Influenza and the heart: a continuum of cardiovascular stress and cardiac injury

Influenza is primarily a respiratory infection, but its cardiovascular complications extend beyond rare fulminant myocarditis. The clinical spectrum includes acute myocardial infarction, biomarker-defined myocardial injury, worsening heart failure, arrhythmias, pericardial syndromes, and ventricular dysfunction (1,2). These manifestations may reflect systemic cardiovascular stress, myocardial involvement, or overlapping contributions from both. The central question is therefore how to interpret this heterogeneity without assigning the same mechanism to every cardiac abnormality.In this Opinion, we use a continuum framework to organize the evidence and identify specific questions for further study. The underlying pathways are well recognized; the framework is an organizing perspective rather than a newly established mechanism or clinical classification. We distinguish clinical associations from experimental mechanisms and preliminary hypotheses, with attention to the evidence required to connect them.The clinical signal is substantial. In adults hospitalized with laboratory-confirmed influenza, acute cardiovascular events were recorded in nearly one in eight patients, with acute heart failure and ischemic heart disease accounting for much of this burden (2). Kwong et al. reported an increased incidence of myocardial infarction during the first week after laboratory-confirmed influenza, while Warren-Gash et al. summarized earlier evidence linking influenza with infarction or cardiovascular death (3,4). The FluHeart study further documented ventricular dysfunction and associations between inflammation and selected echocardiographic abnormalities in hospitalized patients (5).These studies establish cardiovascular burden and temporal associations, but do not determine the frequency of direct myocardial infection. Pre-existing disease, acute respiratory stress, and differences in ascertainment complicate attribution.Echocardiographic abnormalities alone cannot establish that myocardial damage is new or caused by influenza.Here, continuum refers to variation in the relative contribution of systemic cardiovascular stress and local myocardial processes across cardiac manifestations. At one end, systemic inflammation, hypoxemia, and hemodynamic stress may predominate; in other settings, local infection or inflammation may make a greater contribution. These processes can coexist, and the term does not imply obligatory progression, a severity score, or discrete patient categories. Pulmonary infection can create an inflammatory, adrenergic, hypoxemic, and thrombotic milieu that destabilizes pre-existing cardiovascular disease. Myocarditis, ventricular dysfunction, and troponin elevation may arise through different combinations of these processes. Separating the observed cardiac phenotype from the proposed route of injury is therefore the central organizing principle. Systemic inflammation, endothelial activation, platelet reactivity, and coagulation provide plausible links to ischemic events, while fever, hypoxemia, and hemodynamic stress can disturb myocardial oxygen supply and demand (1,4). These processes need not involve myocardial infection. Importantly, myocardial injury should not be equated with infarction: an elevated troponin concentration alone does not establish myocardial ischemia or myocarditis. The framework therefore separates clinical manifestations from the mechanisms that might underlie them.Experimental studies help explain how myocardial involvement can occur, although their conclusions remain specific to the models studied. Filgueiras-Rama et al.reported myocardial and conduction-system infection in mice (6). Downey et al.identified a myeloid-cell-associated route to cardiac injury and a contribution of type I interferon signaling, with causal experiments in mice and complementary human observations (7). Cable and Yount discussed these findings in a commentary (8). Pan et al. linked myocardial trypsin up-regulation to viral replication and cardiac injury in mice (9). Together, these studies support routes of injury involving viral access to the heart and local host responses. They do not establish how frequently those routes account for cardiovascular complications in patients.Host-defense studies further indicate that cardiac susceptibility depends on the response to infection as well as viral presence. IFITM3 deficiency increased cardiac susceptibility in mice (10), and a separate experimental study supported a contribution of cardiomyocyte viral replication to cardiac dysfunction and fibrosis (11). Endothelial FBXL19 overexpression reduced cardiac viral burden, inflammation, and senescenceassociated markers in mice (12). These results support roles for antiviral defense and endothelial responses in the tested models. Read alongside the interferon-associated injury reported by Downey et al., they also caution against treating antiviral signaling as uniformly protective or harmful (7,12). Differences in cell type and timing may help explain the apparent contrast, but have not been resolved across these models. The clinical question is which local processes contribute to a defined cardiac phenotype alongside systemic illness.Metabolic vulnerability provides a further, preliminary hypothesis. In a bioRxiv preprint, Leumi et al. reported improvements in cardiac electrical abnormalities and fibrosis after treatment with an AMPK activator in a mouse model, together with changes in mitochondrial gene expression and survival (13). This report has not been peer reviewed, and its findings are considered preliminary. It supports further investigation of metabolic responses to infection, but does not establish AMPK activation as a treatment for patients. Whether metabolic abnormalities contribute independently to persistent dysfunction or accompany severe infection remains unresolved.One priority is to determine whether adults hospitalized with influenza have more persistent ventricular dysfunction than adults hospitalized with other respiratory infections. A prospective cohort could enroll consecutive adults with laboratoryconfirmed influenza and a contemporaneous non-influenza respiratory-infection comparator, document pre-infection cardiac status where available, and assess cardiac findings during admission and at 6-12 weeks. Serial high-sensitivity troponin, NT-proBNP, electrocardiography, and protocolized echocardiography could characterize myocardial injury, hemodynamic stress, rhythm, and ventricular function. Cardiac magnetic resonance could provide additional characterization in a prespecified substudy of clinically appropriate cases.A possible primary endpoint is total persistent left ventricular systolic dysfunction, defined by the same prespecified echocardiographic criterion during admission and at follow-up. This would measure burden, not the incidence of new disease. Pre-existing, new or worsened, and uncertain-onset dysfunction should be reported separately using prior cardiac records where available. The primary comparison could estimate the association with influenza after accounting for age, baseline cardiovascular disease, and baseline renal function. A separate analysis at comparable respiratory illness severity would address whether a difference remains conditional on the degree of respiratory illness. Because severity and treatment may mediate part of the association, they should not automatically be treated as baseline confounders. A near-null estimate would weaken the excess-risk hypothesis only if its confidence interval excluded a prespecified, clinically relevant excess; an imprecise estimate would remain inconclusive. Neither result would establish or exclude myocardial infection. Acute infarction, heart failure, arrhythmias, and suspected myocarditis should be adjudicated separately. Deaths and missing follow-up should be reported because they may bias estimates of persistent dysfunction.An exploratory biomarker substudy could examine whether circulating interferonrelated signals add prognostic information beyond illness severity and routine cardiac markers. Such signals would remain systemic correlates, not direct measurements of cardiac antiviral competence. Where cardiac tissue is already available for clinical or postmortem assessment, cell-resolved localization of viral material alongside inflammation and injury could strengthen anatomical attribution. Localization alone would not establish that infection caused the observed cardiac injury or dysfunction.Functional studies in cardiac models would then be needed to link an implicated host response to matched measures of cell injury, electrophysiology, or contractile function. Independent replication would be required before these observations could guide pathway-directed treatment.Several limitations constrain interpretation of the framework. Cardiac biomarkers and imaging findings are not mechanism-specific, and available clinical tissue samples are highly selected. Experimental findings depend on host background, cell type, and the model studied, and cannot establish the prevalence of myocardial infection in patients. Pre-existing disease, pulmonary severity, treatment, and sampling time may also explain differences between cardiac phenotypes. Comparisons restricted to hospitalized patients would not estimate risk across all influenza infections. The continuum therefore remains a conceptual framework, without a validated measure that assigns an individual patient to a particular mechanism.The practical contribution is to improve attribution and reporting of cardiovascular findings while keeping clinical management within established indications. Chest discomfort, syncope, arrhythmia, hemodynamic instability, or otherwise unexplained myocardial injury already warrant evaluation according to the clinical presentation. The framework does not justify additional routine screening for every patient with influenza.Rather, ischemic events, heart failure, rhythm disorders, and suspected myocarditis should be distinguished when reporting influenza-associated complications, with followup guided by objective abnormalities and existing clinical indications. This distinction avoids equating troponin elevation with myocarditis or inferring myocardial infection from a nonspecific cardiac finding.Vaccination remains an established prevention consideration. A meta-analysis of randomized trials associated influenza vaccination with fewer major cardiovascular events (14). These benefits support cardiovascular prevention messaging, but do not establish which pathway of cardiac injury is prevented. Further progress requires longitudinal characterization of cardiac phenotypes and validation of the mechanisms proposed to explain them. The value of the continuum framework lies in keeping those two tasks connected without treating every cardiovascular complication as evidence of myocardial infection.