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Influenza A vaccination in patients with type II diabetes induces an increase in platelet activation and a cardiac sympathovagal imbalance

Numerous studies have shown that inflammation has a relevant role in the pathogenesis of atherosclerosis as well as of acute coronary syndromes.
Moreover, markers of inflammation predict cardiovascular events in several disease states.
Increased platelet activation and sympathovagal imbalance of cardiac autonomic nervous system ( ANS ) activity are also well-known predictors of acute coronary events.
Inflammatory stimuli are believed to induce a prothrombotic state, but there is a relative lack of data about their effects on platelet activation in the clinical setting.
Similarly, a relation between autonomic nervous system activity and inflammation has recently been reported in experimental studies as well as in several diseases, but the exact relation between autonomic nervous system activity and inflammation in the clinical setting remains unclear. In particular, how inflammatory stimuli affect sympathovagal balance in humans has not been explored.

Influenza A vaccination is globally recommended each year for patients with increased risk of life threatening complications from influenza A disease, including patients with diabetes.

A study has investigated the effects of the inflammatory reaction induced by influenza A vaccination on platelet activation and on cardiac ANS activity in a group of patients with type II diabetes.

Thirty patients followed at the Diabetic Center of Gemelli Hospital ( Rome, Italy ) for an established diagnosis of type II diabetes mellitus who underwent influenza A vaccination in the autumn of 2008 were initially included in the study.
This number of patients was planned according to the short period of enrolment ( during the few autumn months of the vaccination programme ) and the limited availability of recorders for 24-h ambulatory Holter electrocardiogram ( ECG ) monitoring.
Patients were excluded in cases of overt cardiovascular disease and⁄ or acute or chronic inflammatory disease, or if they were taking beta-adrenergic blocking agents.

Patients underwent influenza A vaccination using an inactivated virus with MF59C.1 adjuvant ( Fluad ).

According to Authors this is the first study to directly assess the effects of an inflammatory stimulus on platelet activation and cardiac autonomic activity, as well as the correlation between these variables, in patients.

The findings, obtained from patients with type II diabetes, have shown that, together with the expected rise in inflammatory cytokines and monocyte activation, influenza A vaccine has induced an increase in platelet activity and changes in cardiac autonomic tone towards reduced vagal activity and a relative sympathetic predominance.

No significant relation was found, however, between the increase in platelet activation and the degree of inflammation as assessed by serum C-reactive protein ( CRP ) level.
On the other hand, significant correlations were found between the changes in CRP level and in heart rate variability ( HRV ) variables, suggesting some pathophysiological link between the inflammatory and the cardiac autonomic responses to vaccine administration.

Inflammation and platelet activation

Influenza A vaccination in the patients has induced a significant increase in monocyte-platelet aggregate ( MPA ) formation and in expression of monocyte and platelet membrane receptors, suggesting that vaccine-related monocyte activation led to a secondary increase in platelet activation.
Of note, no significant association was found between serum CRP levels and MPA, suggesting that the increased platelet activation was not significantly dependent on the degree of the humoral reaction to the inflammatory stimulus.

The observation of increased MPA formation and monocyte ⁄platelet receptor expression following influenza A vaccination may be clinically relevant, as these changes suggest the development of a prothrombotic state.
Moreover, in previous studies, MPAs have been shown to be associated with acute coronary events.

Infectious diseases, including influenza, have been associated with an increased occurrence of acute cardiovascular events, in particular in patients with evidence of increased risk of cardiovascular disease.
Several abnormalities induced by infections can favour acute cardiovascular events, including endothelial dysfunction, prothrombotic changes in the blood and direct damage to coronary plaques.

Vaccination is recommended each year as a valid way to reduce morbidity and mortality related to seasonal influenza A disease in moderate- to high-risk patients, including those with diabetes. However, the ability of the influenza A vaccination to reduce the risk of acute coronary events remains debated, as discordant results have been reported.
The increased platelet activation observed after vaccination in this study might transiently increase the risk of thrombosis in high-risk patients. This might significantly counteract the benefits on the cardiovascular system deriving from the prevention of influenza disease by vaccination, contributing to explain the controversial results about the protection of influenza A vaccine against acute coronary events.

Inflammation and cardiac autonomic function

Many studies have also shown that even an alteration of cardiac autonomic nervous system activity towards a predominance of adrenergic tone is associated with an increased risk of cardiac events in several disease settings, including diabetes.

It is noteworthy that, in recent years, several experimental studies have shown a link between autonomic nervous function and inflammation.
Early studies in rats showed that vagotomy increased, whereas vagus nerve stimulation decreased, mortality related to endotoxin-induced sepsis.

The capacity of parasympathetic stimulation to limit the response to inflammatory stimuli was confirmed in several other studies and seems to be mainly mediated by the inhibition of tissue macrophage activation through acetylcholine-mediated stimulation of alpha-7 nicotinic receptors.

Other studies have shown that inflammation in peripheral tissues can be sensed by afferent nerve fibres stimulated by inflammatory cytokines.
Sensing of inflammation triggers autonomic vagal activation that determines anti-inflammatory effects with a probable attempt to avoid tissue damage as a consequence of excessive local inflammatory reactions ( the inflammatory reflex ).

A relation between impaired cardiac parasympathetic function and a subclinical inflammatory state has recently been reported in several clinical studies. Such a relation implies that impairment of the autonomic modulation of inflammation, because of significant autonomic dysfunction, may favour an increase in subclinical inflammation.

To obtain insight into the complex link between the autonomic nervous system and inflammation, researchers have assessed the effects of beta-blockade on HRV and CRP levels in a small group of patients with type 1 diabetes. As expected, beta-blockade improved HRV, but, at the same time, also reduced serum CRP levels, suggesting that the improvement of sympathovagal balance by beta-blockers may translate into anti-inflammatory effects.

In the study, researchers investigated the cardiac autonomic response to an inflammatory stimulus in a group of patients with type II diabetes without overt cardiovascular disease.
The results have shown that vaccine administration induced a cardiac sympathovagal imbalance towards relative sympathetic predominance, as expressed by the reduction in HRV parameters, which probably resulted from systemic changes induced by inflammation ( including possible mild increase in body temperature and peripheral vasodilation ).
Of note, the changes in most HRV parameters correlated with those of CRP levels, confirming the evidence from previous studies of a pathophysiological link between subclinical inflammation and cardiac sympathovagal balance

The increase in MPA, however, did not show any significant correlation with HRV changes, suggesting that the acute cell-mediated inflammatory response to viral vaccine did not result in appreciable effects on cardiac autonomic activity. Accordingly, no significant relation was found between HRV changes and platelet activation in this context.


In the study, researchers have shown that influenza A vaccination in patients with type II diabetes induces, together with the expected inflammatory reaction, an increase in platelet activation and a cardiac sympathovagal imbalance.
Overall, the vaccine-induced changes in platelet activity and autonomic nervous activity may transiently increase the risk of cardiovascular events in vaccinated patients. ( Xagena )

Lanza GA et al, J Intern Med 2011;269: 118–125