Influenza and cardiovascular disease pathophysiology: strings attached

Abstract

A link between influenza infection and cardiovascular morbidity has been known for almost a century. This narrative review examined the cardiovascular complications associated with influenza and the potential mechanisms behind this relationship. The most common reported cardiovascular complications are cardiovascular death, myocardial infarction, and heart failure hospitalization. There are multiple proposed mechanisms driving the increased risk of cardiovascular complications. These mechanics involve influenza-specific effects such as direct cardiac infection and endothelial dysfunction leading to plaque destabilization and rupture, but also hypoxaemia and systemic inflammatory responses including increased metabolic demand, biomechanical stress, and hypercoagulability. The significance of the individual effects is unclear, and thus whether influenza directly or indirectly causes cardiovascular events is unknown. In conclusion, the risk of acute cardiovascular morbidity and mortality is elevated during influenza infection. The proposed underlying pathophysiological mechanisms support this association, but systemic responses to infection may drive this relationship.

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Introduction

Cardiovascular disease is among the most common comorbidities of hospitalized influenza patients and is associated with a more severe disease course.^1,2 Clinical findings in influenza patients do not only include respiratory symptoms, high fever, fatigue, and myalgia but also frequent cardiovascular involvement.^3–6 Increasing attention has been given to this association between influenza infection and cardiovascular conditions during the last two decades. Apart from an elevated risk of cardiovascular mortality, influenza has been linked to both ischaemic and myocardial complications including myocardial infarction (MI), stroke, exacerbation of heart failure (HF), myocardial injury, and in lower magnitude stress cardiomyopathy, myocarditis, and pericarditis (Figure 1).^6–23 The underlying mechanisms driving this relationship between influenza infection and cardiovascular disease are currently not fully elucidated. However, the mechanisms may involve effects specific to the influenza virus, the systemic inflammatory response to infection, or a combination of both.

Figure 1.

Cardiovascular complications of influenza virus. Multiple cardiovascular complications have been associated with influenza infection. Among these are cardiovascular death, vascular complications, and myocardial complications. Created with BioRender.com.

In this narrative review article, we explored influenza-related cardiovascular disease pathophysiology. We aimed to provide an overview of the cardiovascular complications associated with influenza and the potential mechanisms behind this relationship. Table 1 lists the principal cardiovascular complications and pathophysiological mechanisms addressed in this review.

Table 1.

Summary table of the cardiovascular complications of influenza and the underlying pathophysiology

Epidemiology	Specific complication	Comment	Selected studies
Vascular complications	Myocardial infarction	Multiple larger studies have found significant associations between influenza and proxies of influenza infection and subsequent myocardial infarction and stroke. However, similar links have been observed with different infections.	Chow et al.6, Kwong et al.7, Warren-Gash et al.13, Smeeth et al.17,a
	Stroke		Kwong et al.7, Warren-Gash et al.13, Smeet et al.17,a, Boehme et al.18,a
Myocardial complications	Acute heart failure	Multiple larger studies have associated influenza with a temporarily elevated risk of acute heart failure. Acute heart failure may be the most common cardiovascular influenza-associated complication.	Chow et al.6, Kytöma et al.15,a, Araz et al.19,a
	Myocardial injury	In prospective and retrospective cohort studies, myocardial injury (elevated troponins) has been observed to be common among hospitalized influenza patients. Similar findings have been made in hospitalized COVID-19 patients	Biasco et al.9, Ludwig et al.20, Pizzini et al.21, Harris et al.22
	Myocarditis	Prevalence of clinically diagnosed influenza-associated myocarditis has varied significantly. Most studies are of small-scale and or case reports. The prevalence of myocarditis appears higher among fatal influenza cases.	Chow et al.6, Sellers et al.16, Kodama et al.23, Oseasohn et al.24, Paddock et al.25
Pathophysiology	Mechanisms	Comment	Selected studies
Directly vascular	Plaque destabilization	Influenza virus replication has been observed in arteries and has been shown to have direct inflammatory effects on atherosclerotic plaques leading to plaque accumulation and instability ultimately resulting in potential myocardial infarction, myocardial injury, and cardiac dysfunction. Influenza vaccination has been demonstrated to reduce pro-atherosclerotic cytokines and increase cytokines linked to plaque stability. Other infectious agents have similarly been linked to worsening of atherosclerosis.	Haidari et al.26,b, Suo et al.27, Van Lenten et al.28, Colden-Stanfield et al.29, Naghavi et al.30,b, Sun et al.31, Wu et al.32, Zhang et al.33, Bermúdez-Fajardo and Oviedo-Orta34,b
Directly myocardial	Myocardial inflammation/infection	Animal models have shown that influenza virus may enter myocardial tissue through up-regulation of ectopic trypsin and subsequently induce myocardial inflammation and viral replication leading to cardiac dysfunction.	Oseasohn et al.24, Paddock et al.25, Witzleb et al.35, Cioc et al. 57, Pan et al.58,b, Kenney et al. 60,b
		Additionally, with a mouse-model influenza-associated severe lung inflammation has been proven to be insufficient to damage cardiomyocytes indicating that direct cardiac infection plays a role in influenza-associated cardiac complications. The effects of direct cardiac infection in humans remain unclear.
Systemic responses	Hypoxaemia, hypercoagulability, myocardial oxygen demand, plaque destabilization, biomechanical stress, coronary vasoconstriction, and hypotension	Influenza affects the pulmonary system, which may by itself cause to hypoxaemia. Additionally, when infection occurs, multiple inflammatory pathways are activated (not exclusive to influenza) resulting in an array of systemic conditions. Many of these can alone and in combination lead to myocardial hypoxia, which can cause Types 1 and 2 myocardial infarction (and myocardial injury) and heart failure exacerbation. These conditions can be detrimental for patients with heart failure as they have reduced circulatory reserve and are often frail.	Visseren et al.36, Kreutz et al.37, Mesters et al.38, Ardlie et al.39, Katritsis et al.40, Li et al.41

General infection, respiratory infection, influenza-like illness, or influenza-activity in the community was used as a proxy for influenza infection.

Study utilizing an animal model.

Methods

PubMed, MEDLINE, and Embase were searched for literature using the terms ‘influenza’, ‘virus’, ‘myocardial infarction’, ‘coronary artery disease’, ‘ischemic heart disease’, ‘heart failure’, ‘decompensation’, ‘cardiomyopathy’, ‘cardiovascular events’, ‘myocardial injury’, ‘stroke’, ‘myocarditis’, ‘echocardiography’, ‘cardiac dysfunction’, ‘influenza vaccine’, ‘pathophysiology’, and ‘immune mechanisms’. Choice of literature was guided by the authors’ experience. Recent and widely cited literature was prioritized. Studies of prospective nature were favoured. Likewise, studies investigating laboratory-confirmed influenza were preferred over studies using respiratory infections and influenza vaccination as exposure.

Pathophysiological mechanisms

Multiple proposed mechanisms drive the increased risk of cardiovascular complications attributed to influenza infection. However, whether influenza infection acts directly through an influenza virus-specific mechanism, whether the complications are primarily caused by the systemic inflammatory response induced by infection, or whether these two mechanisms work in tandem to increase the risk of cardiovascular complications is currently debated. Nonetheless, the pathophysiology is presumably complex and nearly impossible to fully determine as influenza-specific reactions and systemic responses may be very difficult to disentangle. In general, the proposed mechanisms responsible for the observed associations between influenza infection and cardiovascular complications may be divided into two overall categories: (i) direct effects of the influenza virus including virus-related effects on the vasculature and myocardium and (ii) general effects of the systemic inflammatory response to infection. Figure 2 illustrates the following proposed pathophysiological mechanisms leading to influenza-associated cardiovascular complications.

Figure 2.

Cardiovascular pathophysiology of influenza. Infection with influenza virus increases risk of acute cardiovascular morbidity and mortality. Both direct and indirect pathophysiological mechanisms have been proposed to drive this relationship. These mechanics include direct cardiac infection and endothelial dysfunction, but also conditions activated by pro-inflammatory cytokines, adrenergic activity, and coagulation cascades. The weight of the individual effects is unclear and likely inseparable. Created with BioRender.com.

Direct vascular mechanics

When infection with influenza virus occurs, influenza enters the epithelial cells of the pulmonary alveoli and commences an array of immune signalling including induction of cytokines leading to both cellular and humoral immune responses.⁴² In addition to provoking systemic inflammatory response, influenza has been shown to have direct inflammatory effects on arteries and atherosclerotic plaques leading to plaque accumulation and instability ultimately resulting in potential MI, myocardial injury, and cardiac dysfunction.⁴³ The presence of influenza virus, its antigens, and influenza RNA has been demonstrated to be present in the arterial walls of mouse models (atherosclerotic and non-atherosclerotic mice) and human endothelial cells.^26–28 The endothelial surface is disturbed by adhesion molecules induced by influenza infection promoting leukocyte invasion, which has been observed as increased density of macrophages in the arterial wall.^29,44 Additionally, influenza virus has been shown to influence the smooth muscle cells within the arterial wall to relocate to the sub-endothelium and upregulate the expression of pro-inflammatory cytokines.^26,30 This local up-regulation of pro-inflammatory pathways and concomitant recruitment of macrophages is suggested to accelerate the accumulation of atherosclerotic plaques. This is hypothesized because macrophages phagocytize the oxidized low-density lipoprotein (LDL) within the arterial wall resulting in the creation of foam cells, which ultimately form the necrotic core of atherosclerotic plaques following apoptosis, which is promoted by ongoing inflammation.⁴⁵ Subsequently, the smooth muscle cells of the arterial wall are recruited to produce a fibrous cap, which engulfs the necrotic core of the atherosclerotic plaque. The influenza-associated accelerated accumulation of the necrotic core weakens the fibrous cap increasing instability of the atherosclerotic plaques leading to plaque rupture. This process is further worsened by the following: (i) Influenza infection aggravates endothelial cell apoptosis induced by oxidized LDL by promoting p53 signalling.²⁷ Endothelial apoptosis attenuates lipid homeostasis of the arterial wall facilitating lipid deposition, increasing inflammation, and cause plaque instability.^31,46 (ii) Influenza replication induces the expression of matrix metalloproteinases, which denature fibrin of the fibrous cap and further plaque instability.³² (iii) Influenza virus activates a cascade of cytokines including tumour necrosis factor alpha (TNFα) and interferon gamma (IFN-γ) influenza infection, which is associated with unstable plaques susceptible to rupture.^33,47 Interestingly, influenza vaccination appears to have the opposite effect by inducing cytokines associated with plaque stability and reducing the levels of cytokines linked to plaque instability. Bermúdez-Fajardo and Oviedo-Orta³⁴ demonstrated lower plasma levels of TNFα and IFN-γ and higher levels of interleukin-4 in a mouse model treated with influenza vaccination which are associated with plaque stability.⁴⁸

Other infectious agents of both bacterial and viral nature have been linked to worsening of atherosclerosis. These pathogens include Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae, herpes simplex virus, enterovirus, Helicobacter pylori, and cytomegalovirus.^49–54 Furthermore, the suggested mechanics of inflammation-driven MI caused by generic infection is very similar to the proposed mechanisms of influenza-associated MI.⁵⁵ Thus, the pathophysiological nature of influenza virus infection is likely not unique in causing MI. Finally, similar to influenza vaccination, S. pneumoniae vaccination has also been demonstrated to decrease the extent of atherosclerotic plaques.⁵⁶

Direct myocardial mechanics

Inflammation of myocardial tissue of influenza patients has been demonstrated, but only two of these studies could observe live influenza virus.^24,25,35,57 The number of studies on influenza-associated myocarditis in humans is limited; consequently, the pathology involved is poorly understood. Multiple studies utilizing animal models have attempted to remedy this. A possible entry mechanism of influenza virus has been suggested to be an up-regulation of ectopic trypsin in the heart.⁵⁸ Influenza entry into host cells is dependent on host-cell trypsin (proteases), as influenza virus has no processing proteases in its own genes.⁵⁹ Pan et al. analysed mice hearts after infection with influenza A virus in a study from 2010. The authors found ectopic trypsin (particularly trypsin₂) to be elevated following influenza infection, which was associated with a high degree of myocardial inflammation and viral replication. Meanwhile, in mice with trypsin inhibition viral replication was suppressed and less cellular damage was observed. Additionally, influenza-induced cardiac dysfunction was improved by trypsin inhibition assessed by echocardiography. Pan et al. consequently argued that influenza infection up-regulates trypsin in the myocardium allowing influenza to replicate and trigger myocarditis. Recently, another study by Kenney et al.⁶⁰ based on mice models (IFITM3 knockout mice, which are susceptible to influenza-induced cardiac pathology) investigated whether influenza lung infection or myocardial viral replication causes influenza-associated cardiac dysfunction. Lung inflammation and direct infection of the heart were decoupled using a recombinant influenza virus, which was attenuated for myocardial replication. In cases with the heart-attenuated influenza virus infection, the presence of severe lung inflammation was insufficient to cause cardiac dysfunction (observed as less cardiac muscle damage, fibrosis, and conduction irregularities) compared with cases with a regular influenza virus infection. Mortality was higher among mice infected with regular influenza infection. However, no difference was observed in systemic inflammatory response and weight loss between the two groups. These proposed mechanisms explain how influenza may infect cardiomyocytes and provoke local inflammation. Subsequent fibrosis and cardiomyocyte apoptosis could lead to myocardial injury, reduced cardiac function, and HF exacerbation in humans infected with influenza. Nevertheless, these proposed consequences of influenza-associated myocarditis or direct cardiac infection in humans come with strings attached. The effects of direct infection remain unclear and are likely intangible in vivo from the systemic effects of influenza. Direct cardiac influenza infection may frequently be asymptomatic because of the normal circulatory reserve of individuals with healthy hearts, thus negating the effects of the virus. As HF patients have reduced circulatory reserve the effects of cardiac infection may be the straw that breaks the camel’s back leading to more frequent HF hospitalizations and cardiovascular death during influenza epidemics. However, it must be stressed that the reason for HF hospitalization may more likely be because of systemic conditions of infection.

Systemic mechanics

Multiple systemic conditions caused by inflammatory responses support a causal relationship between influenza and cardiovascular complications, but they are not necessarily exclusive to influenza infection. The systemic reactions to infection caused by activation of an array of cytokines have been theorized to cause plaque destabilization similar to influenza.⁵⁵ Consequently, it may be very difficult to separate the specific effects of influenza virus on atherosclerotic plagues from the systemic effects. Beyond plaque deterioration, infections are known to create a thrombogenic environment by induction of procoagulant activity and platelet receptors resulting in reduced clotting time and increased platelet aggregation elevating risk of thromboembolic events.^36,37,61 The prothrombotic state appears proportional to disease severity as the risk of thromboembolic events is increased in conditions such as superinfection and sepsis.^38,62 Moreover, systemic infections are accompanied by an adrenergic state, which induces variations in vascular tone exerting biomechanical stress on existing coronary plaques increasing risk of Type 1 infarction.^39,40 During influenza infection the metabolic demand is elevated requiring higher cardiac output. In some cases, if cardiac output cannot be sufficiently increased, this may lead to hypotension. Combined with potential hypoxia, a discrepancy between oxygen supply and demand may arise and lead to Type 2 MI.⁶³ This is further exacerbated as acute infection can lead to coronary vasoconstriction reducing oxygen supply to the potentially already stressed myocardium.⁴¹ Many of the mechanics presented will also contribute to myocardial injury and exacerbation of HF in patients with influenza. Myocardial hypoxia due to hypoxaemia, thrombosis, vasoconstriction, and increased metabolic demand will naturally lead to myocyte destruction and concomitant release of cardiac biomarkers. These conditions can be detrimental for patients with HF as they have reduced circulatory reserve and are often frail.⁶⁴ Thus, in conditions with HF and concurrent influenza infection cardiac function may fail to meet the demand resulting in decompensation, worsening of HF symptoms, and the need for hospital care.

Conclusion

In conclusion, increasing evidence has established that the risk of cardiovascular events, particularly MI and HF, is elevated during infection with influenza. Additionally, myocardial injury is frequent in influenza patients requiring hospitalization, but whether this is caused by direct infection or systemic conditions is unclear. However, these conclusions come with strings attached. Other infections of both respiratory and non-respiratory nature are also linked to cardiovascular events and the pathophysiological effects of influenza are likely not unique. Therefore, we must not focus solely on influenza virus as a pathogen driving cardiovascular morbidity and mortality.

Funding

K.G.S. was financed by a research grant from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation and The Danish Heart Foundation (NNF20SA0067242). K.G.S. also received a research grant from the Hospital Research Council of the Copenhagen University Hospital—Herlev and Gentofte. This paper was published as part of a supplement financially supported by Sanofi. Manuscripts were accepted after rigorous peer review process that was managed by an expert Guest Editor independently appointed by the Editor-in-Chief. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of Sanofi.

Data availability

No new data were generated or analysed in support of this research.