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OBESIDADE COMO CAUSA DE HIPERTENSÃO
PRIMÁRIA OU SECUNDÁRIA
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 e Hipertensão - Framingham
Arch Intern Med. 2002;162:1867-1872
THE BOGALUSA HEART STUDY
Srinivasan and cols
Hypertension. 2006;48:33-39
The childhood origins of obesity-related
hypertension are well illustrated in a study of
260,000 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
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 adults
group
IV
normal
BMI
in
childhood
-
obese
as
adults
N Engl J Med 2011;365:1876-85
Consistently stable or decreased body mass index in young adulthood
and longitudinal changes in metabolic syndrome components
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).
Lloyd-Jones, DM and cols
Circulation. 2007;115:1004-1011
Mensagem 1
Obesidade parece ser causa de hipertensão secundária…
…Inconsistências
Burden and Rates of Treatment and Control of Cardiovascular Disease Risk
Factors in Obesity
The Framingham Heart Study
Molenaar E A and cols
Diabetes Care 31(7):1367–1372, 2008
Population attributable risk percentage effects for overweight and obesity
Framingham men and women followed up for 44 years.
Overweight and hypertension: a 2-way street?
Obesidade e hipertensão se associam
Julius S et al. (2000)
Hypertension 2000; 35: 807–813
Acúmulo central de gordura em obesos com história familiar de
hipertensão - 5 anos
Allemann Y and cols
Journal of Hypertens 2001, 19:2143±2148
Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric Surgery
- SOS Study -
Sjöström
N Engl J Med 2004;351:2683-93
AFERIÇÃO PRESSÓRICA EM OBESOS
MAPA EM OBESOS - “white-coat”
Hipert. Consult.
Normotensos
Hipertensos
12,5% magros vs 35,3% obesos
58,1% magros vs 10,6% obesos
43,7% obesos vs 23,4% magros
Kotsis V and cols
Hypertension. 2005;45:602-607
“The first step to improving your health is to
choose healthy parents” (Anonymous)
Association of angiotensin-converting enzyme DD genotype
with blood pressure sensitivity to weight loss
Am Heart J 2002;144:625-9
Association of Rho/Rho-kinase gene polymorphisms and
expressions with obesity-related metabolic syndrome
European Review for Medical and Pharmacol Sciences
… in obese NOS3 894T allele may enhance hypertension
Journal of Physiol and Pharmacol
2015, 66, 5, 681-689
risk…
2015; 19: 1680-1688
Urate Transporter Gene SLC22A12 Polymorphisms Associated
with Obesity and Metabolic Syndrome in Caucasians with
Hypertension
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
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
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
Fatores genéticos e co-segregação de HA e OBE
Heritability Estimates of Obesity Measures in Siblings With and Without Hypertension
Pausova Z and cols
Hypertension 2001;38:41-47
Journal of Hypertension 2015, 33:1499–1508
FTO gene variant and risk of hypertension: A meta-analysis of 57,464
hypertensive cases and 41,256 controls
He D and cols
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
Hipertensos Graves - ASS (943 pacientes)
Circunferência da cintura aumentada
Excesso de peso
Sedentarismo
Etilismo
Tabagismo
Síndrome metabólica
Glicemia de jejum ≥100 mg/dL
Triglicérides ≥150 mg/dL
Colesterol total ≥ 200 mg/dL
Baixo HDL colesterol
LDL colesterol ≥100 mg/dL
Disfunção diastólica
Hipertrofia ventricular esquerda
Índice tornozelo braço alterado
Taxa de filtração glomerular estimada <60mL/min
85,8%
78,6%
69,0%
18,0%
13,0%
40,0%
60,0%
45,0%
49,6%
43,3%
23,5%
76,0%
46,0%
42,0%
50,0%
MECANISMOS DA HIPERTENSÃO ASSOCIADA À OBESIDADE
Retenção salina
Ativação renina-angiotensina
Ativação simpático
… apnéia sono, microbiota, inflamação, ácido úrico, insulina,
disfunção endotelial...
Mechanisms of obesity-associated hypertension
What about aldosterone ?
Hall JE, Kuo JJ, Silva AA, Paula RB, Liu J and Tallam L
Current Opinion in Nephrology and Hypertyension, 2003
Lipotoxicidade
Inflamed fat:
what starts the fire?
C-C motif chemokine ligand 2
(CCL2 = MCP-1)
Aldosterone
Neels, J. G. et al. J. Clin. Invest. 2006;116:33-35
ALDOSTERONA – NOVO PARADIGMA
CÓRTEX ADRENAIS – RIM – CORAÇÃO
CÉREBRO – TEC ADIPOSO
ESTIMULO - K+ - ACTH – AII
É APENAS UM DOS LIGANTES DO MR
NON-NUCLEAR ACTIONS
AGE DCC – Retenção Na+ Excreção K+
Inflamação
HIPERTENSÃO 1a / REFRATÁRIA/ OBESIDADE
Fibrose
Estresse Oxidativo
Apoptose
Fuller PJ and Young MJ
Hypertension. 2005;46:1227-1235
MR blockade in a model of obese dogs - high fat diet
Hemodinâmica
Metabólica
Renal
MR Blockade attenuates blood pressure increase
during high fat diet
High Fat Diet
20
untreated
eplerenone
 MAP (mmHg)
16
12
8
*
*
*
4
0
C
1
2
3
Time (weeks)
4
5
de Paula and cols
Hypertension 2004
de Paula RB et al
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.
Hypertension. 2003;43:1-7.
BLOQUEIO DA ALDO EM OBESOS NÃO DIABÉTICOS
GRUPO 1
GRUPO 2
ESPIRO (N=5)
ESPIRO (n=6)
BASAL
(n=11)
GRUPO 2
PLACEBO
(n=5)
GRUPO 1
PLACEBO
(n=6)
8 SEMANAS
Av. Clinica
Laboratorial
8 SEMANAS
Av. Clinica
Laboratorial
8 SEMANAS
Av. Clinica
Laboratorial
Costa MB and cols
Bloqueio da Aldosterona reduziu PA obesos
140
*
*
120
100
**
80
**
PA sist
PA diast
60
40
20
* p=0,001
0
Pré-espiro
Pós-espiro
** p=0,005
Costa MB and cols
Bloqueio da aldosterona reduziu hiperfiltração
ClCr (ml/min)
Microalbuminúria
(mg/24hs)
BASAL
ESPIRO
PLACEBO
171 ± 33
137 ± 41 *
146 ± 42
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
Aldosterone Antagonist Decreases Blood Pressure and Improves Metabolic
Parameters in Obese Patients With the Metabolic Syndrome
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….
Costa MB and cols
Journal of Clin Hypertens, 2010
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
Ezequiel DAG e cols
JBN 2013
Parametros clínicos - MAPA
IMC
Pré-espiro
Pós-espiro
34,0 ± 3,83
34,1 ± 3,93
C Abdominal
PAS 24 horas
109,6 ± 8,17
143,3 ± 15,79
PAD 24 horas
84,8 ± 11,23
p
0,822
111,3 ± 8,01
0,155
132,1 ±17,53 0,024
78,4 ± 10,99
0,023
Ezequiel DAG e cols
JBN 2013
Aldosterona e disfunção endotelial
Tsuchiya, 2009
VDFM EM SM
%
*
14
12
10
8
6
4
2
0
PRÉ
PÓS
Lovisi JCM et al
JBN 2012
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
Mineralocorticoid receptor blockade lowers systolic blood pressure in obese
patients with metabolic syndrome
15.2±5.3 mmHg
5.9±5.3 mmHg
Ezequiel DAG and cols
Submmited, 2016
Mineralocorticoid receptor blockade lowers blood pressure and improves
endothelial function in obese patients with metabolic syndrome
Effect
P-value
5.5 (1.37: 9.57)
-4.7 (-10. 25:0. 90)
0.096
0.2 (-0.60: 0.92)
0.8 (-0.17: 1.75)
-0.6 (-1.86: 0.61)
0.306
0.1
0.1
0.0
0.907
(-0.03: 0.33)
(-0.08: 0.35)
4.6
1.8
2.7
0.202
(1.88: 7.32)
(-1.44: 5.15)
(-1.6: 7.07)
-14.1
-22.7
7.9
(-35.90: 7.67)
(-48.36: 4.33)
(-26.52: 42.33)
-1.0
1.9
-2.9
(-1.93: -0.69)
(0.81: 3.06)
(-4.42:- 1.45)
9.15
0.83
8.3
(5.7: 12.5)
(-3.75: 5.41)
(2.53: 14.11)
-10.9
-0.19
-10.7
(-19.79:- 1.99)
(-11.62: 11.23)
(-25.63: 4.24)
4.9
-3.9
8.8
(2.18: 7.70)
(-7.25: -0.54)
(4.39: 13.28)
ESPIRO diff.
AMLO diff.
(CI 95%)
(CI 95%)
FPG (mg/dL)
0.8 (-2.53: 4.13)
HOMA-IR
Potassium
(mEq/L)
Variable
HDL-cholesterol
(mg /dL)
Triglycerides
(mg/dL)
CRP-hs (mg/L)
Plasma
aldosterone
(ng/dL)
Urinary Albumin
Excretion
(mg/gcreatinine)
FMD (%)
0.639
0.000
0.007
0.152
0.000
Ezequiel DAG and cols
Submmited, 2016
CLINICAL TRIAL
EVALUATION OF EFFICACY, TOLERABILITY AND
METABOLIC EFFECTS OF MCR BLOCKADE IN OBESE
HYPERTENSIVE PATIENTS
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
HDL
4,0 ± 5,73
38,0±7,10
3,2 ± 1,98
44,9±6,97
0,478
0,000
Rel TRIG/HDL
4,6 ± 3,14
3,5 ± 1,51
0,010
187,4 ±97,38
6,9 ±3,91
167,4 ± 71,34
21,2 ±12,34
0,065
0,000
4,2 ±0,32
4,4 ±0,35
0,026
11,4 ±13,86
10,46 ± 8,33
0,705
6,4 ± 3,91
4,7 ±6,40
0,079
HOMA IR
Triglicérides
Aldosterona
Potássio
Rel ALDO/APR
PCR ultra-sensível
Ezequiel DAG e cols
JBN 2013
Obesity-associated hypertension is ameliorated in patients
with 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)
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
Yang J and cols
PLOS ONE, 2014; 9 (6): 1-8
insulin resistanc
Mineralocorticoi
insulin resistance
in contrast to ind
Airway
Weight loss
obstruction
sterone levels are
cPAP
insulin resistance
Leptin
pathways, includi
OSA
and SNS over act
Oxidized
coid receptor an
fatty acids
Angiotensinogen
(non-classical
this context.40,165
pathway)
SNS
higher binding s
activation
receptor than spi
dilation in health
Renal
Kidney
over, impaired e
denervation
obese mice or exo
with an endothe
Renin
tor deletion.167 A
ARBs
and hypertensio
related hyperaldo
Ang II
Adrenal
receptor inhibito
Attenuation of
Mineralocorticoid
Aldosterone
Vascular dysfunction
mineralocorticoi
receptor antagonist
talk between the A
ways.84,169 For exa
Sodium
Hypertension
retention
muscle contract
V. G. et al. mice with a deleti
Figure 2 | Possible mechanisms of obesity-associated hypertensionDeMarco,
and therapeutic
fic to smooth mu
Nat. Rev. Endocrinol. 10, 364–376 (2014)
Adipose
tissue
strategies. Adipose tissue releases leptin, angiotensinogen and oxidized fatty acids
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 glucosestimulated 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 IImight
increase 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 cols
Plos One 2014;9(6); e100548
ALDOSTERONA
Eplerenone attenuated GFR increase
GFR (ml/min)
High Fat Diet
110
untreated
100
eplerenone
90
80
*
*
*
*
*
*
70
60
50
40
C
1
2
3
4
5
Time (weeks)
* p<0.05 vs untreated
Crianças e Adolescentes
Nguyen JV and cols
Journal of Primary Care & Community Health 2014, Vol. 5(2) 152–155
DeMarco, V. G. et al. Nat. Rev. Endocrinol. 10, 364–376 (2014)
ADIPOSOPATIA
CORTISONA
PPARs ()
CORTISOL
HSD
CB1
ESTRÓGENO
RESISTINA
RANTES - MCP-1 – Células T
LEPTINA
INTERLEUCINAS 6,8 – TNF-alfa
ADIPONECTINA
PAI-1
SRA AGL
ADRENALINA
(SNS)
INSULINA
GH
IGF
TG
FRUTOSE – ACIDO URICO
LIPASE LIPOPROTEICA
AGL
FETUÍNA
ALDOSTERONA
Modificado de Ribeiro-Filho, FF e cols.
Arq Bras Endocrinol e Metab -2006
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 cols
Hypertension 2005;45:1083-1087
OBESIDADE E HIPERTENSÃO - NHANES