In Response
We appreciate Li and colleagues’ insightful comments on our infection and cardiovascular event study.1 Li et al suggested a case-control approach over our time-to-event method. Thus, we reanalysed the UK Biobank data using a case-control design and conditional logistic regression, matching 5 controls per case for birth year, baseline year, and sex, and adjusting for baseline cardiovascular risk factors. This yielded a 30-day odds ratio of 7.73 (95% CI, 5.85–10.20) for major cardiovascular events in relation to severe infection, consistent with our article’s adjusted hazard ratio of 7.87 (95% CI, 6.36–9.72) from the time-dependent Cox model. This reanalysis reinforces the strong association between acute infections and cardiovascular risk.
The low incidence of cardiovascular events in the UK Biobank is well known. Comparisons of risk factor associations in this cohort against representative, general population based studies suggest this is an unlikely source of major bias.2 The 11 647 major cardiovascular events in our study consisted of 5269 (45.2%) myocardial infarctions, 3459 (29.7%) ischaemic strokes, 1261 (10.8%) coronary deaths, 709 (6.1%) intracerebral haemorrhages, 512 (4.4%) subarachnoid haemorrhages, and 437 (3.8%) unspecified strokes, a disease pattern also observed in the general English population.
We agree with Li et al that the association between infection and risk of cardiovascular disease is not a new topic. Earlier studies have assessed several infectious diseases in relation to short-term cardiovascular risk, and also some infections in relation to long-term risk. We extended this evidence by assessing a wide range of infections in relation to both short- and long-term cardiovascular risk in two large cohorts. We differentiated between sepsis (infection with life-threatening organ dysfunction) versus other infections (mostly less severe), finding evidence that more severe infections might be associated with higher cardiovascular risk (Figure 3 in the article). We also assessed infections by site (Figures 2 and 3), by duration of hospital treatment (Figure S14), and by calendar period (Figure S5).
Much more work is still needed to determine the most effective measures for averting infection-related adverse cardiovascular outcomes. Given that biomarker and imaging technologies are rapidly advancing, mechanistic understanding in this field is likely to progress rapidly. Gaining insight into how treatments influence cardiovascular risk following infections is also pivotal. Although randomized trials have not shown benefits from interventions like statins, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers for severely ill infection patients,3,4 they indicate reduced cardiovascular complications with influenza vaccination in patients with pre-existing coronary heart disease and reduced mortality with ultrashort-acting β1-blockers in treating sepsis.5 Systematic assessment of the benefits, drawbacks, and cost-effectiveness of population-wide and targeted strategies, as well as personalized interventions, is warranted.
Disclosures Statement
The analyses presented in this response were conducted using data from the UK Biobank (https://www.ukbiobank.ac.uk/) via application 60565. PNS reports grant support from the Finnish Medical Foundation during the writing of the author response and from NordForsk (75021), Academy of Finland (311492, 329202), Helsinki Institute of Life Science, the Emil Aaltonen Foundation, and the Finnish Medical Foundation during the conduct of the original study. MK reports grant support from Wellcome Trust (221854/Z/20/Z), UK Medical Research Council (MRC R024227/1), the US National Institute on Aging (R01AG056477), the Academy of Finland (350426), and the Finnish Foundation for Cardiovascular Research (a86898) during the writing of the author response.
References
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