blood pressure (SBP) and pulse pressure (PP) to a significantly greater extent than beta-blocker, and these benefits were more pronounced for the central values;

LVH is affected more by central rather than peripheral haemodynamic changes.

Results of the analysis of the PICXEL study showed a significantly greater decrease in LVH parameters and blood pressure over 1 year in favour of the low-dose combination. This reduction cannot be entirely explained by the better efficacy of the low-dose combination on blood pressure reduction.

Estudio CAMELOT

Regresión de ateromasEstudio CAMELOT

Estudio CAMELOT

EL MOSAICO DE LA PROTECCION CARDIO VASCULAR

ESTUDIOS RECIENTES HAN DEMOSTRADO QUE LOS EFECTOS BENEFICOS DEL BLOQUEO DEL SISTEMA “RAA” NO PUEDEN SER EXPLICADOS SÓLO POR EL CONTROL DE LA T.A. * ANTIHIPERTROFIA Y REMODELACION * EFECTOS ANTITROMBOTICOS * DONANTE DE OXIDO NITRICO * ANTIINFLAMATORIOS + ANTIFIBROTICOS?

Am J Cardiol 2001:87(Supl):25C.32C * MODULADOR DE APOPTOSIS ? CIRCULATION. 2004: 109: 8-13

* DIFERENCIACION DEL ADIPOCITO? Circulation. 2004;109:2054-2057.

* MEJORIA EN ACTIVIDAD DE LA INSULINA? Hypertension. 2004; 43;1003-1010

* INDUCCION DE PPAR? Circulation. 2004;109:2054-57

CUAL ES EL PRESENTE Y EL FUTURO EN LA PROTECCION DEL RIESGO GLOBAL?

Eventos en UKPDS: Control Estricto vs Control Menos Estricto de la PA

0

10

20

30

40

50

60

70

80

UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

PA media alcanzada con control PA media alcanzada con control estricto 144/82 mm estricto 144/82 mm HgHgPA media alcanzada con control PA media alcanzada con control estricto 144/82 mm estricto 144/82 mm HgHg

PA media alcanzada con control PA media alcanzada con control menos estricto menos estricto 154/87 mm Hg154/87 mm HgPA media alcanzada con control PA media alcanzada con control menos estricto menos estricto 154/87 mm Hg154/87 mm Hg

Eve

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s po

r 1

000

pa

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Eve

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000

pa

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Cualquier punto Cualquier punto final relacionado final relacionado

con diabetescon diabetes

Muerte Muerte relacionada relacionada con diabetescon diabetes

Accidente Accidente cerebrovascularcerebrovascular

ComplicacionesComplicacionesmicrovascularesmicrovasculares

PP=.005=.005

- 24% - 24%

PP=.02=.02

- 32%- 32%

PP=.02=.02

- 32%- 32%PP=.01=.01

- 44%- 44%

PP=.01=.01

- 44%- 44%

PP=.009=.009

- 37%- 37%

PP=.009=.009

- 37%- 37%

n= 1148 (25-65 AÑOS) 8.4 años Segn= 1148 (25-65 AÑOS) 8.4 años Seg

EXPEDITED REVIEW: EDITORIAL COMMENT

Optimal Blood Pressure Levels in Patients With Coronary Artery Disease

Jonathan Tobis, MD, FACC ,* and Gregg C. Fonarow, MD, FACC Division of Cardiology,

University of California, Los Angeles, California * Reprint requests and correspondence: Dr. Jonathan Tobis, UCLA Division of

Cardiology, 47-123 CHS, 10833 Le Conte Avenue, Los Angeles, California 90095-1679 (Email: jtobis@mednet.ucla.edu ).

Perhaps what has traditionally been considered "normal" BP is not

necessarily optimal nor healthy in patients with coronary artery disease.

Gracias por su atención