Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC HM7hPtWPbKB66YPPNPDvDFr S0066-782X2022000900502 abc.20210931 10.36660/abc.20210931 Carta ao Editor Impacto da Síndrome Metabólica Relacionada à Infecção por Helicobacter pylori Ativa na Hipertensão Arterial Sistêmica 0000-0001-6459-5136 Kountouras Jannis 1 Papaefthymiou Apostolis 1 2 3 Polyzos Stergios A. 3 0000-0002-3045-720X Kazakos Evangelos 1 Vardaka Elisabeth 1 4 Touloumtzi Maria 1 0000-0001-6051-0860 Tzitiridou-Chatzopoulou Maria 1 5 Liatsos Christos 6 Sgantzou Ioanna-Konstantina 7 Knuchel Jürg 8 Doulberis Michael 1 3 8 School of Medicine Ippokration Hospital Aristotle University of Thessaloniki Macedônia Grécia Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Macedônia – Grécia Department of Gastroenterology University Hospital of Larisa Larisa Grécia Department of Gastroenterology, University Hospital of Larisa, Larisa – Grécia First Laboratory of Pharmacology School of Medicine Aristotle University of Thessaloniki Macedônia Grécia First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Macedônia – Grécia Department of Nutritional Sciences and Dietetics School of Health Sciences International Hellenic University Macedônia Grécia Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Macedônia – Grécia School of Healthcare Sciences Midwifery Department University of West Macedonia Macedônia Grécia School of Healthcare Sciences, Midwifery Department, University of West Macedonia, Macedônia – Grécia Department of Gastroenterology General Military Hospital of Athens Atenas Grécia Department of Gastroenterology - General Military Hospital of Athens, Atenas – Grécia Radiology Department University Hospital of Larisa Larisa Grécia Radiology Department, University Hospital of Larisa, Larisa – Grécia Division of Gastroenterology and Hepatology Medical University Department Aarau Suíça Division of Gastroenterology and Hepatology, Medical University Department, Aarau – Suíça Correspondência: Jannis Kountouras • 8 Fanariou St, Byzantio. 551 33, Thessaloniki, Macedônia – Grécia E-mail: jannis@auth.gr , ancoratus2010@gmail.com 05 09 2022 09 2022 119 3 502 504 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Helicobacter pylori Hipertensão Síndrome Metabólica Aterosclerose Dislipidemias

Ao Editor

Em sua metanálise, Huang et al.,1 concluíram que a infecção por Helicobacter pylori (infecção por H. pylori) está positivamente associada à hipertensão arterial sistêmica, particularmente pela introdução do teste respiratório diagnóstico de 13C-ureia, significando infecção atual por H. pylori.

Nesse sentido, a hipertensão arterial sistêmica é um dos parâmetros mais significativos da síndrome metabólica (SM), e sua patogênese pode consistir principalmente de uma interação nociva entre mecanismos vasculares, renais, neurais e hormonais, dos quais a ativação aumentada do sistema simpático sistema nervoso (SNS) e o sistema renina-angiotensina-aldosterona (SRAA) predominam2 A atividade aumentada do SNS é uma característica usual de hipertensão arterial sistêmica resistente, acompanhada de aumento da liberação de norepinefrina, significando um elemento neurogênico que contribui para o desenvolvimento da hipertensão arterial sistêmica; e a superativação do SNS está associada a morbidade e mortalidade de distúrbios cardiovasculares relacionados à SM.3 Além disso, a desregulação do SRAA, incluindo o SRAA sistêmico e cerebral, tem sido documentada como uma das principais causas de vários tipos de hipertensão arterial sistêmica; e a superativação do SRRA também contribui para a obesidade associada à SM e morbidade e mortalidade cardiovascular.4

Da mesma forma, a infecção por H. pylori também está associada a patologias sistêmicas relacionadas à SM, especialmente doenças cardiocerebrovasculares e neurodegenerativas, os desfechos da SM.5 - 8 Especificamente, a infecção por H. pylori parece contribuir para a resistência à insulina (RI), o principal mecanismo subjacente responsável pela SM,9 que também desempenha um papel crítico na patogênese e progressão das lesões de órgãos-alvo desencadeadas pela hipertensão arterial sistêmica.10 A SM contribui para um risco aumentado de desenvolver aterosclerose,11 e, nesse sentido, a invasão de H. pylori em ateroma foi detectada pela introdução da reação em cadeia da polimerase (PCR).12 Foi observada a colonização direta de H. pylori nas paredes arteriais foi observada. H. pylori está associada à rigidez arterial, marcador precoce de aterosclerose sistêmica correlacionado com hipertensão arterial sistêmica e preditor independente de complicações cardiovasculares e mortalidade por todas as causas. Assim, o H. pylori tem sido associado à aterosclerose relacionada à SM por meio de uma diversidade de mecanismos envolvidos, potencialmente desencadeando hipertensão arterial sistêmica. A infecção por H. pylori pode estar envolvida independentemente na aterosclerose e na hipertensão arterial por meio de mecanismos distintos das causas convencionais de aterosclerose, incluindo os três fatores de risco não convencionais para doença arterial coronariana homocisteína, fibrinogênio e lipoproteína(a).6 , 13 , 14

Além disso, a dislipidemia relacionada à SM está associada à hipertensão arterial sistêmica15 e, nesse sentido, a infecção crônica por H. pylori pode desencadear metabolismo lipídico anormal do hospedeiro, incluindo, além da lipoproteína(a) mencionada, o colesterol de lipoproteína de baixa densidade (LDL- C), colesterol de lipoproteína de alta densidade (HDL-C) e colesterol total (TC),16 também citados pelos autores;1 O HDL-C mais baixo relacionado ao H. pylori parece promover dislipidemia.17 Em contraste, a erradicação do H. pylori diminui significativamente os níveis de CT, TG, LDL-C e fibrinogênio, um fator de risco independente para doença cardiovascular,6 enquanto aumenta as concentrações de HDL-C.18 , 19 Além de dislipidemia e hipertensão arterial sistêmica, a erradicação do H. pylori também melhora outros parâmetros relacionados à SM, incluindo índice de massa corporal (IMC),20 RI,21 e status oxidante total.22 Portanto, a erradicação da infecção por H. pylori reduz a ocorrência de dislipidemia relacionada à SM e outros parâmetros, incluindo hipertensão arterial sistêmica,23 , 24 potencialmente prevenindo a ocorrência de doença cardiovascular relacionada à SM acompanhada de hipertensão arterial.

Dados recentes indicam que sarcopenia relacionada à SM, infecção por H. pylori, dislipidemia, hipertensão arterial sistêmica, diabetes mellitus, tabagismo, consumo de álcool e dieta (salgada e/ou condimentada) estão ligados a lesões pré-cancerosas da mucosa gástrica, incluindo atrofia gástrica, metaplasia intestinal e displasia.25 A este respeito, evidências recentes interessantes também indicam que pacientes bariátricos com infecção por H. pylori apresentam taxas basais significativamente altas das lesões pré-malignas gástricas mencionadas, incluindo atrofia gástrica e metaplasia intestinal acompanhada de RI e hipertensão arterial.26

Finalmente, a doença hepática gordurosa não alcoólica (DHGNA), recentemente renomeada como doença hepática gordurosa associada à disfunção metabólica (DHGM), é o componente hepático da SM também associada à infecção por H. pylori, que parece contribuir para o seu desenvolvimento e progressão;27 DHGNA/DHGM é associado a um risco aumentado de cerca de 1,6 vezes de desenvolver hipertensão arterial sistêmica; e características relacionadas à SM, incluindo IMC alto, dislipidemia e diabetes mellitus tipo 2 no contexto da infecção por H. pylori apresentam uma tendência maior para o desenvolvimento de DHGNA/DHGM. A respeito disso, dados recentes indicam que a infecção por H. pylori está relacionada com RI e aumento da permeabilidade intestinal, o que poderia contribuir para o desenvolvimento de DHGNA/DHGM;28 e a infecção ativa por H. pylori é independentemente positivamente associada com a gravidade da esteato-hepatite não alcoólica e fibrose, achados que sugerem prováveis implicações clínicas.27 Entre os pacientes com DHGNA/MAFLD, a prevalência de hipertensão arterial varia de 40-70%, e estudos relativos mostraram que DHGNA/MAFLD está fortemente relacionada ao risco aumentado de pré-hipertensão arterial sistêmica e hipertensão.29 Em contrapartida, além da redução da referida hipertensão arterial sistêmica, a erradicação do H. pylori aumenta particularmente o HDL-C e reduz o LDL-C,30 restaurando assim a atividade cardioprotetora da relação HDL-C/LDL-C e diminuindo o risco cardiovascular associado a DHGM.30

Observando os dados mencionados, a infecção por H. pylori parece apresentar efeitos pleiotrópicos além do trato gastrointestinal e evidências crescentes a associam à SM, incluindo hipertensão arterial sistêmica. Mais pesquisas são necessárias, no entanto, para esclarecer o impacto potencial do H. pylori relacionado à SM na hipertensão arterial sistêmica, que representa um grave problema de saúde pública com alta incidência e prevalência globais que continuam aumentando e podem contribuir para a alta morbidade e mortalidade global. Identificar H. pylori e DHGNA/DHGM relacionados à SM e outros distúrbios relativos – como importantes fatores de risco para hipertensão arterial sistêmica – pode ser útil para melhorar a predição de risco, identificar estratégias de prevenção primária e selecionar um programa terapêutico para hipertensão arterial sistêmica.

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Nazligul Y Aslan M Horoz M Celik Y Dulger AC Celik H et al The effect on serum myeloperoxidase activity and oxidative status of eradication treatment in patients Helicobacter pylori infected Clin Biochem 2011 44 8-9 647 649 10.1016/j.clinbiochem.2011.03.001 23. Migneco A, Ojetti V, Specchia L, Franceschi F, Candelli M, Mettimano M, et al. Eradication of Helicobacter pylori Infection Improves Blood Pressure Values in Patients Affected by Hypertension. Helicobacter 2003;8(6): 585–9. doi: 10.1111/j.1523-5378.2003.00180.x. Migneco A Ojetti V Specchia L Franceschi F Candelli M Mettimano M et al Eradication of Helicobacter pylori Infection Improves Blood Pressure Values in Patients Affected by Hypertension Helicobacter 2003 8 6 585 589 10.1111/j.1523-5378.2003.00180.x 24. Fang Y, Xie H, Fan C. Association of hypertension with helicobacter pylori: A systematic review and meta-analysis. PLoS One. 2022;17(5):e0268686. doi: 10.1371/journal.pone.0268686. Fang Y Xie H Fan C Association of hypertension with helicobacter pylori: A systematic review and meta-analysis PLoS One 2022 17 5 e0268686 10.1371/journal.pone.0268686 25. Kim YM, Kim JH, Baik SJ, Chun J, Youn YH. Sarcopenia and Sarcopenic Obesity as Novel Risk Factors for Gastric Carcinogenesis: A Health Checkup Cohort Study. Front Oncol. 2019;9:1249. doi: 10.3389/fonc.2019.01249 Kim YM Kim JH Baik SJ Chun J Youn YH Sarcopenia and Sarcopenic Obesity as Novel Risk Factors for Gastric Carcinogenesis: A Health Checkup Cohort Study Front Oncol 2019 9 1249 10.3389/fonc.2019.01249 26. Doulberis M, Pierre NT, Manzini G, Papaefthymiou A, Kountouras J, Klukowska-Rotzlwer J, et al. Helicobacter pylori-Related Metabolic Parameters and Premalignant Gastric Mucosdoi: 10.3389/fonc.2019.01249a Histological Lesions in Swiss Bariatric Patients. Microorganisms. 2021;9(7):1361. doi: doi: 10.3390/microorganisms9071361. 10.3390/microorganisms9071361. Doulberis M Pierre NT Manzini G Papaefthymiou A Kountouras J Klukowska-Rotzlwer J et al Helicobacter pylori-Related Metabolic Parameters and Premalignant Gastric Mucosdoi: 10.3389/fonc.2019.01249a Histological Lesions in Swiss Bariatric Patients Microorganisms 2021 9 7 1361 10.3390/microorganisms9071361 10.3390/microorganisms9071361 27. Doulberis Mdoi: 10.1097/MD.0000000000026706., Srivastava S, Polyzos SA, Kountouras J, Papaefthymiou A, Klukowska-Rotzlwer J, et al. Active Helicobacter pylori Infection is Independently Associated with Nonalcoholic Steatohepatitis in Morbidly Obese Patients. J Clin Med. 2020;9(4):933. Doulberis M doi: 10.1097/MD.0000000000026706 Srivastava S Polyzos SA Kountouras J Papaefthymiou A Klukowska-Rotzlwer J et al Active Helicobacter pylori Infection is Independently Associated with Nonalcoholic Steatohepatitis in Morbidly Obese Patients J Clin Med 2020 9 4 933 28. Wei L, Ding H-G. Relationship between Helicobacter pylori infection and nonalcoholic fatty liver disease. Medicine (Baltimore). 2021:100(31):e26706. doi: 10.1097/MD.0000000000026706. Wei L Ding H-G Relationship between Helicobacter pylori infection and nonalcoholic fatty liver disease Medicine (Baltimore) 2021 100 31 e26706 10.1097/MD.0000000000026706 29. Aneni EC, Oni ET, Martin SS, Blaha MJ, Agatston AS, Feldman T, et al. Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk. J Hypertens. 2015;33(6):1207–14. doi: 10.1097/HJH.0000000000000532. Aneni EC Oni ET Martin SS Blaha MJ Agatston AS Feldman T et al Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk J Hypertens 2015 33 6 1207 1214 10.1097/HJH.0000000000000532 30. Adachi K, Mishiro T, Toda T, Kano N, Fujihara H, Mishima Y, et al. Effects of Helicobacter pylori eradication on serum lipid levels. J Clin Biochem Nutr. 2018;62(3):264-9. doi: 10.3164/jcbn.17-88 Adachi K Mishiro T Toda T Kano N Fujihara H Mishima Y et al Effects of Helicobacter pylori eradication on serum lipid levels J Clin Biochem Nutr 2018 62 3 264 269 10.3164/jcbn.17-88 Letter to the Editor Impact of Active Helicobacter pylori Infection-related Metabolic Syndrome on Systemic Arterial Hypertension 0000-0001-6459-5136 Kountouras Jannis 1 Papaefthymiou Apostolis 1 2 3 Polyzos Stergios A. 3 0000-0002-3045-720X Kazakos Evangelos 1 Vardaka Elisabeth 1 4 Touloumtzi Maria 1 0000-0001-6051-0860 Tzitiridou-Chatzopoulou Maria 1 5 Liatsos Christos 6 Sgantzou Ioanna-Konstantina 7 Knuchel Jürg 8 Doulberis Michael 1 3 8 Greece Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, Macedonia – Greece Greece Department of Gastroenterology, University Hospital of Larisa, Larisa – Greece Greece First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Macedonia – Greece Greece Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Macedonia – Greece Greece School of Healthcare Sciences, Midwifery Department, University of West Macedonia, Macedonia – Greece Greecee Department of Gastroenterology - General Military Hospital of Athens, Athens - Greecee Greecee Radiology Department, University Hospital of Larisa, Larisa – Greecee Switzerland Division of Gastroenterology and Hepatology, Medical University Department, Aarau – Switzerland Mailing Address: Jannis Kountouras • 8 Fanariou St, Byzantio. 551 33, Thessaloniki, Macedonia - Greece E-mail: jannis@auth.gr, ancoratus2010@gmail.com Helicobacter pylori Hypertension Metabolic Syndrome Atherosclerosis Dyslipidemias

To the Editor,

In their meta-analysis, Huang et al.1 concluded that Helicobacter pylori infection ( H. pylori infection) is positively associated with systemic arterial hypertension, particularly by introducing the diagnostic 13C-urea breath test, signifying current H. pylori infection.

In this regard, systemic arterial hypertension is one of the most significant parameters of the metabolic syndrome (MetS), and its pathogenesis may mostly comprise of a noxious interplay between vascular, renal, neural, and hormonal mechanisms, of which augmented activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) predominate.2 Augmented activity of SNS is a usual feature of resistant systemic arterial hypertension, accompanied by increased release of norepinephrine, signifying a neurogenic element that contributes to the development of systemic arterial hypertension; and overactivation of SNS is associated with morbidity and mortality of MetS-related cardiovascular disorders.3 Moreover, RAAS dysregulation, including the systemic and brain RAAS, has been documented as one of the chief causes of several types of systemic arterial hypertension; and RAAS overactivation also contributes to MetS-associated obesity and cardiovascular morbidity and mortality.4

Likewise, H. pylori infection is also associated with MetS-related systemic pathologies, especially cardio-cerebrovascular and neurodegenerative diseases, the endpoints of MetS.5 - 8 Specifically, H. pylori infection seems to contribute to insulin resistance (IR), the chief underlying mechanism responsible for MetS,9 which also plays n critical role in the pathogenesis and progression of systemic arterial hypertension-triggered target organ injuries.10 MetS contributes to an increased risk of developing atherosclerosis,11 and in this respect, invasion of H. pylori into atheroma has been detected by introducing polymerase chain reaction (PCR).12 Direct H. pylori colonization in the arterial walls has been observed. H. pylori is associated with arterial stiffness, an early marker of systemic atherosclerosis correlated with systemic arterial hypertension and an independent predictor of cardiovascular complications and all-cause mortality. Thus, H. pylori have been associated with MetS-related atherosclerosis via a diversity of involved mechanisms, thereby potentially triggering systemic arterial hypertension. H. pylori infection might independently be involved in atherosclerosis and arterial hypertension through mechanisms distinct from the conventional causes of atherosclerosis, including the three non-conventional coronary artery disease risk factors homocysteine, fibrinogen and lipoprotein(a).6 , 13 , 14

Besides, MetS-related dyslipidemia is linked with systemic arterial hypertension15 and in this regard, chronic H. pylori infection can trigger abnormal lipid metabolism of the host, including, beyond the mentioned lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC),16 also mentioned by the authors;1 H. pylori -related lower HDL-C appears to promote dyslipidemia.17 In contrast, H. pylori eradication significantly decreases the levels of TC, TG, LDL-C and fibrinogen, an independent risk factor for cardiovascular disease,6 whereas increases HDL-C concentrations.18 , 19 Moreover, beyond dyslipidemia and systemic arterial hypertension, H. pylori eradication also improves other MetS-related parameters, including body mass index (BMI),20 IR,21 and total oxidant status.22 Therefore, eradication of H. pylori infection reduces the occurrence of MetS-related dyslipidemia and other parameters including systemic arterial hypertension,23 , 24 thereby potentially preventing the occurrence of MetS-related cardiovascular disease accompanied by arterial hypertension.

Recent data indicate that MetS-related sarcopenia, H. pylori infection, dyslipidemia, systemic arterial hypertension, diabetes mellitus, smoking, alcohol consumption, and diet (salty and/or spicy diets) are linked with precancerous gastric mucosa lesions, including gastric atrophy, intestinal metaplasia, and dysplasia.25 In this respect, interesting recent evidence also indicates that bariatric patients with H. pylori infection display baseline significantly high rates of the mentioned gastric pre-malignant lesions, including gastric atrophy and intestinal metaplasia accompanied with IR and arterial hypertension.26

Finally, nonalcoholic fatty liver disease (NAFLD), recently renamed as metabolic dysfunction-associated fatty liver disease (MAFLD), is the hepatic component of MetS also associated with H. pylori infection, which appears to contribute to its development and progression;27 NAFLD/MAFLD is associated with an about 1.6-fold augmented risk of developing systemic arterial hypertension; and MetS- related characteristics including high BMI, dyslipidemia, and type 2 diabetes mellitus in the setting of H. pylori infection exhibit a greater tendency for the development of NAFLD/MAFLD. In this regard, recent data indicate that H. pylori infection is connected with IR and augmented intestinal permeability, which could contribute to the development of NAFLD/MAFLD;28 and active H. pylori infection is independently positively associated with the severity of nonalcoholic steatohepatitis and fibrosis, findings suggesting probable clinical implications.27 Among patients with NAFLD/MAFLD, the prevalence of arterial hypertension varies from 40-70%, and relative studies have shown that NAFLD/MAFLD is strongly related to the augmented risk of systemic arterial prehypertension and hypertension.29 In contrast, beyond the reduction of the mentioned systemic arterial hypertension, H. pylori eradication particularly increases HDL-C and reduces LDL-C,30 thus restoring the cardioprotective activity of the HDL-C/LDL-C ratio and diminishing the cardiovascular risk linked to MAFLD.30

Viewing the aforementioned data, H. pylori infection seems to display pleiotropic effects beyond the gastrointestinal tract and rising evidence associates it with MetS, including systemic arterial hypertension. Further research is warranted, however, to clarify the potential impact of H. pylori related MetS on systemic arterial hypertension, which represents a serious public health problem with high global incidence and prevalence that continues to increase and may contribute to global high morbidity and mortality. Identifying H. pylori and MetS-related NAFLD/MAFLD and other relative disorders – as important risk factors for systemic arterial hypertension – may be helpful for improving the risk prediction, identifying primary preventive strategies, and selecting a therapeutic program for systemic arterial hypertension.