Prior work has demonstrated that a significant proportion of mortality within 90 days of admission for pneumonia is attributable to other comorbid conditions,3
and that there are a number of cardiovascular events that occur during, or soon after, hospitalization for pneumonia.4–6, 9–12
A 1996 meta-analysis of CAP mortality rates found an overall mortality rate of 13.6% for hospitalized patients, and 36.5% for CAP patients admitted to the ICU.34
In their 2007 study, Musher, et al. reported a mortality rate of 21/170 (12.4%), with congestive heart failure or myocardial infarction either causing or contributing to the mortality in 9/21 (42.9%) of the deaths10
. Our study confirms that hospitalization for pneumonia is associated with a clinically significant number of cardiovascular events occurring either during the hospital admission for pneumonia or shortly thereafter, and demonstrates some factors associated with risk of cardiovascular disease.
While we did find substantial incidence of cardiovascular events in our cohort, the incidence of myocardial infarction was considerably lower than reported in previous studies. Musher, et al., reported an incidence of myocardial infarction of 7.1% at the time of hospital admission in 170 patients hospitalized with bacterial pneumonia caused by S. pneumoniae
Additionally, Ramirez et al. reported an incidence of myocardial infarction at the time of hospital admission of 5.8% in 500 patients hospitalized with community-acquired pneumonia.9
Corrales-Medina et al. reported an incidence of myocardial infarction of 10.7% in 206 patients hospitalized with bacterial pneumonia caused by either S. pneumoniae
or H. influenzae
. This incidence was measured during the first 15 days following hospital admission.12
All three of these incidence rates appear to include both repeat and new myocardial infarction events. When considering both repeat and new events, the incidence of myocardial infarction occurring during the reference hospitalization in our cohort was 1.4% (722/50,119). Potential explanations may include the differences in the patient populations, decreased testing (e.g., electrocardiograms and/or cardiac enzymes) in the VA, reliance by prior studies on mildly elevated levels of serum troponins as the primary way to diagnose an myocardial infarction, or that due to our age cutoff (≥ 65 years of age) congestive heart failure rather than myocardial infarction is more likely.
Musher et al. also reported on the incidence of post-pneumonia cardiovascular events other than myocardial infarction,10
describing an incidence of new onset or worsening congestive heart failure for 14% of their sample and an incidence of new onset arrhythmia (including atrial flutter, atrial fibrillation, and ventricular tachycardia with the exclusion of terminal arrhythmias) of 5.8%. These incidences were measured at the time of admission for pneumonia. During the reference hospitalization for our cohort, the incidence of new or repeat congestive heart failure was 19.2% and for cardiac arrhythmias 6.4%, which were similar to those reported by Musher, et al. However, our definition of arrhythmia was more inclusive including symptomatic bradycardias and cardiac arrest.
Both Musher and Ramirez cited a number of explanations for the significant incidence of post-pneumonia cardiovascular events observed in their studies. One possible explanation is that an acute increase in inflammatory cytokines leads to instability of previously established atherosclerotic plaques. A number of studies have shown acutely increased levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), and anti-inflammatory cytokine IL-10 at the time of admission for pneumonia.8, 16, 17
Other studies have demonstrated a relationship between elevated levels of inflammatory cytokines and cardiovascular disease,18, 19
which many believe may be due to increased plaque rupture. This hypothesis is supported by decreased pneumonia mortality associated with the administration of corticosteroids at the time of intensive care unit admission for severe pneumonia.20
In addition, patients with pre-existing cardiovascular disease such as prior myocardial infarction, ventricular fibrillation, and unstable angina show enhanced coagulation activation and an up regulation of CD40L on platelets.21
The resulting pro-coagulant state may contribute to the formation of thrombosis in the coronary arteries during an episode of acute infection. Finally, both Musher and Ramirez suggest that mismatches between oxygen supply and demand may also cause increased cardiovascular events for patients with pneumonia.9, 10
Another potential mechanism for pneumonia-related cardiovascular events should also be considered. The common organisms involved in community-acquired pneumonia are well known, and a recent study characterizing the etiology of community-acquired pneumonia confirmed that the major causative organisms as Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Staphylococcus aureus
, and a number of viral pathogens including influenza A and B.22
Several of these pathogens have demonstrated the ability to directly infect cardiomyocytes, and cause conduction and contractility dysfunction.23–31
For example, the most common cause of community-acquired pneumonia, Streptococcus pneumoniae
, has recently been implicated in causing decreased cardiac contractility through immune-mediated uptake of bacterial cell wall antigen into cardiomyocytes.32
This study showed that the uptake of pneumococcal cell wall was mediated by platelet activating factor receptor (PAFr), and that once inside cardiomyocytes, a loss in contractility occurred in vitro as well as in isolated rat hearts. These findings may provide further explanation to an earlier study that found high prevalence of pneumococcal infection in intensive care unit patients with elevated Troponin I levels.33
Factors associated with increased risk of cardiovascular events (congestive heart failure and arrhythmias) are straightforward (e.g., intensive care unit admission and prior cardiovascular disease) and clinicians should take these factors into consideration when caring for patients with pneumonia. We hypothesize that the factors associated with decreased risk of cardiovascular events, such as hemiplegia, are due to clinicians not looking as hard in these patients for cardiovascular disease rather than actually being protective.
There were a number of limitations in our analysis. The VA patient population is less than 2% female, which makes the study results poorly generalizable to women. Another limitation was reliance on ICD-9 diagnosis of cardiovascular events rather than clinical information, which particularly may impact the diagnosis of congestive heart failure. Not infrequently there is clinical confusion about whether patients have congestive heart failure, pneumonia, or both. We are unable to determine the extent to which these conditions may have been improperly differentiated. However due to our definition of pneumonia we are confident that the treating physicians believed that pneumonia was present, and that by excluding those with pre-existing history of congestive heart failure, we were able to identify subjects that were very likely to have had a new diagnosis of congestive heart failure. Another limitation is that we did not examine the rates of CV events for other illnesses such as urinary tract infection and chronic obstructive pulmonary disease, which may have acted as confounding variables in our analysis.
In conclusion, a clinically important number of subjects have at least one cardiovascular event within 90 days following hospitalization for pneumonia. Congestive heart failure and cardiac arrhythmia, even for those with no history of these events, are the most common events, and the majority of these events occur during the initial hospitalization. Further research is needed to better determine cardiovascular risk among patients hospitalized with pneumonia, shed light on the mechanisms responsible for these cardiovascular events, and determine potential therapies to minimize the morbidity and mortality associated with cardiovascular events following serious infections such as pneumonia.