ROGÉRIO BAUMGRATZ DE PAULA

PROFESSOR TITULAR - NEFROLOGIA

UNIVERSIDADE FEDERAL DE JUIZ DE FORA - MG

OBESIDADE COMO CAUSA DE HIPERTENSÃO PRIMÁRIA OU SECUNDÁRIA

1- Obesidade causa hipertensão - secundária

2- Obesidade associa-se à hipertensão primária

3- Resumo mecanismos

OBESIDADE COMO CAUSA DE HIPERTENSÃO PRIMÁRIA OU SECUNDÁRIA

Arch Intern Med. 2002;162:1867-1872

Obesidade e Hipertensão - Framingham

Srinivasan and cols

Hypertension. 2006;48:33-39

THE BOGALUSA HEART STUDY

The childhood origins of obesity-relatedhypertension are well illustrated in a study of260,000 overweight and obese children in Germany

and Switzerland, in which 35% had hypertension

with increased ventricular mass or arterial stiffness.

International Journal of Obesity (2010) 34, S32–S36

Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors

N Engl J Med 2011;365:1876-85

group I normal BMI in childhood - non obese as adults;group II overweight or obese in childhood - non obese as adults;group III overweight or obese in childhood - obese as adultsgroup IV normal BMI in childhood - obese as adults

Consistently stable or decreased body mass index in young adulthood and longitudinal changes in metabolic syndrome components

Lloyd-Jones, DM and cols

Circulation. 2007;115:1004-1011

Solid, baseline BMI of 20.0 to 24.9 kg/m2; dashed, baseline BMI of 25.0 to 29.9 kg/m2;

dotted, baseline BMI of 30.0 to 34.9 kg/m2).

Mensagem 1

Obesidade parece ser causa de hipertensão secundária…

…Inconsistências

Molenaar E A and cols

Diabetes Care 31(7):1367–1372, 2008

Burden and Rates of Treatment and Control of Cardiovascular Disease Risk Factors in Obesity

The Framingham Heart Study

Arch Intern Med. 2002;162:1867-1872

Population attributable risk percentage effects for overweight and obesity

Framingham men and women followed up for 44 years.

Obesidade e hipertensão se associam

Overweight and hypertension: a 2-way street?

Julius S et al. (2000) Hypertension 2000; 35: 807–813

Allemann Y and cols

Journal of Hypertens 2001, 19:2143±2148

Acúmulo central de gordura em obesos com história familiar de hipertensão - 5 anos

Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric Surgery

- SOS Study -

SjöströmN Engl J Med 2004;351:2683-93

Kotsis V and cols

Hypertension. 2005;45:602-607

AFERIÇÃO PRESSÓRICA EM OBESOS

Hipert. Consult. 12,5% magros vs 35,3% obesosNormotensos 58,1% magros vs 10,6% obesosHipertensos 43,7% obesos vs 23,4% magros

MAPA EM OBESOS - “white-coat”

“The first step to improving your health is to choose healthy parents” (Anonymous)

Association of Rho/Rho-kinase gene polymorphisms and expressions with obesity-related metabolic syndrome

European Review for Medical and Pharmacol Sciences

2015; 19: 1680-1688

… in obese NOS3 894T allele may enhance hypertension

risk…

Journal of Physiol and Pharmacol2015, 66, 5, 681-689

Urate Transporter Gene SLC22A12 Polymorphisms Associatedwith Obesity and Metabolic Syndrome in Caucasians withHypertension

Kidney Blood Press Res 2012 ; 35(6): 477–482

Genetic Variation in the Raptor Gene Is Associated With Overweight But Not Hypertension in American Men of Japanese Ancestry

Am Journal of Hyperten2015; 28(4):

Association Between SAH, an Acyl-CoA Synthetase Gene, and Hypertriglyceridemia, Obesity, and Hypertension

Circulation. 2002;105:41-47

Association between the Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma2 gene and increased 24-h diastolic blood pressure in obese patients with type II diabetes

Journal of Human Hypertension (2006) 20, 684–692 & 2006

Association of angiotensin-converting enzyme DD genotype

with blood pressure sensitivity to weight lossAm Heart J 2002;144:625-9

B2- and B3 -Adrenergic Receptor Polymorphisms Are Related to

the Onset of Weight Gain and Blood Pressure Elevation Over 5 Years

Circulation. 2005;111:3429-3434

…

Pausova Z and cols

Hypertension 2001;38:41-47

Fatores genéticos e co-segregação de HA e OBE

Heritability Estimates of Obesity Measures in Siblings With and Without Hypertension

Journal of Hypertension 2015, 33:1499–1508

He D and cols

Metabolism 2014; 63:633 – 639

FTO gene variant and risk of hypertension: A meta-analysis of 57,464

hypertensive cases and 41,256 controls

Mensagem 2

Co-segregação entre HA e obesidade (SM)

Pacientes de alto risco cardiovascular e metabólico

Excesso de peso mecanismo central na indução de hipertensão primária

Circunferência da cintura aumentada 85,8%

Excesso de peso 78,6%

Sedentarismo 69,0%

Etilismo 18,0%

Tabagismo 13,0%

Síndrome metabólica 40,0%

Glicemia de jejum ≥100 mg/dL 60,0%

Triglicérides ≥150 mg/dL 45,0%

Colesterol total ≥ 200 mg/dL 49,6%

Baixo HDL colesterol 43,3%

LDL colesterol ≥100 mg/dL 23,5%

Disfunção diastólica 76,0%

Hipertrofia ventricular esquerda 46,0%

Índice tornozelo braço alterado 42,0%

Taxa de filtração glomerular estimada <60mL/min 50,0%

Hipertensos Graves - ASS (943 pacientes)

MECANISMOS DA HIPERTENSÃO ASSOCIADA À OBESIDADE

Retenção salina

Ativação renina-angiotensina

Ativação simpático

… apnéia sono, microbiota, inflamação, ácido úrico, insulina, disfunção endotelial...

What about aldosterone ?

Hall JE, Kuo JJ, Silva AA, Paula RB, Liu J and Tallam L

Current Opinion in Nephrology and Hypertyension, 2003

Mechanisms of obesity-associated hypertension

Lipotoxicidade

C-C motif chemokine ligand 2

(CCL2 = MCP-1)

Neels, J. G. et al. J. Clin. Invest. 2006;116:33-35

Inflamed fat:

what starts the fire?

Aldosterone

ALDOSTERONA – NOVO PARADIGMA

CÓRTEX ADRENAIS – RIM – CORAÇÃO

CÉREBRO – TEC ADIPOSO

ESTIMULO - K+ - ACTH – AII

É APENAS UM DOS LIGANTES DO MR

AGE DCC – Retenção Na+ Excreção K+

HIPERTENSÃO 1a / REFRATÁRIA/ OBESIDADE

Fuller PJ and Young MJHypertension. 2005;46:1227-1235

Inflamação

Fibrose

Estresse Oxidativo

Apoptose

NON-NUCLEAR ACTIONS

Hemodinâmica Metabólica Renal

MR blockade in a model of obese dogs - high fat diet

MR Blockade attenuates blood pressure increase

during high fat diet

M

AP

(m

mH

g)

0

4

8

12

16

20

High Fat Diet

* *

C 1 2 3 4 5

*

untreated

eplerenone

de Paula and cols

Hypertension 2004Time (weeks)

de Paula RB et al

Hypertension. 2003;43:1-7.

Hypertension. 2003;43:1-7.

... results from our studies suggest another potential

target for treating obese hypertensive subjects who are

resistant to the usual therapeutic approaches.

Av. ClinicaLaboratorial

BASAL (n=11)

ESPIRO (n=6)

PLACEBO (n=5)

PLACEBO

(n=6)

8 SEMANAS 8 SEMANAS 8 SEMANAS

BLOQUEIO DA ALDO EM OBESOS NÃO DIABÉTICOS

GRUPO 1

GRUPO 2

GRUPO 2

GRUPO 1

Av. ClinicaLaboratorial

Av. ClinicaLaboratorial

ESPIRO (N=5)

Costa MB and cols

Bloqueio da Aldosterona reduziu PA obesos

0

20

40

60

80

100

120

140

Pré-espiro Pós-espiro

PA sist

PA diast

*

*

****

* p=0,001

** p=0,005

Costa MB and cols

Bloqueio da aldosterona reduziu hiperfiltração

BASAL ESPIRO PLACEBO

ClCr (ml/min) 171 ± 33 137 ± 41 * 146 ± 42

Microalbuminúria(mg/24hs)

5,5 ± 2 11 ± 7 21 ± 35

* p<0,05 vs controle

Costa MB and cols

PERFIL METABÓLICO FAVORÁVEL EM INDIVÍDUOS COM SM

BASAL ESPIRO PLACEBO

Glucose (mg/dL) 99 ± 9.2 86 ±14.2 * 86 ±12.7 *

HOMA-IR 3.3 ± 2.49 2.7 ± 1.95 2.4 ±1.66

LDL-cholesterol (mg/dL)

115 ± 33.2 117 ± 57.1 93 ± 34.0

HDL-cholesterol (mg/dL)

41± 9.1 49 ±12.2 * 52 ± 18.7 *

Triglycerides (mg/dL)

199 ± 86.3 160 ± 66.5 *

170 ± 96.7

Potassium mEq/L 4 ± 0.1 4 ± 0.3 4 ± 0.3

Costa MB and cols

In the present study, it was demonstrated for the first time that

spironolactone promoted a significant reduction in BP in obese and

hypertensive patients with MetS without changing plasma glucose or

lipids levels….

Aldosterone Antagonist Decreases Blood Pressure and Improves Metabolic

Parameters in Obese Patients With the Metabolic Syndrome

Costa MB and cols

Journal of Clin Hypertens, 2010

Ezequiel DAG e cols

JBN 2013

Existe espaço para a espirolactona no tratamento

da HA associada à SM?

Hipertensos com SM não diabéticos (n=27)

16 semanas Espirolactona 25-50 mg/dia

Pré-espiro Pós-espiro p

IMC 34,0 ± 3,83 34,1 ± 3,93 0,822

C Abdominal 109,6 ± 8,17 111,3 ± 8,01 0,155

PAS 24 horas 143,3 ± 15,79 132,1 ±17,53 0,024

PAD 24 horas 84,8 ± 11,23 78,4 ± 10,99 0,023

Parametros clínicos - MAPA

Ezequiel DAG e cols

JBN 2013

Tsuchiya, 2009

Aldosterona e disfunção endotelial

0

2

4

6

8

10

12

14

PRÉ PÓS

*

Lovisi JCM et al

JBN 2012

%

VDFM EM SM

Espiro reduziu inflamação em hipertensos com SM

VARIÁVEL PRÉ-ESPIRO PÓS-ESPIRO P

IL- 6 71 + 30 59 + 20 0,004

log PCR 0,63 + 0,40 0,40 + 0,46 0,003

Lovisi JCM, Ezequiel DGA et al

15.2±5.3 mmHg 5.9±5.3 mmHg

Ezequiel DAG and colsSubmmited, 2016

Mineralocorticoid receptor blockade lowers systolic blood pressure in obese patients with metabolic syndrome

Mineralocorticoid receptor blockade lowers blood pressure and improves endothelial function in obese patients with metabolic syndrome

Ezequiel DAG and colsSubmmited, 2016

Variable ESPIRO diff.

(CI 95%)

AMLO diff.

(CI 95%)

Effect P-value

FPG (mg/dL) 0.8 (-2.53: 4.13) 5.5 (1.37: 9.57) -4.7 (-10. 25:0. 90) 0.096

HOMA-IR 0.2 (-0.60: 0.92) 0.8 (-0.17: 1.75) -0.6 (-1.86: 0.61) 0.306

Potassium (mEq/L)

0.1

(-0.03: 0.33)

0.1

(-0.08: 0.35)

0.0 0.907

HDL-cholesterol (mg /dL)

4.6

(1.88: 7.32)

1.8

(-1.44: 5.15)

2.7

(-1.6: 7.07)

0.202

Triglycerides

(mg/dL)

-14.1

(-35.90: 7.67)

-22.7

(-48.36: 4.33)

7.9

(-26.52: 42.33)

0.639

CRP-hs (mg/L) -1.0

(-1.93: -0.69)

1.9

(0.81: 3.06)

-2.9

(-4.42:- 1.45)

0.000

Plasma

aldosterone (ng/dL)

9.15

(5.7: 12.5)

0.83

(-3.75: 5.41)

8.3

(2.53: 14.11)

0.007

Urinary Albumin

Excretion

(mg/gcreatinine)

-10.9

(-19.79:- 1.99)

-0.19

(-11.62: 11.23)

-10.7

(-25.63: 4.24)

0.152

FMD (%) 4.9

(2.18: 7.70)

-3.9

(-7.25: -0.54)

8.8

(4.39: 13.28)

0.000

EVALUATION OF EFFICACY, TOLERABILITY AND METABOLIC EFFECTS OF MCR BLOCKADE IN OBESE

HYPERTENSIVE PATIENTS

CLINICAL TRIAL

ROMPER INÉRCIA

Resultados: parâmetros metabólicos

Pré-espiro Pós-espiro valor p

Glicemia jejum 89,9 ± 3,83 91,50 ± 3,93 0,822

Insulina jejum 18,3 ± 24,40 14,8 ± 9,18 0,434

HOMA IR 4,0 ± 5,73 3,2 ± 1,98 0,478

HDL 38,0±7,10 44,9±6,97 0,000

Rel TRIG/HDL 4,6 ± 3,14 3,5 ± 1,51 0,010

Triglicérides 187,4 ±97,38 167,4 ± 71,34 0,065

Aldosterona 6,9 ±3,91 21,2 ±12,34 0,000

Potássio 4,2 ±0,32 4,4 ±0,35 0,026

Rel ALDO/APR 11,4 ±13,86 10,46 ± 8,33 0,705

PCR ultra-sensível 6,4 ± 3,91 4,7 ±6,40 0,079

Ezequiel DAG e cols

JBN 2013

Obesity-associated hypertension is ameliorated in patientswith TLR4 single nucleotide polymorphism (SNP) rs4986790

…in obesity associated hypertension TLR4 SNP rs4986790 cases present a lower SBP,

pulse pressure and less hypertension.

Schneider et al.Journal of Inflammation (2015)

Yang J and colsPLOS ONE, 2014; 9 (6): 1-8

Genetic Association Study with Metabolic Syndrome and Metabolic-Related Traits in a Cross-Sectional Sample and a 10-Year Longitudinal Sample of Chinese Elderly Population

NATURE REVIEWS | ENDOCRINOLOGY VOLUME 10 | JUNE 2014 | 369

adi pose tissue stimulate adrenal aldosterone secre-

tion.157–159 Endo thelial dysfunction160 and enhanced

vas cular smooth muscle reactivity have both been

impli cated in the modulation of vascular remodelling

by aldo sterone.98 Patients with primary hyper aldo stero-

nism can be insulin- resistant, and aldosterone levels

have been corre lated with BMI and insulin resistance

in patients with obesity who are normotensive.161 The

precise role of aldosterone-induced vascular insulin

resis tance has not been fully elucidated; however, sup-

pression of local inflammation and vascular stiffness

by the mineralocorticoid antagonist spironolactone in

rodent models of hyper tension and insulin resistance has

been reported.98,162 Aldo sterone activates nicotinamide

adenine dinucleotide phosphate-oxidase (NADPH),

which promotes oxidative stress and decreases NO bio-

availability.163 Aldosterone also increases endothelial

stiff ness by modulating epithelial sodium channel expres-

sion on the endothelial cell surface and NO release.163

Spironolactone can lower blood pressure in patients with

obesity with elevated plasma aldosterone levels, although

insulin resistance is unchanged in these patients.161,164

Mineralocorticoid receptor antagonists might improve

insulin resistance in patients with hyperaldostero nism

in contrast to indivi duals with obesity in whom aldo-

sterone levels are only moderately elevated.164 How ever,

insulin resistance in obesity can also develop via other

pathways, including through the effects of over nutrition

and SNS over activation, meaning that mineralo corti-

coid receptor antagonists might not be appropriate in

this con text.40,165 In this regard, eplerenone, a drug with

higher binding specificity for the mineralo corticoid

receptor than spironolactone, improved flow- mediated

dilation in healthy indivi duals 55–79 years old.166 More-

over, impaired endothelial function was improved in

obese mice or exogenous- aldosterone-infused lean mice

with an endothelial-specific mineralo corticoid recep-

tor deletion.167 A subset of individuals with obesity

and hypertension might also have insulin-resistance-

related hyperaldosteronism, for which mineralocorticoid

receptor inhibitors might be useful to treat.168

Attenuation of Ang II-induced vascular damage by

mineralocorticoid receptor antagonists suggests a cross-

talk between the Ang II and aldosterone signalling path-

ways.84,169 For example, Ang II-induced vascular smooth

muscle contraction and hypertension are reduced in

mice with a deletion of mineralocorticoid receptor speci-

fic to smooth muscle cells.148 This study also suggests

mineralocorticoid receptor-regulated blood pressure is

indepen dent of hypertension induced by renal mecha-

nisms. Both the direct beneficial effects of mineralo-

corticoid receptor antagonists, and their role in reducing

Ang II-induced pathology support the adjunctive use

of mineralo corticoid receptor antagonists to manage

re sistant hy pertension in obesity.29,38

Immune and inflammatory mechanisms

Accumulating evidence suggests that in patients with

obesity, dysfunctional innate and adaptive immune and

inflammatory responses contribute to vascular dysfunc-

tion and the pathogenesis of hypertension. However, the

mechanisms and mediators of this relationship are still

not well understood. Immune-mediated injury in obesity

and hypertension can occur in the vasculature, central

nervous system, kidney and adipose tissue, including

perivascular tissue (Figure 1).112,170,171

Innate immunity

Macrophage infiltration into adipose tissue is associ-

ated with systemic insulin resistance.172 Distinct macro-

phage phenotypes elicit either a proinflammatory

(M1 macrophages) or an anti-inflammatory res ponse

(M2 ma crophages).172 Lipid-filled foam cells are a type of

acti vated M1 macrophage that secrete pro inflam matory

cytokines within the vascular wall.173 Pro inflamma-

tory cy tokines secreted by macrophages, such as TNF

and IL-6, contrib ute to insulin resistance by activating

kinases that phosphory late serine residues of IRS-1

and IRS-2 and lead to suppression of metabolic insulin

signal ling and promotion of growth factor signalling in

the vasculature.104

Adiposetissue

Airwayobstruction

OSA

SNSactivation

Kidney

Renin

Adrenal

LeptincPAP

Renaldenervation

Weight loss

Angiotensinogen

Oxidizedfatty acids

(non-classicalpathway)

Aldosterone

Sodiumretention

Hypertension

Vascular dysfunction

Ang II

Mineralocorticoid receptor antagonist

ARBs

Figure 2 | Possible mechanisms of obesity-associated hypertension and therapeutic

strategies. Adipose tissue releases leptin, angiotensinogen and oxidized fatty acids

to stimulate adrenal release of aldosterone via activation of the classic RAAS, as

well as a non-classical pathway mediated by oxidized fatty acids. Leptin stimulates

the central SNS which in turn leads to renin release from the kidney. Activation of

RAAS in other tissues contributes to renal and vascular dysfunction. Increased

adipose tissue can lead to OSA, which can be treated by therapeutic weight loss or

application of cPAP. OSA leads to activation of the SNS which activates RAAS in the

kidney. Increased aldosterone can be reduced with mineralocorticoid receptor

antagonists. Abbreviations: , increased; , decreased; ARBs, angiotensin type 1

receptor blockers; cPAP, continuous positive airway pressure; OSA, obstructive

sleep apnoea; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic

nervous system.

REVIEWS

© 2014 Macmillan Publishers Limited. All rights reserved

DeMarco, V. G. et al.

Nat. Rev. Endocrinol. 10, 364–376 (2014)

Am J Clin Nutr, 1956

Figure 1. Functional associations between the SNPs and the phenotypes. The figure depicted the biological functional associations between four SNPs and different traits of MetS. KCNQ1 (potassium voltage-gated channel KQT-like subfamily, member 1) is a gene encoding the poreforming subunit of a voltage-gated K+ channel (KvLQT1) that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport in the beta cells. T allele variant might inhibit the KV-channels in beta cells and enhance glucose-stimulated insulin secretion, which leads to an increased risk of diabetes. ACE gene encoding the angiotensin (Ang) and transform Ang I into Ang II, and the activation of Ang IImightincrease the storage of TG by influencing the glycolysis process and lead to the adipocyte hypertrophy. C allele variant of the INSIG2 gene was involved in the reversed cholesterol transport by an interaction with sterol regulatory element-binding proteins (SREBPs), which are transcription factors that activate the synthesis of cholesterol and fatty acids in the liver and other organs. In addition, A to C transition at nucleotide 1298 (A1298C, rs1801131) of the coding sequence in gene MTHFR, have been shown to be the most frequent genetic causes for mild hyperhomocysteinemia, and a high plasma concentration of homocysteine may predispose to atherosclerosis by injuring the vascular endothelium, which might result in

hypertension.

Yang J and colsPlos One 2014;9(6); e100548

ALDOSTERONA

Eplerenone attenuated GFR increaseG

FR

(m

l/m

in)

40

50

60

70

80

90

100

110

C 1 2 3 4 5

High Fat Diet

untreated

eplerenone

* p<0.05 vs untreated

Time (weeks)

* * * * * *

Nguyen JV and cols

Journal of Primary Care & Community Health 2014, Vol. 5(2) 152–155

Crianças e Adolescentes

DeMarco, V. G. et al. Nat. Rev. Endocrinol. 10, 364–376 (2014)

PPARs ()

ADRENALINA(SNS)

INSULINA

GH

IGF

CORTISONA CORTISOL

CB1

ESTRÓGENO

RESISTINA

RANTES - MCP-1 – Células T

LEPTINA

INTERLEUCINAS 6,8 – TNF-alfa

ADIPONECTINA

PAI-1

SRA AGL

LIPASE LIPOPROTEICA

TG

AGL

Modificado de Ribeiro-Filho, FF e cols.Arq Bras Endocrinol e Metab -2006

ADIPOSOPATIA

HSD

FRUTOSE – ACIDO URICO

FETUÍNA

ALDOSTERONA

Effect of Body Mass Index Changes Between Ages 5 and 14

on Blood Pressure at Age 14 Findings From a Birth Cohort

Study

Mamun AA and colsHypertension 2005;45:1083-1087

OBESIDADE E HIPERTENSÃO - NHANES