Gender and tachycardia: independent modulation of platelet reactivity in patients with atrial fibrillation

Abstract

Background: Female patients with atrial fibrillation (AF) experience increased risk of thromboembolism compared to males, an observation that is reflected by its inclusion in the CHA2DS2VASc score. New onset AF (often associated with tachycardia) also confers upon patients increased thromboembolic risk. The mechanisms underlying this risk are uncertain, but new onset AF is associated with profound impairment of platelet nitric oxide (NO) signalling. Given that cardiovascular responses to catecholamines are gender-dependent, and that the presence of tachycardia in new onset AF may represent a response to catecholaminergic stimulation, we explored the potential impact of gender and tachycardia on platelet aggregation and NO signalling.

Methods: Interactions were sought in 87 AF patients between the extent of adenosine diphosphate (ADP)-induced platelet aggregation, the anti-aggregatory effects of the NO donor, sodium nitroprusside, gender, and admission heart rate. The potential impact of platelet expression of thioredoxin-interacting protein (Txnip) was also evaluated.

Results: Analysis of covariance confirmed the presence of physiological antagonism between platelet ADP and NO responses [F (1, 74) = 12.212, P < 0.01], while female sex correlated with impaired NO responses independent of platelet aggregability [F (2, 74) = 8.313, P < 0.01]. Admission heart rate correlated directly with platelet aggregation (r = 0.235, P < 0.05), and inversely with NO response (r = -0.331, P < 0.01). Txnip expression varied neither with gender nor with heart rate.

Conclusions: These results indicate that gender and heart rate are independent determinants of platelet function. Prospective studies of the putative benefit of reversal of tachycardia on restoration of normal platelet function are therefore a priority.

Keywords: Atrial fibrillation; Gender; Heart rate; Nitric oxide; Platelet aggregation.

Figure 1.. Evaluation of the impact of gender upon the physiological antagonism between pro-aggregatory ADP and anti-aggregatory NO responses in AF patients.

ANCOVA demonstrated physiological antagonism: NO response varied inversely with extent of aggregation [F(1, 74) = 12.212, P < 0.01]. (1) Independent impact of female sex: diminished NO response per unit ADP-induced platelet aggregation [F(2, 74) = 8.313, P < 0.01]; (2) A non-significant trend [F(1, 74) = 2.244, P = 0.138] towards diminution of gender differences (as regards platelet NO response) at greater ADP responses. ADP: adenosine diphosphate; AF: atrial fibrillation; ANCOVA: analysis of covariance; NO: nitric oxide.

Figure 2.. Evaluation of the impact of duration of AF on the interaction between tachycardia and extent of platelet aggregation.

ANCOVA confirms that aggregation tends to increase (P = 0.071) with tachycardia. However, the relationship does not vary significantly according to duration of AF [F(1, 83) = 0.192, P = 0.662]. As previously reported, there was a significant (r = 0.235, P < 0.05) relationship overall between heart rate and aggregability. AF: atrial fibrillation; ANCOVA: analysis of covariance.

Figure 3.. ANCOVA evaluation of the impact of gender on the interaction between tachycardia and extent of platelet aggregation (A) and platelet response to NO (B).

While increasing heart rate was associated with both incremental aggregation (P < 0.05) and diminished NO response (P < 0.05), these relationships did not vary significantly according to gender [F(1, 83) = 0.702, P = 0.405; F(1, 73) = 0.049, P = 0.825, respectively]. ANCOVA: analysis of covariance; NO: nitric oxide.

Figure 4.. Platelet Txnip content does not vary significantly with heart rate in the entire population evaluation (P = 0.971).

ANCOVA (data not shown) revealed no heterogeneity of this relationship according to duration of AF or gender. AF: atrial fibrillation; ANCOVA: analysis of covariance; Txnip: thioredoxin-interacting protein.