Letter to the Editor: Helicobacter pylori eradication restores aspirin responsiveness - a thromboinflammatory interpretation

Abstract

This letter comments on the recent prospective study by Semeya et al in the World Journal of Gastroenterology showing that Helicobacter pylori (H. pylori) eradication reduces peptic ulcer bleeding and cardiovascular progression in chronic aspirin users. While the original authors attributed the cardiovascular benefit mainly to attenuation of inflammation-driven atherosclerosis, the short follow-up period and event-based endpoints suggest an alternative interpretation. We propose that the observed benefit may instead reflect restoration of aspirin responsiveness through resolution of infection-driven thromboinflammation. Persistent H. pylori infection may promote systemic inflammatory signaling, accelerate platelet turnover, increase reticulated platelets, and amplify platelet activation, thereby weakening effective cyclooxygenase-1 inhibition and producing functional aspirin resistance. Eradication may therefore normalize platelet pharmacodynamics without requiring short-term structural plaque regression. This hypothesis-generating interpretation links infection biology with antiplatelet variability and may help explain the rapid divergence in cardiovascular outcomes observed after eradication.

Key Words: Helicobacter pylori; Aspirin resistance; Thromboinflammation; Platelet reactivity; Antiplatelet pharmacodynamics

Core Tip: Helicobacter pylori infection may influence cardiovascular outcomes beyond peptic ulcer disease, particularly in chronic aspirin users. Persistent infection can sustain a thromboinflammatory state that increases platelet turnover and reactivity, thereby weakening effective cyclooxygenase-1 inhibition and producing functional aspirin resistance. We propose that the apparent cardiovascular benefit after eradication may reflect pharmacologic resensitization rather than short-term vascular remodeling. This hypothesis-generating perspective links infection biology with antiplatelet pharmacodynamics and may help explain inter-individual variability in aspirin efficacy.

TO THE EDITOR

A recent prospective study by Semeya et al[1] in the World Journal of Gastroenterology, describes how the eradication of Helicobacter pylori (H. pylori) can contribute to significant reductions in the bleeding of peptic ulcers and progression of cardiovascular disease in chronic aspirin users, with a consequent anticipation of gastrointestinal benefits. However, given the reported rapid changes in cardiovascular outcomes within a short follow-up period, this raises a temporal question, as structural atherosclerotic regression generally occurs less rapidly than event-level clinical change, and, consequently, warrants a mechanistic interpretation beyond the conventional paradigm of inflammation-driven atherosclerotic modifications.

The authors interpreted the observed cardiovascular improvements primarily in terms of an attenuation of systemic inflammation and retardation of atherosclerotic progression. However, the clinical endpoints examined, including unstable angina, re-vascularization, and worsening angina class, are event-triggered phenomena rather than structural measures of the plaque burden. Moreover, whereas atherosclerosis rarely regresses measurably over timescales of months, thrombogenic triggers can show rapid change[2]. This temporal mismatch would thus tend to indicate that the observed cardiovascular benefits may reflect altered thrombotic susceptibility rather than changes in vascular anatomy.

Against this temporal backdrop, and before re-visiting the clinical endpoints, we propose an alternative, albeit complementary, mechanistic framework in which an eradication of H. pylori could plausibly restore the responsiveness to aspirin by resolving infection-driven thromboinflammation. Within this framework, rather than primarily reflecting the modification of vascular disease progression, the findings of study may be interpreted as revealing a normalization of antiplatelet pharmacodynamics (Figure 1).

Figure 1 Infection-driven aspirin resistance and pharmacologic resensitization after Helicobacter pylori eradication. Panel A illustrates the proposed persistent infection phase, in which chronic Helicobacter pylori colonization is associated with cagA-related inflammatory signaling, increased interleukin-6 and tumor necrosis factor-α activity, platelet priming, increased platelet turnover, enhanced platelet activation, and functional aspirin resistance, culminating in thrombotic triggers such as unstable angina or revascularization. Panel B depicts the post-eradication phase, characterized by reduced inflammatory signaling, normalized platelet turnover, restored cyclooxygenase-1 inhibition, and effective aspirin responsiveness, with reduced thrombotic events shown as a hypothesis-generating downstream interpretation. The background plaque represents relatively stable structural atherosclerotic burden during short-term follow-up. The lower timeline highlights the faster timescale of platelet recalibration relative to the slower timescale of plaque remodeling. Solid arrows indicate literature-supported pathways, whereas dashed arrows indicate proposed interpretive links. H. pylori: Helicobacter pylori; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; COX-1: Cyclooxygenase-1; UA: Unstable angina.

INFECTION-DRIVEN THROMBOINFLAMMATORY STATE

As opposed to being merely confined to gastric mucosal injury, chronic H. pylori infection can be viewed as representing a persistent systemic inflammatory stimulus[3]. Beyond local gastritis, sustained colonization promotes the release of circulating cytokines, endothelial activation, oxidative stress, and platelet-leukocyte interactions[4]. Collectively, these processes generate a biologically recognized thromboinflammatory phenotype characterized by heightened platelet reactivation, impaired endothelial quiescence, and an unstable hemostatic equilibrium[5]. In addition to cardiovascular contexts, the systemic biological relevance of H. pylori infection has also been examined in other disease settings, with emerging evidence indicating that persistent infection may influence extra-gastric immune regulation, metabolic signaling, and aspects of tumor biology through chronic inflammatory signaling, epithelial stress responses, and host-microbe interactions. In gastric carcinogenesis, these processes have been associated with a pro-tumorigenic microenvironment characterized by dysregulated proliferation, migration, invasion, and immune remodeling. Emerging evidence further suggests that long noncoding RNAs participate in host-pathogen interactions[6]. For example, H. pylori infection has been reported to suppress lncRNA AF147447 expression, whereas lncRNA AF147447 itself inhibits gastric cancer proliferation and invasion through modulation of MUC2 and upregulation of miR-34c. These observations are cited here as contextual evidence that localized gastric pathogen infection can exert biologically meaningful effects in broader disease systems.

Given that the structural burden of atherosclerotic burden rarely regresses within months, particularly in patients with established coronary diseases[2], the temporal profile of cardiovascular changes observed by Semeya et al[1] warrant careful consideration. In contrast, thrombogenic susceptibility can rapidly fluctuate in response to inflammatory signaling, and the early separation of unstable angina and re-vascularization events reported by these authors would tend to be more consistent with dynamic trigger-dependent ischemia than with an accelerated accumulation or regression of plaques.

The nature of the clinical endpoints provides further support for this interpretation, with worsening angina class, hospitalization for unstable angina, and procedural re-vascularization representing the event-driven consequences of a supply-demand mismatch or thrombotic activation superimposed on pre-existing coronary lesions[7]. These outcomes reflect physiological instability rather than anatomical remodeling, and thus instead of structural vascular progression, the pattern of events observed in persistently infected individuals may indicate episodic prothrombotic activation.

Other signals detected in the study population were consistent with systemic inflammatory priming. Among these, the lower levels of albumin and higher inflammatory burden detected in infected patients indicates that chronic immune activation can modulate vascular and platelet biology[8]. The clustering of cardiovascular events in patients with persistent infection, rather than solely on baseline disease severity, reinforces the possibility that ongoing inflammatory stimulation continuously lowers the ischemic threshold.

Collectively, these considerations indicate that rather than revealing a change in atherosclerotic substrates, the findings of this study may provide evidence for a shift in thrombogenic propensity.

ASPIRIN RESISTANCE AS A FUNCTIONAL CONSEQUENCE OF CHRONIC INFECTION

The cardioprotective effects of low-dose aspirin are mediated primarily via an irreversible acetylation of platelet cyclooxygenase-1 (COX-1), thereby suppressing the thromboxane A₂-mediated aggregation of platelets[9]. However, whereas this pharmacological model assumes the relative stability of platelet turnover and thromboxane generation, chronic inflammation can disrupt these mechanisms and thereby attenuate platelet inhibition[10].

Infection-immune-platelet axis

As opposed to being a purely gastric-associated phenomenon, persistent H. pylori infection represents a sustained systemic inflammatory stimulus, partly mediated by virulence determinants, such as cagA-associated host signaling, that amplify downstream immune activation[11]. Continuous immune activation, characterized by elevated levels of interleukin-6, tumor necrosis factor-α, and acute-phase reactants, can influence megakaryopoiesis, accelerate platelet turnover, and promote increases in the proportion of newly released reticulated platelets that retain uninhibited COX-1 activity despite exposure to aspirin[12]. In parallel, inflammatory signaling promotes platelet-leukocyte aggregation, endothelial activation, oxidative stress, and tissue factor expression, collectively generating a thromboinflammatory milieu that amplifies the responsiveness of platelets[13]. Under these conditions, ischemic events may arise from transient prothrombotic activation superimposed on existing coronary lesions, rather than from a progressive enlargement of plaques.

Mechanisms attenuating the responsiveness to aspirin

Several converging pathways may contribute to mediating an infection-associated functional resistance to aspirin, among which, an accelerated renewal of platelets results in a narrowing of the effective inhibitory window for irreversible COX-1 acetylation, thereby facilitating an uninhibited accumulation of platelets between repeat doses[14]. In addition, inflammatory induction of COX-2 in monocytes and vascular cells may generate thromboxane independent of a suppression of platelet COX-1[15], and the cytokine-mediated activation of alternative platelet signaling cascades, including ADP- and thrombin-dependent pathways, can enhance aggregation independent of the synthesis of thromboxane[16]. Rather than implying therapeutic non-adherence, these mechanisms tend to reflect an altered pharmacodynamic responsiveness in the context of chronic immune stimulation. We also acknowledge that a resistance to aspirin is mechanistically heterogeneous and may also involve variability in drug absorption, the generation of non-platelet thromboxane, or alternative platelet activation pathways. Within this broader framework, infection-driven thromboinflammation is proposed as a plausible, potentially reversible, contributor.

Eradication as pharmacological re-sensitization

Within this framework, eradication therapy may function less as a modifier of atherosclerotic structures and more as a modulator of antiplatelet efficacy. A resolution of infection-associated inflammation can contribute to a normalization of cytokine levels, stabilization of platelet turnover dynamics, and restoration of endothelial quiescence, thereby reducing the proportion of functionally uninhibited platelets. Given that platelet biology can be recalibrated over weeks[17], we believe that such pharmacological re-sensitization provides a plausible explanation for the relatively rapid divergence in cardiovascular outcomes reported in this study. Consequently, rather than anatomical vascular remodeling, the observed benefits may more plausibly reflect the restoration of effective platelet inhibition. However, this interpretation remains inferential, as direct functional evidence linking active H. pylori infection to altered aspirin pharmacodynamics is still limited. The proposed pathway should therefore be regarded as a biologically plausible and hypothesis-generating framework requiring further validation.

REINTERPRETING THE CLINICAL FINDINGS

Mechanistically, persistent infection-associated inflammation may accelerate platelet turnover, enhance thromboxane-dependent platelet reactivity, and increase thrombotic susceptibility, thereby providing a plausible intermediate link between upstream biological signaling and downstream cardiovascular events. Having initially established the aforementioned temporal mismatch and subsequently the thromboinflammatory framework, we apply this model to re-interpret the collective findings reported by Semeya et al[1]. If we assume that platelet reactivity rather than a plaque burden is the predominant modulator of events, the early separation of cardiovascular outcomes becomes biologically plausible. Whereas platelet turnover and inflammatory signaling can be recalibrated within weeks following a resolution of infection, structural atherosclerotic regression typically requires prolonged lipid and metabolic interventions[17]. Consequently, rather than reflecting an accelerated plaque progression, a clustering of unstable angina and re-vascularization in patients with persistent infection is more consistent with episodic thrombotic activation superimposed on pre-existing coronary disease.

The parallel reduction in gastrointestinal bleeding and cardiovascular events is also less paradoxical in this model. Whereas a restoration of effective platelet inhibition reduces thrombogenic triggers, eradication-associated mucosal recovery reduces the susceptibility to bleeding. Importantly in this regard, adverse cardiovascular outcomes were tracked most closely with the persistence of infection[18] rather than with baseline coronary severity, providing further evidence for the notion that an ongoing prothrombotic inflammatory state, rather than a progression of anatomical disease, underlies the observed differences. Collectively, the findings of this study may thus be interpreted as potentially illustrating pharmacological re-sensitization to antiplatelet therapy rather than vascular remodeling. In addition, responses such as reduced systemic inflammation, enhanced endothelial homeostasis, and a broader stabilization of thromboinflammatory signaling, may have contributed to the observed clinical benefits.

TESTABLE PREDICTIONS

If this interpretation is correct, it might be predicted that measurable alterations in platelet biology would be accompanied by persistent infection and subsequent eradication. It is anticipated that patients with active H. pylori infection will have higher urinary or serum levels of thromboxane metabolites, elevated proportions of reticulated platelets, and more pronounced variability in platelet aggregation responses, despite standardized aspirin dosing[19]. In this regard, functional assays, such as light transmission aggregometry, point-of-care platelet function testing, and measurement of 11-dehydro-thromboxane B₂, could reveal an attenuation of pharmacodynamic responsiveness in the infected state.

Following eradication, normalization of platelet inhibition should occur in the absence of any parallel structural changes in the coronary anatomy, consistent with the concept of pharmacological re-sensitization rather than vascular remodeling. Importantly, such an improvement should be temporally correlated with reductions in inflammatory biomarkers, including C-reactive protein or interleukin-6, rather than with imaging-based plaque modifications.

Prospective studies that integrate determinations of infection status, inflammatory profiling, assessments of platelet function, and monitoring of longitudinal cardiovascular outcomes could clarify whether H. pylori infection is a reversible determinant of aspirin efficacy. In particular, serial evaluation before and after eradication therapy, including thromboxane metabolites, reticulated platelet fractions, and platelet aggregation indices, may help determine whether resolution of infection-associated inflammation is accompanied by restoration of aspirin responsiveness. Moreover, demonstrating that eradication reduces a laboratory-defined resistance to aspirin independent of lipid or angiographic changes would contribute to distinguishing drug-response modulation from atherosclerotic disease modification. Experimental models examining inflammatory regulation of platelet turnover and COX-1 responsiveness may further strengthen causal inference. Further investigations should also account for concomitant medications that may independently influence platelet function, inflammatory signaling, or cardiovascular outcomes. Even negative findings could facilitate a meaningful refinement of the mechanistic interpretation of the original study.

CLINICAL IMPLICATIONS

By considering H. pylori as a modulator of the responsiveness to aspirin, we can reframe the traditional view of eradication therapy as a purely gastroprotective intervention in terms of a potential component of precision antithrombotic management. Rather than simply preventing mucosal injury, screening for infection may enable the identification of a subset of patients with biologically attenuated responsiveness to aspirin therapy, particularly among those who experience recurrent ischemic symptoms despite a documented adherence to appropriate dosing. In such individuals, persistent infection could be a reversible contributor to apparent treatment failure.

This perspective also highlights a broader translational concept, namely, that chronic infection may, in specific contexts, influence aspects of cardiovascular pharmacotherapy via immunohematological pathways that modify the responsiveness to drugs rather than the disease burden per se[20]. Consequently, incorporating infection status within cardiovascular risk assessments could contribute to enhancing therapeutic predictability without necessarily intensifying antithrombotic regimens, which is associated with a heightened risk of bleeding. Rather than advocating routine changes in practice, this hypothesis instead highlights the need for a stratified investigation. If validated, infection-directed management may serve as a biologically targeted strategy that could be adopted to optimize antiplatelet efficacy, whilst maintaining the requisite levels of safety. Beyond conventional eradication regimens, future infection-control strategies, including optimized pharmacological approaches and the administration of adjunctive bioactive compounds, may further broaden the preventive and therapeutic relevance of this concept. Such directions warrant prospective evaluation within precision cardiovascular risk management frameworks.

CONCLUSION

The reported cardiovascular benefits obtained following the eradication of H. pylori infection may not solely reflect a modification of the atherosclerotic structure, but rather a restoration of effective platelet inhibition within a previously primed thromboinflammatory milieu. Viewing the findings through this lens reconciles the observed rapid changes in clinical outcomes with the biological timescale of platelet recalibration, and offers a unifying explanation for the parallel reductions in ischemic and bleeding events.

By framing persistent infection as a potentially reversible determinant of the responsiveness to aspirin, the findings of the study by Semeya et al[1] provide mechanistic insights that extend beyond inflammation-driven vascular remodeling. Although hypothesis-generating, this interpretation highlights a potentially under-recognized interaction between chronic infection and antiplatelet pharmacodynamics, which merits further targeted investigation. Clarifying this relationship may ultimately contribute to refining both gastroenterological risk mitigation and strategies for the prevention of cardiovascular disease.