Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure

Hariri, Essa; Kakouros, Nikolaos; Bunsick, David A.; Russell, Stuart D.; Mudd, James O.; Laws, Katherine; Lake, Mikhailia; Rade, Jeffrey J.

doi:10.1152/ajpheart.00212.2022

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…116 In patients with HF, urine thromboxane B 2 metabolite levels are independently associated with the risk of death and the need for transplant or mechanical support. 117 Altogether, TxA 2 contributes to CVD by favoring adverse cardiac remodeling, in addition to inducing platelet aggregation (Table 5).…”

Section: Txa 2 In Myocardial Remodelingmentioning

confidence: 99%

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Prostanoids in Cardiac and Vascular Remodeling

Ricciotti,

Haines,

Chai

et al. 2024

ATVB

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Prostanoids are biologically active lipids generated from arachidonic acid by the action of the COX (cyclooxygenase) isozymes. NSAIDs, which reduce the biosynthesis of prostanoids by inhibiting COX activity, are effective anti-inflammatory, antipyretic, and analgesic drugs. However, their use is limited by cardiovascular adverse effects, including myocardial infarction, stroke, hypertension, and heart failure. While it is well established that NSAIDs increase the risk of atherothrombotic events and hypertension by suppressing vasoprotective prostanoids, less is known about the link between NSAIDs and heart failure risk. Current evidence indicates that NSAIDs may increase the risk for heart failure by promoting adverse myocardial and vascular remodeling. Indeed, prostanoids play an important role in modulating structural and functional changes occurring in the myocardium and in the vasculature in response to physiological and pathological stimuli. This review will summarize current knowledge of the role of the different prostanoids in myocardial and vascular remodeling and explore how maladaptive remodeling can be counteracted by targeting specific prostanoids.

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Section: Txa 2 In Myocardial Remodelingmentioning

confidence: 99%

“…In patients with HF, urine thromboxane B 2 metabolite levels are independently associated with the risk of death and the need for transplant or mechanical support. 117…”

Section: Txa2 In Myocardial Remodelingmentioning

confidence: 99%

Prostanoids in Cardiac and Vascular Remodeling

Ricciotti,

Haines,

Chai

et al. 2024

ATVB

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Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites

Barton,

Kronsberg,

Hariri

et al. 2024

Clinical Chemistry

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Background Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. Methods Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. Results Optimized cutpoints of TXB2-M were 1291 and 5609 pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73 m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). Conclusion Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.

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A network medicine approach to study comorbidities in heart failure with preserved ejection fraction

Lanzer

Valdeolivas

Pepin

et al. 2023

BMC Med

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Background Comorbidities are expected to impact the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model phenome-wide comorbidity profiles to improve our understanding of HFpEF and infer associated genetic profiles. Methods We retrospectively explored 569 comorbidities in 29,047 HF patients, including 8062 HFpEF and 6585 HF with reduced ejection fraction (HFrEF) patients from a German university hospital. We assessed differences in comorbidity profiles between HF subtypes via multiple correspondence analysis. Then, we used machine learning classifiers to identify distinctive comorbidity profiles of HFpEF and HFrEF patients. Moreover, we built a comorbidity network (HFnet) to identify the main disease clusters that summarized the phenome-wide comorbidity. Lastly, we predicted novel gene candidates for HFpEF by linking the HFnet to a multilayer gene network, integrating multiple databases. To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature. Results We found a high degree of variance between the comorbidity profiles of HFpEF and HFrEF, while each was more similar to HFmrEF. The comorbidities present in HFpEF patients were more diverse than those in HFrEF and included neoplastic, osteologic and rheumatoid disorders. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups, and sex. Based on the HFpEF comorbidity profile, we predicted and recovered gene candidates, including genes involved in fibrosis (COL3A1, LOX, SMAD9, PTHL), hypertrophy (GATA5, MYH7), oxidative stress (NOS1, GSST1, XDH), and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature providing additional plausibility for their relevance. Conclusions We applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data provides insights that may be leveraged to improve diagnosis and identify treatment targets for HFpEF patients. Graphical Abstract

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Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure

Cited by 3 publications

References 37 publications

Prostanoids in Cardiac and Vascular Remodeling

Prostanoids in Cardiac and Vascular Remodeling

Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites

A network medicine approach to study comorbidities in heart failure with preserved ejection fraction

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