The study was supportive of the hypothesis that recent respiratory illnesses and, in particular, ILIs occurring during the second wave of the influenza A H1N1 pandemic were more common in patients hospitalised with AMI than with acute surgical conditions. Influenza vaccination was also associated with protection against myocardial infarction, although differences were not statistically significant. While we had hypothesised that more adults would be infected during the second pandemic wave due to the expected upward shift in age distribution of infections, the national rates of ILI remained low,5
especially in age groups typically affected by AMI. The study was therefore underpowered to detect an effect, partly due to the limited numbers of infections among participants.
Using self-reported recent respiratory illness and ILI as exposures introduced the possibility of reporting or recall bias. Nonetheless, this method allows greater sensitivity to detect recent respiratory symptoms than relying on reports of medically attended illnesses, which comprise only a small minority of influenza cases.13
As cases and controls were frequency matched in the week of admission, external factors such as media coverage of the influenza pandemic should not have had a differential effect on respiratory illness reporting. We chose to test both nasopharyngeal and throat swabs to increase the sensitivity of virus detection. It was perhaps unsurprising, however, that none of the nasopharyngeal and throat swabs were positive for influenza virus given (1) the low rates of infection in this age-group5
and (2) that the majority of viral shedding in influenza occurs in the first 2–3 days after symptom onset,14
whereas most of the reported respiratory symptoms in study participants occurred 8–14 days before admission. Based on our findings, it seems unlikely that any delayed cardiac effect of influenza is linked to ongoing or prolonged virus replication or shedding in the respiratory tract. Influenza serology is difficult to interpret in vaccinated participants as it not possible to distinguish antibody rises caused by infection from those caused by vaccination. Validation of the IgA assay used suggests that it has acceptable sensitivity and specificity to detect recent seasonal influenza A infection,15
but its effect with the pandemic strain H1N1pdm09 is unclear. It has previously been noted that serological studies carried out during the 2009 influenza pandemic were severely hampered by crossreactivity both with the vaccine and with the seasonal influenza strains.7
Previous observational studies using large electronic primary care databases have found an association between GP consultation for acute respiratory infection in the previous month and risk of AMI.16–18
Although studies were conducted over different time periods, they encompassed the effect of varying seasonal influenza strains. In the present study, we controlled for important potential confounders such as influenza vaccination status, and showed that statin use was equally prevalent in cases and controls. We did not, however, have complete data on other drugs that have been hypothesised to have immune-regulatory effects (such as ACE inhibitors, angiotensin receptor blockers, metformin, glitazones and fibrates). If these agents reduce the likelihood of people experiencing ILI, and were more commonly used in cases than controls, they could potentially have confounded the relationship between ILI and AMI. It was reassuring, however, that our results were consistent with those obtained in our recent self-controlled case series study—a design that implicitly controls for fixed confounders. In this study, we used linked primary care and cardiac disease registry records from 3927 patients from 2003–2009, which also included acute respiratory infection consultations occurring during the first wave of H1N1pdm09 circulation.19
We found an incidence ratio for AMI of 4.19 (95% CI 3.18 to 5.53) in the first 1–3 days after acute respiratory infection, with the risk falling to baseline after 28 days.19
Elderly people and those consulting for an infection judged most likely to be due to influenza were at greatest risk. During the 2009 influenza, pandemic people with underlying cardiovascular disease were much more likely to be hospitalised13
and to die20
from a range of causes attributable to pandemic influenza. Although most deaths from H1N1pdm09 occurred in younger people, this was partly a function of the age distribution of infections: in the UK, the case death rate in the elderly was much higher than in younger age-groups,5
but overall, the numbers of deaths were small as few elderly people were infected.
Various biological mechanisms are proposed to underlie a relationship between influenza or acute respiratory infection and myocardial infarction.21
Acute respiratory infections may result in a host of acute inflammatory and haemostatic effects leading to systemic inflammation, altered plasma viscosity, coagulability and haemodynamic changes22
as well as promoting local endothelial dysfunction, coronary inflammation and plaque rupture.23
Immobility associated with bedrest and dehydration might potentiate these processes.
In conclusion, this study suggests that recent ILI occurring during the 2009 influenza pandemic was more common in AMI patients. Taken in the context of previous work, this helps to support the hypothesis that, as with other influenza strains, H1N1pdm09 could potentially trigger AMI in vulnerable groups. It is likely, however, that the effect is not specific to influenza and could have also been caused by other viruses circulating at the time. The population impact of H1N1pdm09 on rates of hospitalisations and deaths from myocardial infarction is also likely to have been relatively low given the mismatch between the ages of those typically affected by H1N1pdm09 and acute coronary events as well as the relatively mild clinical effects of this influenza strain.