Heart–Lung Interaction via Infection

Abstract

Lung and cardiovascular disease are increasingly recognized to occur in the same patient populations. Infections, either through stimulation of inflammation or through direct infection, can lead to end-organ damage and have been postulated as a potential link between lung and cardiovascular diseases. Mechanisms by which infections may link lung and cardiac diseases include effects of systemic infections, microbial translocation of pathogens from the gastrointestinal tract or other sites, damaging effects of metabolic products, or influences of smoking on the microbiome. Other mechanisms, such as alterations in the local microbiome, environmental exposures, or immune regulation by microbial communities, may be important. These relationships are likely quite complex, with multiple routes between infection and disease possible. A better understanding of the links of infection to lung and heart disease can improve our understanding of the pathogenesis of these disorders and uncover novel therapeutic approaches.

Lung and cardiovascular diseases are increasingly recognized as occurring in concert in many individuals. Whether these diseases develop as a result of unique mechanisms or shared pathways remains uncertain, but growing evidence indicates that they may share common origins. Although environmental exposures such as cigarette smoking may lead to lung and cardiovascular disease (CVD), the relationship between diseases in these two organ systems seems to have a component independent of smoking and likely results from other shared host or environmental causes. Infections, including systemic pathogens and the microbiota of various body niches, may contribute to the development of lung disease and CVD directly or through stimulation of inflammation. Understanding the mechanisms of infection in lung and CVD could identify novel treatment modalities for these diseases, such as antibiotics or probiotics. This review discusses the links of lung disease and CVD, reviews the potential roles of infections, and provides examples to support various pathogenic mechanisms.

Clinical Links of Lung and Cardiovascular Diseases

Chronic obstructive pulmonary disease (COPD) frequently coexists with cardiac diseases, including atherosclerosis and pulmonary hypertension. The coexistence of COPD and CVD is acknowledged as an important clinical syndrome that is likely stimulated by common inflammatory pathways and is associated with poor outcomes, including increased use of health resources and mortality (1–5). COPD is associated with adverse cardiovascular effects, including increases in endothelial dysfunction, arterial stiffness, and atherogenesis, which are independent of the effects of cigarette smoking (1, 6–8). FEV₁ is an important independent predictor of CVD even in nonsmokers, and smokers with COPD are more likely to have CVD than smokers without COPD (9). A metaanalysis of large studies or CVD found an increased risk of cardiovascular mortality in smokers and nonsmokers in the lowest quintile of FEV₁ (10). COPD is also an independent risk factor for increased carotid intima medial thickness (5, 6). Decreases in endothelial reactivity as measured by flow-mediated dilation have been correlated with decreases in FEV_1% predicted and FEV₁/FVC and increases in CT-documented emphysema independent of smoking history (8, 11). Pulmonary hypertension is increased in the COPD population as well (12, 13). Increases in systemic inflammatory markers, such as high-sensitivity C-reactive protein, IL-8, and IL-6, and increases in sputum neutrophils in COPD are associated with reduced lung function (14, 15). These findings suggest that chronic inflammation may be the common pathway to end-organ damage in these conditions directly by release of damaging cell products or via effects on vascular cell activation and apoptosis, increased thrombogenicity, or oxidative stress. Although this inflammation may result from multiple causes, infections are likely candidates to initiate or perpetuate such inflammation.

Hypothesized Mechanisms of Heart–Lung Interactions via Infection

There are a multitude of potential pathways that could link lung and heart disease via infections (Figure 1). For example, systemic infections could stimulate inflammation and immune activation, thus worsening lung and heart disease. Alternatively, localized lung infections could result in or worsen CVD via stimulation of local inflammation that “spills over” and becomes systemic. Microbial translocation of bacteria or other organisms from the gastrointestinal (GI) tract or other sites could travel to the lung or the vasculature and directly infect tissues. Translocated microorganisms could also stimulate local and systemic inflammation, resulting in tissue damage. Metabolic products of microbes or the resulting inflammation could alter the course of lung and CV diseases. Metabolomic effects could result from translocated bacteria or from systemic products of microbial communities in various body habitats. Alterations in lung and GI microbial communities resulting from environmental exposures, including cigarette smoking and pollution, could also influence disease. The composition of the GI microbiota shapes development of the immune system and could influence lung and CVD via this route. A detailed discussion of the literature supporting the various aspects of all possible routes from infection to lung and heart disease is beyond the scope of this review, but we highlight specific examples of possible links between lung and heart disease via infection (Table 1).

Figure 1.

Possible pathways linking lung and heart diseases via infection, including direct effects of lung infection, stimulation of systemic inflammation, translocation of gastrointestinal microbes, and effects of metabolomics pathways.

Table 1.

Potential mechanisms linking lung and heart disease via infection

Potential Mechanism	Examples of Related References
Direct effects of pathogens (local, systemic, or translocated)	16–23, 25, 26, 29, 32–34, 39, 40
Stimulation of systemic inflammation	7, 23, 25, 26, 29, 39
Alterations in microbiota of lung, gastrointestinal tract	32, 35, 36, 41, 42
Metabolic products of microbiota or inflammation	41–44
Alterations of microbiota from cigarette smoking	45–48

Effects of Systemic Infection

HIV as a Representative Infection

One potential way in which infection could link lung and heart disease is via systemic infection. Chronic systemic infections could promote disease via activation of systemic inflammation that leads to end-organ damage. An example of one such infection is HIV. Lung and cardiac diseases, including CVD and pulmonary hypertension, have been reported to be accelerated in individuals with HIV and seem to occur together (16–20). For example, in a cohort of HIV-infected outpatients, we found that pulmonary function is significantly associated with multiple aspects of cardiovascular disease, including coronary artery calcification and echocardiographic evidence of pulmonary hypertension (17; Morris, unpublished data). HIV-infected participants with elevated pulmonary artery pressures on echocardiography (defined as tricuspid regurgitant jet velocity [TRV] ≥ 3.0 m/s) had significantly worse airflow (17). This relationship with abnormal lung function was similar with pulmonary artery systolic pressure (PASP). Studies have shown that particular mutations in the nef allele of HIV are associated with pulmonary hypertension and that nef can be found in endothelial cells from HIV-infected patients with pulmonary hypertension and in a nonhuman primate model (21, 22), suggesting that the direct effects of HIV may contribute to pulmonary hypertension.

Relationship of Inflammation

It is possible that chronic immune activation and inflammation from the virus or its coinfections could cause lung and cardiac disease, but there are complex mechanisms involved, including effects of immunosuppression, coinfections, antimicrobial prophylaxis, and antiretroviral therapy (ART) for HIV. Lung and CVD in HIV appear related to local and systemic inflammation, although a direct role for HIV in stimulating this inflammation is not yet proven. The inflammation may be exaggerated by smoking, but does not depend on smoke exposure. In one study of HIV-infected individuals, lower Dl_CO was associated with greater sputum neutrophils in smokers and nonsmokers (23). We also examined the relationship of pulmonary artery pressure measurements to pulmonary and systemic inflammation in the cohort of HIV-infected individuals described above (17). Percent sputum neutrophils tended to increase with increasing TRV, and increasing sputum IL-8 was significantly associated with higher PASP and TRV. Plasma IL-8 was also significantly associated with increasing PASP and TRV. These studies suggest that HIV may be a systemic infection linked to lung and heart disease via inflammation.

The Role of Microbial Translocation

Microbial translocation (MT) is commonly defined as transmucosal passage of microorganisms and/or microbial products across a mucosal surface. Although most commonly studied in the GI tract, translocation could occur via other mucosal surfaces, such as the mouth, lung, or urogenital tract. Microbial translocation could lead to heart and lung disease by direct infection of these organs or via stimulation of inflammation.

Bacteria and the GI Tract

Translocation of bacteria is assessed by measurement of LPS (a component of the outer bacterial membrane that is strongly immunogenic) levels, detection of bacterial 16S ribosomal DNA (a ubiquitous gene in bacteria) in peripheral blood, or measurement of soluble CD14 (a receptor for LPS). Bacterial translocation from the GI tract to the peripheral circulation has been extensively studied in HIV infection, but is also common in liver disease and other conditions (24–27). Translocation occurs early in HIV infection due to depletion of gut CD4+ lymphocytes and is not completely eradicated by ART, particularly in patients with a suboptimal CD4 cell count or HIV viral level responses (25, 28). Persistent systemic exposure to bacterial antigens from MT triggers immune activation and inflammation in HIV-infected adults (25, 26). MT is associated with T-cell activation, which predicts systemic inflammation, mortality, HIV progression, and progression of comorbidities such as cardiovascular disease (25, 26, 29–31).

Although direct evidence of GI translocation in HIV resulting in lung infection is lacking, a recent study from the Lung HIV Microbiome Program found evidence of Trophyrema whipplei in bronchoalveolar lavage (BAL) from an HIV-infected ART-naive individual (32). T. whipplei was also found to be much more prevalent in BAL samples from HIV-infected individuals than from HIV-uninfected individuals in a mutlicenter cohort from this group (32). T. whipplei is the agent of Whipple’s disease, a predominantly GI condition that is rarely seen in the lung. Although stool studies were not performed in the larger cohort and the stool sample for the initial T. whipplei–infected individual did not contain T. whipplei DNA, it is possible that the organism previously had translocated from the GI tract. Future studies are needed to determine the origin of T. whipplei in HIV and its relationship to lung disease.

The potential for GI bacteria to infect the lung via translocation has been confirmed by animal models showing that inoculation of the gut with pathogenic bacteria can result in pulmonary infection with the same organisms. In a study of newborn rabbits, animals fed with traditional formula and gavaged with Enterobacter cloacae had E. cloacae in blood, lung, and other tissues by traditional culture (33). Animals also fed a probiotic had decreased detection of E. cloacae. These findings illustrate the ability of GI bacteria to translocate to the lung and suggest the potential for therapy of lung infections via modulation of GI microbiota.

Fungi as Possible Agents of Microbial Translocation

Although bacteria translocation is common in HIV, it is also possible that fungal translocation from mucosal surfaces of the GI, respiratory, and genitourinary tracts or from diseased skin could occur. HIV-infected individuals are at increased risk of oral and esophageal candidiasis and other fungal diseases, and Candida is a normal colonizer of mucosal surfaces. We have also found that the fungus Pneumocystis is a frequent respiratory colonizer in HIV-infected individuals, particularly in those with COPD (34–36). (1→3)-β-D-glucan (BG) is a component of fungal cell walls that is shed into the blood and can be detected in the serum of patients with fungal pneumonia (37, 38). We have recently found detectable BG levels in HIV-infected adult outpatients without pneumonia, and BG levels correlate strongly with airway obstruction, Dl_CO, echocardiographic pulmonary artery pressures, higher inflammatory cytokines, increased sputum neutrophils, and activated peripheral lymphocytes (39). These results indicate that fungal translocation is an unrecognized contributor to inflammation and chronic complications of HIV.

Viruses as Possible Agents of Microbial Translocation

Viral translocation may occur, but this process has not been extensively studied. One study examined intratracheal inoculation of Apo E–deficient mice with influenza (40). After 7 days, influenza was detected by real-time polymerase chain reaction, immunohistochemistry, and viral culture in aortic plaques. The virus was sporadically detected in the blood, but not in other organs. Animals inoculated with respiratory syncytial virus as a control did not show dissemination of virus. The virus was associated with up-regulation of inflammatory cytokines and up-regulation of inflammatory gene expression. These findings demonstrate that viruses generally thought to be confined to the lung can translocate to areas of cardiovascular pathology.

The Role of Metabolomics Products

Metabolites reflect small molecules that are generated by cellular metabolic activities and represent the host genome, transcriptome, and proteome. Metabolomics measures byproducts of microbes and microbial communities most commonly in the GI tract, but potentially in other body sites as well. The effects of metabolomics on lung and heart disease may also arise from metabolic products of inflammation stimulated by microbial communities. This area is just beginning to be explored for its relationship to infection and disease.

Links of the Metabolome to Cardiovascular Disease and GI Microbiota

Most work in this field has focused on the role of metabolic products of the GI microbiota on CVD. Red meat and egg consumption have been linked to CVD, and it has been hypothesized that commensal intestinal microbes could modify the interaction of diet with the host to alter this risk. A recent study examined the relationship of intake of phosphatidylcholine to trimethylamine-N-oxide (TMAO) in human volunteers fed hard-boiled eggs (a source of phosphatidylcholine) followed by blood and urine TMAO measurements (41). They were then treated with antibiotics, and blood and urine TMAO measurements were repeated. TMAO levels increased after egg consumption, but diminished after treatment with antibiotics, with a return to previous levels after antibiotic cessation. In a large cohort in the same study, TMAO levels were independent predictors of cardiovascular events (41). The relationship with metabolomic products, the microbiota, and infection is likely quite complex; a recent study in rats demonstrated that treatment with oral vancomycin increased infarct size after coronary artery ligation and that this effect could be diminished by probiotics (42). These studies support the concept that the GI microbiota can interact with host factors to influence non-GI diseases and suggest novel therapeutic approaches.

Links of the Metabolome to Lung Disease

Little is known about the relationship of the metabolome to lung disease. There could be effects of changes in the lung metabalome or systemic metabolic products that could influence disease, but few studies have examined this relationship. A study of Pseudomonas strains from patients with cystic fibrosis showed different metabolites, and other studies of patients with cystic fibrosis have shown a relationship of sputum metabolites to lung function (43, 44), but much remains to be learned about metabolomics in lung disease.

The Role of Smoking

Smoking may influence the development of lung disease and CVD through modulation of infection. Studies have found alterations in the oral microbiome in smokers compared with nonsmokers, with increases in some species and decreases in others (45, 46). A recent study from the Lung HIV Microbiome Program found that oral microbial composition differed significantly by smoking status, but BAL communities in smokers and nonsmokers were not significantly different (47). Smoking may also affect the GI microbiota. A study of smoking cessation reported that microbial populations found in stool samples clustered by smoking status and that samples taken after smoking cessation were distinguishable from those taken before smoking cessation and from current smokers (48).

Conclusions

Epidemiologic data support the coexistence of lung and cardiovascular diseases such as CVD and pulmonary hypertension. Infections are an attractive unifying cause or modifier of these diseases given the potential for direct or systemic effects of infectious organisms, their resulting inflammation, and/or metabolic compounds. These relationships are likely quite complex, with multiple routes between infection and disease possible. A better understanding of the links of infection to lung and heart disease will improve our understanding of the pathogenesis of these disorders and uncover novel therapeutic approaches.