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Suppression of cyclooxygenase-2 predisposes to heart failure with preserved ejection fraction
Abstract:
Heart failure (HF) is one of the most strongly associated adverse cardiovascular events linked to the use of cyclooxygenase (COX)-2 selective and non-selective nonsteroidal anti-inflammatory drug (NSAID). Nevertheless, it remains uncertain whether NSAID exposure is more likely to lead to heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). In adult mice, postnatal genetic deletion or pharmacological inhibition of COX-2 did not affect cardiac function. In contrast, aged female inducible COX-2 (iCOX-2) knockout (KO) mice displayed diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and elevated levels of plasma N-terminal pro B-type natriuretic peptide (BNP) when compared to age- and sex- matched controls, while their ejection fraction (EF) remained preserved (≥ 50%). No such phenotype was observed in aged male iCox-2 KO mice. Aged female iCox-2 KO mice showed a shift from prostanoid to leukotriene biosynthesis, along with changes in the expression of mitochondrial genes and calcium-handling proteins in the myocardium. The ratio of phospholamban to SERCA2a was increased, indicating an inhibitory effect on SERCA2a activity, which may contribute to impaired myocardial relaxation. In larval zebrafish, COX-2 inhibition by celecoxib caused a modest yet significant reduction in heart rate and diastolic function, while EF was preserved. Additionally, celecoxib increased BNP expression and ventricular calcium transient amplitude. Diabetic patients in the Harvard-Partners electronic medical record exposed to NSAIDs selective for COX-2 inhibition were more strongly associated with an increased risk of HFpEF compared to HFrEF. Collectively, these findings indicate that COX-2 deletion or inhibition does not impair systolic cardiac function but instead leads to an HFpEF phenotype in mice, zebrafish, and humans. An imbalance in calcium handling may mediate the impairment of myocardial relaxation following COX-2 suppression.
Summary:
Genetic deletion or pharmacological inhibition of COX-2 results in heart failure with preserved ejection fraction across zebrafish, mice, and humans.
Insights
Cyclooxygenase-2 (COX-2) inhibition impairs cardiac diastolic function, leading to heart failure with preserved ejection fraction (HFpEF) in female mice, zebrafish, and humans. This effect is linked to calcium handling imbalances.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Molecular Medicine
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly cyclooxygenase-2 (COX-2) inhibitors, are associated with adverse cardiovascular events, including heart failure.
- The specific impact of COX-2 inhibition on different types of heart failure (reduced vs. preserved ejection fraction) remains unclear.
Purpose of the Study:
- To investigate whether COX-2 inhibition preferentially leads to heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF).
- To elucidate the underlying mechanisms of COX-2 inhibition-induced cardiac dysfunction.
Main Methods:
- Utilized aged female inducible COX-2 knockout (iCOX-2 KO) mice and larval zebrafish models.
- Administered celecoxib (a COX-2 inhibitor) to larval zebrafish.
- Analyzed cardiac function, including ejection fraction (EF) and diastolic function.
- Examined plasma N-terminal pro B-type natriuretic peptide (BNP) levels.
- Investigated gene expression, protein levels (phospholamban, SERCA2a), and calcium handling in cardiac tissue.
- Retrospectively analyzed electronic medical records of diabetic patients exposed to COX-2 selective NSAIDs.
Main Results:
- Aged female iCOX-2 KO mice exhibited diastolic dysfunction, cardiac hypertrophy, and elevated BNP, with preserved EF, unlike males.
- COX-2 inhibition in zebrafish resulted in reduced heart rate and diastolic dysfunction, with preserved EF and increased BNP.
- Analysis of human patient data showed a stronger association between COX-2 selective NSAID use and HFpEF risk compared to HFrEF.
- Impaired myocardial relaxation in female iCOX-2 KO mice was linked to altered calcium handling, specifically an increased phospholamban to SERCA2a ratio.
Conclusions:
- COX-2 inhibition does not impair systolic cardiac function but induces a heart failure with preserved ejection fraction (HFpEF) phenotype.
- The HFpEF phenotype observed in mice, zebrafish, and humans following COX-2 suppression is mediated by impaired myocardial relaxation due to calcium handling imbalances.
- These findings highlight a specific mechanism by which COX-2 inhibitors can contribute to HFpEF.
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