Introduction

Influenza infection is a caused by a family of influenza viruses which are generally spread through respiratory droplets and can lead to a spectrum of disease, from mild forms of respiratory illness, to significant and life threatening severe respiratory failure. During the 2018-2019 influenza season, the Centers for Disease Control and Prevention estimate influenza contributed to 490,561 (95% confidence Interval [CI]: 387,283-766,472) hospitalizations in the United States and over 34,000 deaths.¹ There is growing evidence that influenza infection may adversely affect cardiovascular health and contribute to acute cardiovascular events through a number of mechanisms.^2,3 Despite seminal advances in pharmacological and interventional-based therapies, patients with cardiovascular disease remain at high risk of morbidity and mortality.  As such, there remains an urgent need for optimal implementation of therapies that are broadly available with favorable safety profiles and low personal cost, including annual influenza vaccination.

Proposed Mechanisms of Influenza-Related Cardiopulmonary Illness

Respiratory infection with influenza, like other viral infections, leads to the release of proinflammatory cytokines, including interleukins, tumor necrosis factor-alpha (TNF-α), and C-reactive protein among others.⁴ The release of these pro-inflammatory cytokines has been linked to the progression of atherogenesis. In animal models, proinflammatory cytokines may upregulate cell adhesion molecule expression on vascular endothelial cells, facilitating transmigration of leukocytes into the vascular intima, a central process in the atherogenic cascade.^5-7 In addition, animal and rodent studies have shown high levels of TNF- α may directly impair myocardial contractility, leading to reductions in stroke volume, and blunting beta-adrenergic responsiveness of cardiac myocytes, all of which may contribute to heart failure (HF).^8,9 In addition to disruptions in the vascular endothelium, influenza infection can indirectly result in increases in myocardial oxygen and metabolic demand both by stimulation of the sympathetic nervous system and hypoxemia due to respiratory infection. This can lead to ischemia in in patients already at high risk of atherosclerotic complications.

Influenza Illness in Patients with Cardiovascular Disease

Influenza infection has been linked to adverse cardiovascular events in patients with underlying atherosclerotic vascular disease and in those with heart failure. Longitudinal data from New York found temporal correlations between influenza-like illness activity and cardiovascular mortality with consistent seasonal trends from 2006-2012.¹⁰ In an elegant self-case control study, Kwong and colleagues examined over three hundred hospitalization for acute myocardial infarction (AMI) in which there was documented influenza infection in the two-year window surrounding AMI hospitalization.¹¹ Patients were six times more likely to experience their AMI event in a risk period of 7 days surrounding influenza diagnosis as compared with the control period extending a year prior and after influenza diagnosis.

As above stated, in addition to the promotion of atherogenesis, influenza infection may have direct myocardial suppressant properties, contributing to the development of heart failure. Respiratory infection remains a common precipitant for worsening heart failure episodes. In an analysis from the from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, respiratory infection and myocardial ischemia were the most common precipitants of acute heart failure, both of which may be important components during influenza infection.¹² Additionally, in a propensity matched analysis of hospitalized heart failure patients with and without concomitant influenza, those with documented influenza had higher rates of acute respiratory failure requiring mechanical ventilation, acute kidney injury, and all-cause in-hospital mortality.¹³

Influenza Vaccination in Patients with Cardiovascular Disease

A number of evaluations of influenza vaccination in patients with known atherosclerotic vascular disease and heart failure have been undertaken. Among others, two randomized clinical trials, Flu vaccination in Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions (FLUVACS) Study¹⁴ and Influenza Vaccination in Prevention From Acute Coronary Events in Coronary Artery Disease (FLUCAD)¹⁵ enrolled patients with suspected or known coronary artery disease and randomized enrolled patients to trivalent influenza vaccination versus placebo. FLUVACS found appreciable reductions in cardiovascular death at 12 months in those treated with influenza vaccination (6% vs 17%, RR 0.34; 95% CI: 0.17 to 0.71; P=0.002) in a population of patients with recent myocardial infarction or planned percutaneous coronary intervention (PCI).¹⁴ FLUCAD enrolled a lower risk populations including those with stable coronary artery disease, and did not find reductions in cardiovascular death, but observed reductions in coronary ischemic events (major adverse cardiac events [MACE] or hospitalization for myocardial ischemia) at 12-months in the vaccination group (6.02 vs. 9.97%, HR 0.54; 95% CI: 0.29-0.99; P=0.047).¹⁵ A meta-analysis of available trials found influenza vaccination was associated with reductions in cardiovascular events (RR 0.64; 95% CI: 0.48-0.86, P = 0.003) in patients with atherosclerotic cardiovascular disease, with even greater association of benefit with vaccination in patients with recent acute coronary syndromes (RR 0.45; 95% CI: 0.32-0.63).¹⁶

To date, evaluations of the efficacy of influenza vaccination in patients with heart failure have generally been limited to large observational analyses. Using a self-case control design, Mohseni et. al evaluated 59,000 patients in England who received influenza vaccination in one year and did not receive vaccination in an adjacent year.¹⁷ Rates of cardiovascular hospitalization were significantly lower during vaccination years. Despite the self-case control design, unmeasured confounding and changes in other health behaviors may have influenced these findings. In 134,000 patients followed after new HF diagnosis from 2003-2018 in Denmark, patients with consistent yearly vaccination and those vaccinated early in the respective influenza season experiences lower risks of all-cause and cardiovascular mortality after adjustment for relevant covariates.¹⁸

There are a number of ongoing investigations of influenza vaccination in patients with cardiovascular disease. The international IVVE trial (NCT02762851) is randomizing patients with heart failure to annual administration of standard trivalent influenza vaccine or placebo over three sequential influenza seasons. Other trials, including the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Health Failure (INVESTED) trial randomized patients with recent myocardial infarction or heart failure hospitalization to standard dose quadrivalent vaccination versus high dose trivalent vaccination with a primary outcome of all-cause mortality and cardiopulmonary hospitalizations.¹⁹ High dose vaccination contains increased levels of the polysaccharide hemagglutinin compared with standard dose vaccination, has been associated with greater immunogenicity,²⁰ and has demonstrated increased efficacy in older adults.²¹

Influenza Vaccination Rates

Despite growing and compelling evidence of a link between influenza infection and cardiovascular events in high-risk patients and support for vaccination in contemporary cardiovascular guidelines,^22-25 influenza vaccination rates in patients with underlying cardiovascular disease have remained disappointingly low. An analysis from the Get With the Guidelines-Heart Failure (GWTG-HF) registry found that over 20% of eligible HF patient refused vaccination, with refusals rates rising from 2012 to 2017, while seasonal vaccination rates declined from 70% to 66% over the same time period.²⁶ In the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) clinical trial, there was marked heterogeneity in vaccination rates across countries.²⁷ Even in a highly monitored clinical trial setting, only 21% of the overall trial population received influenza vaccination; vaccination rates were higher in those enrolled in the United States (55%), but significant gaps persisted. Similar gaps in vaccination have been seen globally, including in England¹⁷ and Demark,¹⁸ despite nationalized healthcare systems.

There remain significant implementation opportunities in supporting influenza vaccination in high-risk patients with existing cardiovascular disease. Best practices should be identified from high-performing centers; a recent analysis found high-performing centers with respect to vaccination of HF patients also had greater adherence to other ACC/AHA HF quality measures, suggesting the adoption of systems-level structural interventions to promote high quality care.²⁶ In addition, adoption of computerized reminders may further facilitate influenza vaccination, particularly in hospitalized patients.²⁸ Most of all, clinician and patient engagement, enhanced educational efforts, reductions in barriers and novel strategies for improving access all will remain central to improve vaccination rates among high risk cardiovascular patients.

Conclusion

In the context of the coronavirus-disease 2019 (COVID-19) pandemic, there is growing appreciation of the link between respiratory illness and cardiopulmonary health. Influenza infection may contribute to progression of atherosclerotic vascular disease and the development of heart failure syndromes. It is clearer than ever that strategies to support cardiovascular risk mitigation, including optimization of cardioprotective regimens should be a central therapeutic priority for cardiovascular care providers. Acknowledging the continued need for additional high-quality evidence, annual influenza vaccination in addition to other infection control measures should remain central components of this charge.

Educational grant support provided by: Sanofi Pasteur, Inc.

To visit the hub for the Taking the Lead: Flu and Cardiovascular Disease Grant, click here!

References

1. Reed C, Chaves SS, Daily Kirley P, et al. Estimating influenza disease burden from population-based surveillance data in the United States. PLoS One 2015;10:e0118369.
2. Vardeny O, Solomon SD. Influenza vaccination: a one-shot deal to reduce cardiovascular events. Eur Heart J 2017;38:334–7.
3. Bhatt AS, DeVore AD, Hernandez AF, Mentz RJ. Can Vaccinations Improve Heart Failure Outcomes?: Contemporary Data and Future Directions. JACC Heart Fail 2017;5:194–203.
4. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 1998;101:643–9.
5. Price DT, Loscalzo J. Cellular adhesion molecules and atherogenesis. Am J Med 1999;107:85–97.
6. Braun M, Pietsch P, Zepp A, Schrör K, Baumann G, Felix SB. Regulation of tumor necrosis factor alpha- and interleukin-1-beta-induced induced adhesion molecule expression in human vascular smooth muscle cells by cAMP. Arterioscler Thromb Vasc Biol 1997;17:2568–75.
7. Berliner JA, Subbanagounder G, Leitinger N, Watson AD, Vora D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc Med 2001;11:142–7.
8. Pagani FD, Baker LS, Hsi C, Knox M, Fink MP, Visner MS. Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-alpha in conscious dogs. J Clin Invest 1992;90:389–98.
9. Bozkurt B, Kribbs SB, Clubb FJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–91.
10. Nguyen JL, Yang W, Ito K, Matte TD, Shaman J, Kinney PL. Seasonal Influenza Infections and Cardiovascular Disease Mortality. JAMA Cardiol 2016;1:274–81.
11. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med 2018;378:345–53.
12. Fonarow GC, Abraham WT, Albert NM, et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med 2008;168:847–54.
13. Panhwar MS, Kalra A, Gupta T, et al. Effect of Influenza on Outcomes in Patients With Heart Failure. JACC Heart Fail 2019;7:112–7.
14. Gurfinkel EP, Leon de la Fuente R, Mendiz O, Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J 2004;25:25–31.
15. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J 2008;29:1350–8.
16. Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA 2013;310:1711–120.
17. Mohseni H, Kiran A, Khorshidi R, Rahimi K. Influenza vaccination and risk of hospitalization in patients with heart failure: a self-controlled case series study. Eur Heart J 2017;38:326–33.
18. Modin D, Jørgensen ME, Gislason G, et al. Influenza Vaccine in Heart Failure. Circulation 2019;139:575–86.
19. Vardeny O, Udell JA, Joseph J, et al. High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial. Am Heart J 2018;202:97–103.
20. Van Ermen A, Hermanson MP, Moran JM, Sweitzer NK, Johnson MR, Vardeny O. Double dose vs. standard dose influenza vaccination in patients with heart failure: a pilot study. Eur J Heart Fail 2013;15:560–4.
21. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of High-Dose Versus Standard-Dose Influenza Vaccine in Older Adults. N Engl J Med 2014;371:635–45.
22. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–81.
23. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;16:e1-194.
24. Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011;124:2458–73.
25. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240-327.
26. Bhatt AS, Liang L, DeVore AD, et al. Vaccination Trends in Patients With Heart Failure: Insights From Get With The Guidelines-Heart Failure. JACC Heart Fail 2018;6:844–55.
27. Vardeny O, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail 2016;18:1228–34.
28. Dexter PR, Perkins SM, Maharry KS, Jones K, McDonald CJ. Inpatient computer-based standing orders vs physician reminders to increase influenza and pneumococcal vaccination rates: a randomized trial. JAMA 2004;292:2366–71.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Interventions and ACS, Interventions and Coronary Artery Disease

Keywords: Primary Prevention, Secondary Prevention, Influenza, Human, Influenza Vaccines, Seasons, Hemagglutinins, Coronary Artery Disease, C-Reactive Protein, Tumor Necrosis Factor-alpha, Acute Coronary Syndrome, Stroke Volume, Percutaneous Coronary Intervention, Hospital Mortality, Myocytes, Cardiac, Cardiovascular Diseases, Endothelium, Vascular, Cytokines

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