OBESIDADE COMO CAUSA DE HIPERTENSÃO PRIMÁRIA ......va s c u la r s m o o t h m u s c le r e a c t...
Transcript of OBESIDADE COMO CAUSA DE HIPERTENSÃO PRIMÁRIA ......va s c u la r s m o o t h m u s c le r e a c t...
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