Recently, some investigators have reported seeing microvascular dysfunction in patients with
cardiac syndrome X (CSX). In addition, Helicobacter pylori (H. pylori), a bacterium causing
chronic gastritis and peptic ulcers, has recently been associated with CSX. Yet the
mechanism(s) by which H. pylori infection leads to CSX is poorly understood. We propose
a link between H. pylori and microvascular dysfunction infection in the development of CSX

Raeisi, Sina

Rasmi, Yousef

English

Via Medica Journals

www.cardiologyjournal.org 585POINT OF VIEWCardiology Journal2009, Vol. 16, No. 6, pp. 585–587Copyright © 2009 Via MedicaISSN 1897–5593Address for correspondence:  Yousef Rasmi, Department of Biochemistry, Faculty of Medicine, Urmia University of MedicalSciences, Urmia, Iran, tel: +984412770698, fax: +984412780801, e-mail: rasmiy@umsu.ac.irReceived: 29.09.2009 Accepted: 18.10.2009Possible role of Helicobacter pylori infection viamicrovascular dysfunction in cardiac syndrome XYousef Rasmi, Sina RaeisiDepartment of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, IranAbstractRecently, some investigators have reported seeing microvascular dysfunction in patients withcardiac syndrome X (CSX). In addition, Helicobacter pylori (H. pylori), a bacterium cau-sing chronic gastritis and peptic ulcers, has recently been associated with CSX. Yet themechanism(s) by which H. pylori infection leads to CSX is poorly understood. We proposea link between H. pylori and microvascular dysfunction infection in the development of CSX.(Cardiol J 2009; 16, 6: 585–587)Key words: cardiac syndrome X, Helicobacter pylori, inflammation, endothelial,microvascular dysfunctionIntroductionCardiac syndrome X (CSX) is a condition char-acterized by the presence of angina pectoris anda positive response to stress or radionuclide tests(thallium scan) with a normal coronary arteriogram[1]. It is found in up to 20% of angina patients un-dergoing angiography [2]. The varied pathogenicmechanisms responsible for the condition, and thevarying diagnostic criteria used by different inves-tigators, have helped complicate the diagnosis andmanagement of CSX patients [3].H. pylori and inflammationPrevious studies have shown an associationbetween viral and bacterial infections (such as Heli-cobacter pylori [H. pylori] infection) with vasculardiseases such as ischemic heart disease and CSX [4].H. pylori is a gram-negative bacterium which infectsthe human stomach [5], may cause extra-intestinalmanifestations some of which are functional ischem-ic heart disease andrespiratory system disease[6, 7], and has recently been associated with CSX [2].Infection with H. pylori may be associated with sys-temic and vascular inflammation. Prevalence of sero-positivity to H. pylori significantly increases in sub-jects with high sensitive C reactive protein (CRP),a sensitive marker of systemic inflammation. Fur-thermore, serum CRP levels positively correlatewith anti-H. pylori antibody titer levels.Therefore, chronic infection with H. pylori mayaccount for, at least in part, the elevated serum CRPlevel [7]. Chronic infection of H. pylori is most pro-bably the cause of increased production of variousinflammatory metabolites, such as interlukin-1,interleukin-6 and tumor necrosis factor-alpha whichalso affect blood vessel motility and induce endothe-lial dysfunction [8]. It has been shown that H. py-lori induces gastric mucosal injury and inflamma-tion that might be caused by the oxidant-mediatedexpression of inflammatory cytokines, and inflam-matory enzymes [9, 10]. Systemic inflammatoryreaction can be detected by showing increased plas-ma levels of different pro-inflammatory cytokinesand acute-phase proteins which then may lead toseveral diseasessuch as CSX [11]. A circulatingsoluble form of intercellular adhesion molecule-1586Cardiology Journal 2009, Vol. 16, No. 6www.cardiologyjournal.org(ICAM-1), which is expressed on the activated en-dothelium in response to inflammatory cytokines,also was elevated in subjects positive to anti-H. py-lori. Moreover, a previous study showed thatH. pylori eradication was associated with a significantreduction in serum CRP levels and a significant risein serum HDL-cholesterol [12].Inflammation and endothelial dysfunctionOn the other hand, many observational stud-ies have indicated that an elevated level of CRP isindependently associated with future risk of coro-nary heart disease and stroke [13], supporting thehypothesis that inflammation plays an importantrole in the pathogenesis of atherosclerosis [14].Recent observations suggest a role of inflam-mation in the pathogenesis of endothelial dysfunc-tion [15] and correlation of CRP-concentration withseverity of symptoms in patients with CSX [16].The potential importance of inflammation in thepathogenesis of CSX is highlighted by the benefi-cial effects observed with the use of statins andangiotensin- converting- enzyme inhibitors in pa-tients with CSX [17]. Chronic inflammation leadsto an increase in the generation of pro-inflammato-ry cytokines, cell adhesion molecules, and growthfactors that can elicit inflammatory and proliferativechanges in the vessel walls, resulting in endothe-lial dysfunction [18]. Leukocyte binding to cellularadhesion molecules on the surface of vascular en-dothelium in response to many inflammatory cy-tokines and CRP may be the earliest event in a vas-cular inflammatory process [14].Endothelial dysfunctionand microvascular dysfunctionCSX encompasses several possible causalmechanisms. Cardiac and non-cardiac mechanismshave been proposed, among which ‘endothelial dys-function’ of the coronary microcirculation featuresprominently [19]. According to the response-to-in-jury hypothesis of atherosclerosis, endothelial dys-function is the first step in atherosclerosis [14]. Thishypothesis has been supported by many studies,indicating that endothelial dysfunction occurs insubjects with classic risk factors such as hyperten-sion, diabetes mellitus, hypercholesterolemia, andsmoking [20]. The mechanisms responsible for en-dothelial dysfunction in CSX patients are not wellunderstood but risk factors such as obesity, hyper-tension, hypercholesterolemia, diabetes, hyperho-mocysteinemia and smoking may play a role [11].Moreover, plasma levels of circulating ICAM-1 andvascular adhesion molecule-1 are increased in pa-tients with CSX, suggesting endothelial cell activa-tion [11, 21]. Also, increased plasma concentrationof the powerful vasoconstrictor endothelin-1 (ET-1)has been reported in peripheral blood of CSX pa-tients and has been shown to correlate with en-dothelial dysfunction; moreover, ET-1 has beenfound to increase the coronary circulation of pa-tients with CSX during arterial pacing [15].On the other hand, CRP levels are known tobe associated with endothelial cell activation andcoronary endothelial dysfunction [22]. Reduced ni-tric oxide bioavailability due to endothelial dysfunc-tion [23] and enhanced ET-1 expression, promotedby raised CRP levels [24], may be implicated insystematic endothelial vasoreactivity leading tomicrovascular angina [25, 26]. Several studies haveshown that patients with CSX have coronary micro-vascular abnormalities [15]. Both vasodilator stim-uli and vasoconstrictor stimuli have been used toassess coronary microvascular function in patientswith CSX. The study of vasodilator function hasfurther concerned the assessment of endothelium-dependent and endothelium-independent mecha-nisms. Thus, endothelial function has an importantrole in microvascular function [15]; and coronaryendothelial dysfunction leading to microvascularangina has been proposed as a pathogenic mecha-nism in CSX [11, 25, 26]. Endothelium-dependentcoronary microvascular function has mainly beenstudied by assessing the coronary blood flow re-sponse to acetylcholine, the vasodilator effect ofwhich is mediated by nitric oxide release by en-dothelial cells [15, 23]. Some studies have shownreduced endothelium-dependent vasodilatation orincreased vasoconstriction (or both) in response tovarious stimuli such as exercise in epicardial coro-nary artery vessels of patients with CSX [15].HypothesisDue to the factors that occur secondary toH. pylori infection, we speculate that H. pylori mayalso cause endothelial dysfunction directly by affect-ing the structure and function of vascular endothe-lial cells via inflammation.H. pylori may cause endothelial dysfunction.H. pylori infection causes chronic inflammation andincreases the generation of pro-inflammatory cy-tokines, cell adhesion molecules, growth factors andacute-phase proteins. An increase in these factorsmay affect vessel motility and can elicit inflamma-tory and proliferative changes in the vessel walls587Yousef Rasmi, Sina Raeisi, Role of Helicobacter pylori in cardiac syndrome Xwww.cardiologyjournal.org(microvascular dysfunction) via endothelial dysfunc-tion (Fig. 1).In conclusion, we hypothesize that H. pyloriinfection can be a trigger for the probable mecha-nism of endothelial dysfunction via chronic inflam-mation in the pathogenesis of CSX.Since endothelial dysfunction is the triggerpoint for many diseases, we must pay more atten-tion to the diagnosis and treatment of H. pylori.H. pylori may be the cause of, or at least one of theleading factors in, many other diseases. To addressthis hypothesis, further prospective studies arewarranted to evaluate the role of H. pylori eradica-tion on endothelial function.AcknowledgementsThe authors do not report any conflict of inter-est regarding this work.References1. Hurst T, Olson TH, Olson LE, Appleton CP. 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Possible role of Helicobacter pylori infection via microvascular dysfunction in cardiac syndrome X

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Possible role of Helicobacter pylori infection via microvascular dysfunction in cardiac syndrome X

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