View of statins as antimicrobials in cardiovascular risk modification

Kozarov E, Padro T, Badimon L
Cardiovasc Res. 2014 Jun 1;102(3):362-374
 Statins are the most prescribed medications for the prevention of cardiovascular disease (CVD), of which atherosclerosis (AS) is the most common cause. Primary or secondary prevention of CVD along with statin therapy has shown clinical benefits. Using statins in combination with percutaneous coronary intervention with stent implantation, gives synergistic effect and safety by reducing ischaemia and necrosis in patients with severe coronary disease. Statins have also been shown to reduce atherosclerotic plaque burden.

2. Infectious component of AS

2.1 Risk factors

Classical atherogenic risk factors can trigger endothelial activation manifested by the expression of endothelial cell adhesion molecules, causing adhesion of monocytes to the arterial tunica intima. These risk factors do, however, not fully explain the incidence of AS. AS has all characteristics of an inflammatory condition. Genetic analyses have shown that both inflammation and lipid metabolism are key biological pathways involved in the pathogenesis of coronary artery disease (CAD)

2.2 Infection component: evidence for the hypothesis that bacterial infections cause CVD

Epidemiological data support the view that infections contribute to AS, as well as insights from animal studies. Several rabbit, mice and larger animal models  have shown that periodontitis was associated with atherogenesis. Also in humans, the infectious burden in stroke-free individuals was shown to be associated with the risk of stroke and carotid plaque thickness. Human data is accumulating suggesting a link between oral infections and increased carotid intima media thickness (cIMT).

2.3 Indirect mechanisms by which infection may contribute to AS

Periodontal pathogens seem to increase the number of macrophages, T cells and lipids within the plaques. Expression of adhesion molecules is also induced by the main periodontal pathogen Porphyromanos gingivalis, thereby stimulating monocyte adhesion to endothelial cells (seen in cell culture). P. gingivalis also appears to increase platelet activation and aggregation.
Increased levels of inflammatory biomarkers such as C-reactive protein (CRP) were found to be predictive of acute events in healthy individuals. Clinical trials have demonstrated clinical benefits of statins in patients with high LDL-c and high CRP levels. Both LDL-reducing and anti-inflammatory (reflected by reduced CRP levels) effects appeared important in CVD-free individuals (JUPITER trial).

2.4 Direct infection of vascular cells

Invasive periodontal bacteria have been identified in atheromatous tissue from patients.

2.5 The quest for causality: clinical interventions

Several large-scale randomised prospective controlled clinical trials have now been conducted to test the hypothesis that infections are an underlying factor in atherogenesis. Unfortunately, results were disappointing in that short- and long-term antibiotic treatment did not prevent outcome events (for detailed summaries of the ACADEMIC, WIZARD, and SPACE trials, see original article). Nevertheless, these trials suffered from some methodologic weaknesses, thus leaving the door open for further testing of the hypothesis.

3. Are statins anti-bacterials?

3.1 Evidence that statin treatment affects bacterial infections

In addition to statins’ effects on CVD-related morbidity and mortality, cholesterol-independent pleiotropic effects have also been demonstrated, including improvement of endothelial function and plaque stability, decreased oxidative stress and inflammation, reduced inflammation and thrombogenic response, and innate immune modulation.

3.2 In vitro investigations

Statins have been shown to inhibit in vitro virulence of a number of bacterial strains, as well as fungi and the parasite Plasmodium falciparum. However, concentrations in these experiments were much higher than those detected in human blood during statin therapy. Findings of statins on pathogens are inconsistent, and require confirmation.

3.3 In vivo investigations

Murine models have shown both anti-chlamydial and immunomodulatory effects of simvastatin during infection. Bacterial infections appear to be suppressed by statins via lipid modifications, and upregulation of a pro-inflammatory chemokine and its receptor. Pre-treatment in mice with statins before infection had beneficial effects.

3.4 Application of statins in bacteraemia

Patients on statins with bacteraemic infections showed lower mortality than patients not taking statins. Pneumococcal pneumonia patients also had better clinical outcomes when they took statins at time of admission.

3.5 Application of statins in sepsis and other infections

Morbidity and survival was improved in patients receiving statins before a sepsis-inducing insult, as compared to patients who did not get statins. A rat model of sepsis also showed benefits of statins, but other studies did not find a significant association between statin administration before bloodstream infection and survival.

3.6 Statins in periodontitis

Hyperlipidaemic patients were found to be more prone to periodontitis, and statins can be beneficial for periodontal health. Other studies also suggested a benefit of statins in this chronic inflammatory condition. Importantly, changes in periodontal inflammation were found to correlate with changes in carotid inflammation.

4 . Possible mechanisms of antimicrobial activity

4.1 Interference with L-mevalonic acid synthesis

Direct antimicrobial activity has not been proven, thus statins seem to affect host cells. Statins have been shown to lower LDL levels by interfering with mevalonate synthesis. Reduction of mevalonate levels can, however, also influence pathogen-induced inflammation, via various pathways.

4.2 COX-2 modulation

Some of the myocardial protective effects of statins have been attributed to modulation of cyclooxygenase-2 (COX-2). Atorvastatin increases COX-2 stability, which could increase dendritic cell function after infectious bouts, and could compensate for some adverse effects of sustained inhibition of COX-2.

4.3 Reactive oxygen species suppression

Simvastatin has been shown to have a protective role in lung inflammatioin, possibly involving reduced formation of reactive oxygen species, oxidation of LDL and adhesion of neutrophils, while apoptosis, bacterial phagocytosis and bacterial clearance are unaffected. It appears that suppression of ROS formation is required for reduced neutrophil adhesion and recruitment.
It is the inflammatory response that destabilizes the atheroma, its suppression by statins reduces plaque vulnerability independently of LDL-c.

5. Discussion

The available evidence suggests that statins may be applicable to reduce both hyperlipidaemia and all-cause mortality. Available meta-analyses evaluating the association between use of statins and the outcome of infections support this.
The evidence, however, mainly comes from observational studies. Furthermore, bias cannot be excluded, in that statin-prescribed patients also have received concomitant adminstaration of anti-hypertension or other drugs.
Caution is needed, as in certain conditions statins used as anti-infectives may even adverse effects.
Results have been variable, thus the true antimicrobial effects of statins remain to be determined.

5.1 Clinical relevance of the mitigation of bacterial infections in addition to the lipid-lowering ant the anti-inflammatory effects of statins

Only a randomised clinical trial, fully controlled for lipid-lowering and anti-inflammatory effects of statins, designed to test the hypothesis that statins exert antimicrobial activity, could provide evidence that the proposed mitigation of bacterial infections has a clinical relevance. The CIRT and CANTOS trials are currently underway to examine the efficacy of anti-inflammatory activity for prevention of acute ischaemic events. The outcomes of these proof-of-concept trials will justify further carefully controlled trials testing the antimicrobial component of statin activity.

6. Conclusion

The mechanism of action of the most widely prescribed drug in atherosclerosis, statins, remains subject to investigation. The anti-inflammatory and possible antimicrobial activities seem attractive targets of intensive investigation, specifically in view of the relatively low cytotoxicity of statins. Proper diagnostic modalities need to be developed and large-scale prospective clinical trials need to be conducted before they can be (re)introduced as a new class of antimicrobials.

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