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inflammation, increased c-IMT and impaired FMD and PD. The results suggested a beneficial effect of
[147]
periodontal treatment on FMD leading to improvement in endothelial function .

EXPLORING CUTTING-EDGE TECHNOLOGIES TO DISCOVER NEW THERAPEUTIC TARGETS

AND APPROACHES FOR DRUG DEVELOPMENT. ATHEROSCLEROSIS MICROBIOME
Presenting major fiscal burden, CVD is the costliest disease in the US at $555 billion (American Heart
2017, http://bit.ly/2LfsC5A) and €210 billion in the European Union (2017, http://bit.ly/2UDXS2F). This
underscores the need for novel diagnostic and therapeutic developments since cost-effective and rapid
approaches are lacking.

A major incentive for novel approaches is that many CVD events have not been explained by classical
risk factors. To address a modifiable risk factor, such as microbial pathogens, Robert Koch’s postulate
must be satisfied, namely the pathogen must be isolated from the diseased tissue. Thus, C. pneumoniae
[148]
was isolated from a carotid endarterectomy specimen . However, it took time before a polybacterial
infectious component from atherosclerotic plaques was identified, and these clinical isolates cultivated.
This achievement demonstrated the existence of atherosclerosis microbiome, a sample of the microbial
community localized within human atheromatous tissues [67,74,75,149] . Such advancement enabled an entirely
new approach to CVD diagnosis and treatment, fulfilling Koch’s postulate.

A natural approach to restore the homeostasis, reversing the atherogenic process, is via control of
the inflammatory component, often originating from periodontal lesions. The latest network analysis
confirmed inflammation and lipid metabolism as the two key biological pathways involved in the
[150]
predisposition to CVD . Of note, there is still no approach successfully addressing the actual source of
the inflammation. Taking the potential opportunities presented by the identification of prokaryotes in
vascular inflammations, randomized placebo-controlled clinical trials using antibiotics in the context of
CVD have been designed [151,152] . However, the results were disappointing, since the administered treatment
may not have reached its target (i.e., intracellular location sheltering bacteria from antibiotics as well as
[153]
[156]
from immune response). The latest anti-inflammation trials (CIRT , CANTOS [154,155] , TETHYS , SOLID-
[157]
TIMI 52 ) did not target the plausible origin of inflammation, intracellular bacteria. The PEGASUS-TIMI
54 trial, although also targeting ischemic events, was strictly thrombosis-related.
As mentioned before, both ethical considerations and the slow progress of atherosclerosis preclude
conducting a clinical trial to establish causality. Importantly, the WIZARD trial design predicted that
a positive effect of drugs would tighten the association between atherosclerosis and bacteria without
proving causality [158] . As stated by Peter Libby, renowned vascular disease physician, “A therapeutic
trial of antibiotics still would not establish a causal relationship between any particular infectious agent
and atherosclerosis. Yet, if antibiotic treatment could reduce atherosclerosis events, the public health
[159]
implications could be enormous; hence the need to keep an open mind” .
In addition, animal studies suggest that atherosclerosis is induced or aggravated by invasive infectious
agents (i.e., persistent IC infection) [45,84,160-163] .

It is becoming clear that atherosclerosis represents chronic vascular inflammation partly of microbial
etiology. Intracellular invasive pathogens induce a low-grade persistent inflammation that exacerbate the
atherogenesis. Therefore, to address intracellular infections as etiologic factors for CVD, entirely novel
anti-infectives and vaccines are required [164] . Alleviating this key pathological feature (i.e., IC bacteria
internalized in vascular tissue) could significantly improve the clinical outcome.