Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study
Identifieur interne : 002F70 ( Pmc/Corpus ); précédent : 002F69; suivant : 002F71Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study
Auteurs : Janaina Salomon Ghizoni ; Luís Antônio De Assis Taveira ; Gustavo Pompermaier Garlet ; Marcos Flávio Ghizoni ; Jefferson Ricardo Pereira ; Thiago José Dionísio ; Daniel Thomas Brozoski ; Carlos Ferreira Santos ; Adriana Campos Passanezi Sant'AnaSource :
- Journal of Applied Oral Science [ 1678-7757 ] ; 2012.
Abstract
This study investigated the role of periodontal disease in the development of stroke or cerebral infarction in patients by evaluating the clinical periodontal conditions and the subgingival levels of periodontopathogens.
Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular
episodes (test group) and 60 systemically healthy patients (control group) were
evaluated for: probing depth, clinical attachment level, bleeding on probing and
plaque index.
The test group showed a significant increase in each of the following parameters:
pocket depth, clinical attachment loss, bleeding on probing, plaque index and
number of missing teeth when compared to control values (p<0.05, unpaired
t-test). Likewise, the test group had increased numbers of sites that were
contaminated with
Stroke patients had deeper pockets, more severe attachment loss, increased
bleeding on probing, increased plaque indexes, and in their pockets harbored
increased levels of
Url:
DOI: 10.1590/S1678-77572012000100019
PubMed: 22437687
PubMed Central: 3928781
Links to Exploration step
PMC:3928781Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Increased levels of <italic>Porphyromonas gingivalis</italic> are
associated with ischemic and hemorrhagic cerebrovascular disease in humans: an
<italic>in vivo</italic> study</title><author><name sortKey="Ghizoni, Janaina Salomon" sort="Ghizoni, Janaina Salomon" uniqKey="Ghizoni J" first="Janaina Salomon" last="Ghizoni">Janaina Salomon Ghizoni</name><affiliation><nlm:aff id="aff01"> DDS, MSc, PhD student, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Taveira, Luis Antonio De Assis" sort="Taveira, Luis Antonio De Assis" uniqKey="Taveira L" first="Luís Antônio De Assis" last="Taveira">Luís Antônio De Assis Taveira</name><affiliation><nlm:aff id="aff02"> DDS, MSc, PhD, Associate Professor, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Garlet, Gustavo Pompermaier" sort="Garlet, Gustavo Pompermaier" uniqKey="Garlet G" first="Gustavo Pompermaier" last="Garlet">Gustavo Pompermaier Garlet</name><affiliation><nlm:aff id="aff03"> DDS, MSc, PhD, Associate Professor, Discipline of Histology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Ghizoni, Marcos Flavio" sort="Ghizoni, Marcos Flavio" uniqKey="Ghizoni M" first="Marcos Flávio" last="Ghizoni">Marcos Flávio Ghizoni</name><affiliation><nlm:aff id="aff04"> MD, MSc, PhD, Associate Professor, Discipline of Neurosurgery, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Pereira, Jefferson Ricardo" sort="Pereira, Jefferson Ricardo" uniqKey="Pereira J" first="Jefferson Ricardo" last="Pereira">Jefferson Ricardo Pereira</name><affiliation><nlm:aff id="aff05"> DDS, MSc, PhD, Associate Professor, Discipline of Prosthodontics, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Dionisio, Thiago Jose" sort="Dionisio, Thiago Jose" uniqKey="Dionisio T" first="Thiago José" last="Dionísio">Thiago José Dionísio</name><affiliation><nlm:aff id="aff06"> Laboratory Specialist, MSc, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Brozoski, Daniel Thomas" sort="Brozoski, Daniel Thomas" uniqKey="Brozoski D" first="Daniel Thomas" last="Brozoski">Daniel Thomas Brozoski</name><affiliation><nlm:aff id="aff07"> Postdoctoral Fellow, PhD, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Santos, Carlos Ferreira" sort="Santos, Carlos Ferreira" uniqKey="Santos C" first="Carlos Ferreira" last="Santos">Carlos Ferreira Santos</name><affiliation><nlm:aff id="aff08"> DDS, MSc, PhD, Professor, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Sant Ana, Adriana Campos Passanezi" sort="Sant Ana, Adriana Campos Passanezi" uniqKey="Sant Ana A" first="Adriana Campos Passanezi" last="Sant'Ana">Adriana Campos Passanezi Sant'Ana</name><affiliation><nlm:aff id="aff09"> DDS, MSc, PhD, Associate Professor, Discipline of Periodontology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22437687</idno><idno type="pmc">3928781</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928781</idno><idno type="RBID">PMC:3928781</idno><idno type="doi">10.1590/S1678-77572012000100019</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002F70</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002F70</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Increased levels of <italic>Porphyromonas gingivalis</italic> are
associated with ischemic and hemorrhagic cerebrovascular disease in humans: an
<italic>in vivo</italic> study</title><author><name sortKey="Ghizoni, Janaina Salomon" sort="Ghizoni, Janaina Salomon" uniqKey="Ghizoni J" first="Janaina Salomon" last="Ghizoni">Janaina Salomon Ghizoni</name><affiliation><nlm:aff id="aff01"> DDS, MSc, PhD student, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Taveira, Luis Antonio De Assis" sort="Taveira, Luis Antonio De Assis" uniqKey="Taveira L" first="Luís Antônio De Assis" last="Taveira">Luís Antônio De Assis Taveira</name><affiliation><nlm:aff id="aff02"> DDS, MSc, PhD, Associate Professor, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Garlet, Gustavo Pompermaier" sort="Garlet, Gustavo Pompermaier" uniqKey="Garlet G" first="Gustavo Pompermaier" last="Garlet">Gustavo Pompermaier Garlet</name><affiliation><nlm:aff id="aff03"> DDS, MSc, PhD, Associate Professor, Discipline of Histology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Ghizoni, Marcos Flavio" sort="Ghizoni, Marcos Flavio" uniqKey="Ghizoni M" first="Marcos Flávio" last="Ghizoni">Marcos Flávio Ghizoni</name><affiliation><nlm:aff id="aff04"> MD, MSc, PhD, Associate Professor, Discipline of Neurosurgery, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Pereira, Jefferson Ricardo" sort="Pereira, Jefferson Ricardo" uniqKey="Pereira J" first="Jefferson Ricardo" last="Pereira">Jefferson Ricardo Pereira</name><affiliation><nlm:aff id="aff05"> DDS, MSc, PhD, Associate Professor, Discipline of Prosthodontics, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Dionisio, Thiago Jose" sort="Dionisio, Thiago Jose" uniqKey="Dionisio T" first="Thiago José" last="Dionísio">Thiago José Dionísio</name><affiliation><nlm:aff id="aff06"> Laboratory Specialist, MSc, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Brozoski, Daniel Thomas" sort="Brozoski, Daniel Thomas" uniqKey="Brozoski D" first="Daniel Thomas" last="Brozoski">Daniel Thomas Brozoski</name><affiliation><nlm:aff id="aff07"> Postdoctoral Fellow, PhD, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Santos, Carlos Ferreira" sort="Santos, Carlos Ferreira" uniqKey="Santos C" first="Carlos Ferreira" last="Santos">Carlos Ferreira Santos</name><affiliation><nlm:aff id="aff08"> DDS, MSc, PhD, Professor, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author><author><name sortKey="Sant Ana, Adriana Campos Passanezi" sort="Sant Ana, Adriana Campos Passanezi" uniqKey="Sant Ana A" first="Adriana Campos Passanezi" last="Sant'Ana">Adriana Campos Passanezi Sant'Ana</name><affiliation><nlm:aff id="aff09"> DDS, MSc, PhD, Associate Professor, Discipline of Periodontology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Applied Oral Science</title><idno type="ISSN">1678-7757</idno><idno type="eISSN">1678-7765</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>This study investigated the role of periodontal disease in the development of
stroke or cerebral infarction in patients by evaluating the clinical periodontal
conditions and the subgingival levels of periodontopathogens.</p></sec><sec><title>Material and Methods:</title><p>Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular
episodes (test group) and 60 systemically healthy patients (control group) were
evaluated for: probing depth, clinical attachment level, bleeding on probing and
plaque index. <italic>Porphyromonas gingivalis</italic> and
<italic>Aggregatibacter actinomycetemcomitans</italic> were both identified and
quantified in subgingival plaque samples by conventional and real-time PCR,
respectively.</p></sec><sec><title>Results:</title><p>The test group showed a significant increase in each of the following parameters:
pocket depth, clinical attachment loss, bleeding on probing, plaque index and
number of missing teeth when compared to control values (p<0.05, unpaired
t-test). Likewise, the test group had increased numbers of sites that were
contaminated with <italic>P. gingivalis</italic> (60%x10%; p<0.001; chi-squared
test) and displayed greater prevalence of periodontal disease, with an odds ratio
of 48.06 (95% CI: 5.96-387.72; p<0.001). Notably, a positive correlation
between probing depth and the levels of <italic>P. gingivalis</italic> in ischemic
stroke was found (r=0.60; p=0.03; Spearman's rank correlation coefficient test).
<italic>A. actinomycetemcomitans</italic> DNA was not detected in any of the
groups by conventional or real-time PCR.</p></sec><sec><title>Conclusions:</title><p>Stroke patients had deeper pockets, more severe attachment loss, increased
bleeding on probing, increased plaque indexes, and in their pockets harbored
increased levels of <italic>P. gingivalis</italic>. These findings suggest that
periodontal disease is a risk factor for the development of cerebral hemorrhage or
infarction. Early treatment of periodontitis may counteract the development of
cerebrovascular episodes.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ainamo, J" uniqKey="Ainamo J">J Ainamo</name></author><author><name sortKey="Bay, I" uniqKey="Bay I">I Bay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Albandar, Jm" uniqKey="Albandar J">JM Albandar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Armitage, Gc" uniqKey="Armitage G">GC Armitage</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ashimoto, A" uniqKey="Ashimoto A">A Ashimoto</name></author><author><name sortKey="Chen, C" uniqKey="Chen C">C Chen</name></author><author><name sortKey="Bakker, I" uniqKey="Bakker I">I Bakker</name></author><author><name sortKey="Slots, J" uniqKey="Slots J">J Slots</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beck, Jd" uniqKey="Beck J">JD 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Appl Oral Sci</journal-id><journal-id journal-id-type="iso-abbrev">J Appl Oral Sci</journal-id><journal-id journal-id-type="publisher-id">J. Appl. Oral. Sci.</journal-id><journal-title-group><journal-title>Journal of Applied Oral Science</journal-title></journal-title-group><issn pub-type="ppub">1678-7757</issn><issn pub-type="epub">1678-7765</issn><publisher><publisher-name>Faculdade de Odontologia de Bauru da Universidade de São
Paulo</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22437687</article-id><article-id pub-id-type="pmc">3928781</article-id><article-id pub-id-type="doi">10.1590/S1678-77572012000100019</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Increased levels of <italic>Porphyromonas gingivalis</italic> are
associated with ischemic and hemorrhagic cerebrovascular disease in humans: an
<italic>in vivo</italic> study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>GHIZONI</surname><given-names>Janaina Salomon</given-names></name><xref ref-type="aff" rid="aff01">1</xref></contrib><contrib contrib-type="author"><name><surname>TAVEIRA</surname><given-names>Luís Antônio de Assis</given-names></name><xref ref-type="aff" rid="aff02">2</xref></contrib><contrib contrib-type="author"><name><surname>GARLET</surname><given-names>Gustavo Pompermaier</given-names></name><xref ref-type="aff" rid="aff03">3</xref></contrib><contrib contrib-type="author"><name><surname>GHIZONI</surname><given-names>Marcos Flávio</given-names></name><xref ref-type="aff" rid="aff04">4</xref></contrib><contrib contrib-type="author"><name><surname>PEREIRA</surname><given-names>Jefferson Ricardo</given-names></name><xref ref-type="aff" rid="aff05">5</xref></contrib><contrib contrib-type="author"><name><surname>DIONÍSIO</surname><given-names>Thiago José</given-names></name><xref ref-type="aff" rid="aff06">6</xref></contrib><contrib contrib-type="author"><name><surname>BROZOSKI</surname><given-names>Daniel Thomas</given-names></name><xref ref-type="aff" rid="aff07">7</xref></contrib><contrib contrib-type="author"><name><surname>SANTOS</surname><given-names>Carlos Ferreira</given-names></name><xref ref-type="aff" rid="aff08">8</xref><xref ref-type="corresp" rid="c01"></xref></contrib><contrib contrib-type="author"><name><surname>SANT'ANA</surname><given-names>Adriana Campos Passanezi</given-names></name><xref ref-type="aff" rid="aff09">9</xref></contrib></contrib-group><aff id="aff01"><label>1</label> DDS, MSc, PhD student, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff02"><label>2</label> DDS, MSc, PhD, Associate Professor, Discipline of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff03"><label>3</label> DDS, MSc, PhD, Associate Professor, Discipline of Histology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff04"><label>4</label> MD, MSc, PhD, Associate Professor, Discipline of Neurosurgery, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</aff><aff id="aff05"><label>5</label> DDS, MSc, PhD, Associate Professor, Discipline of Prosthodontics, University of Southern of Santa Catarina - UNISUL, Tubarão, SC, Brazil.</aff><aff id="aff06"><label>6</label> Laboratory Specialist, MSc, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff07"><label>7</label> Postdoctoral Fellow, PhD, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff08"><label>8</label> DDS, MSc, PhD, Professor, Discipline of Pharmacology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><aff id="aff09"><label>9</label> DDS, MSc, PhD, Associate Professor, Discipline of Periodontology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil.</aff><author-notes><corresp id="c01"><bold>Corresponding address:</bold> Prof. Dr. Carlos F. Santos - Faculdade de
Odontologia de Bauru - USP - Departamento de Ciências Biológicas - Disciplina de
Farmacologia - Alameda Dr. Octávio Pinheiro Brisolla, 9-75 - Bauru - São Paulo -
17012-901 - Brazil - Phone: +55 14 32358282 - Fax: +55 14 32234679 - e-mail:
<email>cebola@usp.br</email></corresp></author-notes><pub-date pub-type="ppub"><season>Jan-Feb</season><year>2012</year></pub-date><volume>20</volume><issue>1</issue><fpage>104</fpage><lpage>112</lpage><history><date date-type="received"><day>27</day><month>10</month><year>2011</year></date><date date-type="rev-recd"><day>26</day><month>11</month><year>2011</year></date><date date-type="accepted"><day>27</day><month>11</month><year>2011</year></date></history><permissions><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This is an Open Access article distributed under the terms of the Creative
Commons Attribution Non-Commercial License which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited. </license-p></license></permissions><abstract><sec><title>Objective:</title><p>This study investigated the role of periodontal disease in the development of
stroke or cerebral infarction in patients by evaluating the clinical periodontal
conditions and the subgingival levels of periodontopathogens.</p></sec><sec><title>Material and Methods:</title><p>Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular
episodes (test group) and 60 systemically healthy patients (control group) were
evaluated for: probing depth, clinical attachment level, bleeding on probing and
plaque index. <italic>Porphyromonas gingivalis</italic> and
<italic>Aggregatibacter actinomycetemcomitans</italic> were both identified and
quantified in subgingival plaque samples by conventional and real-time PCR,
respectively.</p></sec><sec><title>Results:</title><p>The test group showed a significant increase in each of the following parameters:
pocket depth, clinical attachment loss, bleeding on probing, plaque index and
number of missing teeth when compared to control values (p<0.05, unpaired
t-test). Likewise, the test group had increased numbers of sites that were
contaminated with <italic>P. gingivalis</italic> (60%x10%; p<0.001; chi-squared
test) and displayed greater prevalence of periodontal disease, with an odds ratio
of 48.06 (95% CI: 5.96-387.72; p<0.001). Notably, a positive correlation
between probing depth and the levels of <italic>P. gingivalis</italic> in ischemic
stroke was found (r=0.60; p=0.03; Spearman's rank correlation coefficient test).
<italic>A. actinomycetemcomitans</italic> DNA was not detected in any of the
groups by conventional or real-time PCR.</p></sec><sec><title>Conclusions:</title><p>Stroke patients had deeper pockets, more severe attachment loss, increased
bleeding on probing, increased plaque indexes, and in their pockets harbored
increased levels of <italic>P. gingivalis</italic>. These findings suggest that
periodontal disease is a risk factor for the development of cerebral hemorrhage or
infarction. Early treatment of periodontitis may counteract the development of
cerebrovascular episodes.</p></sec></abstract><kwd-group><kwd>Periodontal diseases</kwd><kwd>Stroke</kwd><kwd>Infection</kwd><kwd>Pathogenesis</kwd><kwd>Atherogenesis</kwd></kwd-group><funding-group><award-group><funding-source>The State of São Paulo Research Foundation</funding-source><award-id>2006/02376-4</award-id></award-group><award-group><funding-source>Coordination of Support for Higher Education</funding-source></award-group></funding-group></article-meta></front><body><sec><title>INTRODUCTION</title><p>Recent findings suggest that atherogenesis and plaque rupture, two critical elements of
cardiovascular pathogenesis leading to chronic disease burden and clinical events,
result from systemic and vascular inflammatory processes<sup><xref rid="r42" ref-type="bibr">42</xref></sup>. In general, infections and low-grade inflammatory
processes influence the development of atherosclerosis and ischemic lesions. Moreover,
an association between atherogenesis and <italic>Porphyromonas gingivalis</italic> and
<italic>Aggregatibacter actinomycetemcomitans</italic>, both anaerobic Gram-negative
bacteria, has been demonstrated<sup><xref rid="r08" ref-type="bibr">8</xref>,<xref rid="r14" ref-type="bibr">14</xref>-<xref rid="r16" ref-type="bibr">16</xref>,<xref rid="r26" ref-type="bibr">26</xref></sup>.</p><p>Periodontal disease, an asymptomatic chronic infectious and inflammatory condition,
harbors large numbers of anaerobic Gram-negative pathogens, including <italic>P.
gingivalis</italic> and <italic>A. actinomycetemcomitans</italic>. In particular,
when bacteria live in periodontal pockets lined with a thin and ulcerated epithelium as
opposed to living on healthy gingival tissue with a robust epithelium, they can more
effectively invade connective tissue, endothelial cells and the bloodstream.
Additionally, these bacteria can induce thrombus formation by platelet aggregation
degrading collagen<sup><xref rid="r28" ref-type="bibr">28</xref></sup>.</p><p>The main prerequisite for atherogenesis induction by periodontal disease may be the
chronic systemic exposure to periodontopathic bacteria<sup><xref rid="r45" ref-type="bibr">45</xref></sup> through bacteremia or endotoxemia, which stimulates the
migration of inflammatory cells within major blood vessels walls, preceding the
formation of atherosclerotic plaques in cerebral vessels<sup><xref rid="r35" ref-type="bibr">35</xref></sup>. Another mechanism for atherogenesis is the induction of
immunological processes, leading to increased levels of C-reactive protein (CRP), and
increases in CRP even within the range of normal values is considered a reliable
predictor of cardiovascular disease (CVD)<sup><xref rid="r12" ref-type="bibr">12</xref>,<xref rid="r46" ref-type="bibr">46</xref></sup>. In brief, periodontal
disease is associated with CVDs in case-controls and prospective studies, and,
additionally, more severe attachment loss, deepened pockets and increased numbers of
missing teeth in patients was positively correlated with CVD<sup><xref rid="r23" ref-type="bibr">23</xref>,<xref rid="r31" ref-type="bibr">31</xref>,<xref rid="r38" ref-type="bibr">38</xref>,<xref rid="r53" ref-type="bibr">53</xref>,<xref rid="r56" ref-type="bibr">56</xref></sup>. Some studies found the
presence of <italic>P. gingivalis</italic> and <italic>A. actinomycetemcomitans</italic>in carotid atherosclerotic plaques, but the role of periodontopathogens in atheroma
formation remains unclear. Recent CVD association studies, which use measurements that
capture clinical findings of periodontal disease and inflammatory measurements as
exposures, generally exhibit stronger association than just clinical parameters of
disease show<sup><xref rid="r05" ref-type="bibr">5</xref>,<xref rid="r40" ref-type="bibr">40</xref>,<xref rid="r42" ref-type="bibr">42</xref></sup>.</p><p>With these findings in mind, the aim of this study was to investigate the role of
periodontal disease in the development of stroke or cerebral infarction in patients by
evaluating the clinical periodontal conditions and the subgingival levels of
periodontopathic bacteria.</p></sec><sec sec-type="materials|methods"><title>MATERIAL AND METHODS</title><sec><title>Sample selection</title><p>This study was approved by the Ethics Committee of Nossa Senhora da Conceição
Hospital (Tubarão, SC, Brazil). Eighty patients, 30 to 80 years of age, were invited
to participate in this study. Totally edentulous and/or pregnant patients and those
patients whose formal consents were unobtainable were ineligible. The test group was
composed of 20 randomly selected patients (12 men, 8 women) from the Neurosurgery
Division of the Intensive Care Unit between January 2006 and December 2006. More
specifically, the first 20 random patients that looked for hospitalization without
any previous history of a cerebrovascular accident (CVA) were included in the test
group. To be included in the test group, patients had to be diagnosed with ischemic
or hemorrhagic stroke for up to 4 days after hospitalization. The control group in
this study was comprised of the first 60 random patients (30 men, 30 women) from the
city of Bauru, São Paulo, Brazil seeking dental treatment at the Operative Dentistry
Clinics of the Bauru School of Dentistry, University of São Paulo, during the same
time period as the test group. Age and gender-matched patients without previous or
current history of stroke were included in the control group.</p><p>Patients included in the test group were randomly procured at the city of Tubarão
(SC), while those included in the control group were randomly selected among the
population of Bauru (SP). Considering the demographic features of the different
populations, a proportion of 1 case to 3 controls was established, being in agreement
with other studies that investigated the influence of periodontal disease in other
systemic conditions<sup><xref rid="r13" ref-type="bibr">13</xref>,<xref rid="r30" ref-type="bibr">30</xref>,<xref rid="r43" ref-type="bibr">43</xref></sup>.</p><p>Before data collection, patients answered a health questionnaire investigating
possible risk factors for stroke, including: genetic predisposition, smoking,
systemic alterations, arterial hypertension, and cardiovascular problems. Smoking was
not evaluated in packs <italic>per</italic> years, but only evaluated whether the
patient smoked. All patients were tested the same way.</p></sec><sec><title>Clinical examination</title><p>A single periodontist evaluated all patients by examining pocket probing depth (PPD)
as measured by a manual periodontal probe (Hu-Friedy, USA), clinical attachment level
(CAL), bleeding on/during probing (BOP)<sup><xref rid="r01" ref-type="bibr">1</xref></sup> and a dichotomous plaque index (PLI). For statistical purposes,
the presence of BOP and dental plaque was recorded as 1 and their absence was
recorded as 2. Additionally, although a whole mouth examination was performed, data
were only recorded from the tooth showing the deepest pocket in each sextant. More
specifically, the deepest site was evaluated after probing 3 buccal and 3 palatal
sites of all the teeth in the volunteers. Data collection was confined to only one
tooth in each sextant since most patients were lying on a bed unconscious making data
collection arduous.</p></sec><sec><title>Subgingival plaque sample</title><p>Subgingival plaque samples were collected from the deepest site of each patient by
introducing absorbent paper strips (PerioPaper, OraFlow Inc., NY, USA) for one minute
into the gingival sulcus to the base of the pocket<sup><xref rid="r36" ref-type="bibr">36</xref></sup>. After removal, the material was stored in a sterile
centrifuge tube containing 500 µL of sterile distilled water and kept in a -20ºC
freezer until DNA extraction.</p></sec><sec><title>PCR analysis</title><p>For DNA extraction, samples were diluted 1:2 with sterile distilled water and
collected by centrifugation at 10,000× <italic>g</italic> for 5 min in a centrifuge
at 4ºC. The supernatant was discarded and the resulting pellet was washed two times
with 1 mL of sterile distilled water, reconstituted with 100 µL of sterile distilled
water and 100 µL of InstaGene Matrix (Bio-Rad Laboratories, Inc., Hercules, CA, USA),
and incubated at 56ºC for 30 min. Samples were then vortexed and boiled for 10 min.
After centrifugation to remove unbroken cells and large debris (10,000×
<italic>g</italic> for 3 min), the supernatant was collected for PCR
analysis<sup><xref rid="r47" ref-type="bibr">47</xref></sup>.</p><p>For conventional PCR, a total of 50 µL of PCR mixture was analyzed. This mixture
contained 10 µL of DNA sample, 5 µL of 10X PCR buffer, 1.25 units of
<italic>Taq</italic> DNA polymerase (Promega, Madison, WI, USA), 0.2 mM each of
deoxyribonucleotides, 1.0 µM of each primer, and 1.5 mM of MgCl<sub>2 </sub>for
<italic>P. gingivalis</italic> or 1.0 mM of MgCl<sub>2</sub> for <italic>A.
actinomycetemcomitans</italic><sup><xref rid="r47" ref-type="bibr">47</xref></sup>. DNA samples of <italic>P.
gingivalis</italic> and <italic>A. actinomycetemcomitans</italic> were used as
positive controls for amplifying reactions. These positive control samples were
obtained from clinical isolations. For each set of primers, PCR was performed on
sterile distilled water to check for DNA contamination (negative controls). Primer
sequences (<xref ref-type="table" rid="f01">Figure 1</xref>) and temperature profiles
were used as previously described<sup><xref rid="r04" ref-type="bibr">4</xref>,<xref rid="r55" ref-type="bibr">55</xref></sup>. PCR amplification products (9 µL)
were analyzed using 2% agarose gel electrophoresis stained with 0.5 µg/mL ethidium
bromide and photographed under ultraviolet light. A 100 bp DNA ladder served as the
molecular weight marker.</p><table-wrap id="f01" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Primer sequences used in PCR tests and respective anneding temperature and the
predicted amplicon size</p></caption><table frame="box" rules="all"><tbody><tr align="center" style="background-color:#CCCCCC"><td valign="top" rowspan="1" colspan="1"><bold>Target </bold></td><td valign="top" rowspan="1" colspan="1"><bold>Sense</bold></td><td valign="top" rowspan="1" colspan="1"><bold>Antisense</bold></td><td valign="top" rowspan="1" colspan="1"><bold>TA (<sup>o</sup>C)</bold></td><td valign="top" rowspan="1" colspan="1"><bold>bp</bold></td></tr><tr align="center"><td valign="top" rowspan="1" colspan="1"><italic>A. actinomycetemcomitans</italic></td><td valign="top" rowspan="1" colspan="1">ATGCCAACTTGACGTTAAAT</td><td valign="top" rowspan="1" colspan="1">AAACCCATCTCTGAGTTCTTCTTC</td><td valign="top" rowspan="1" colspan="1">60</td><td valign="top" rowspan="1" colspan="1">557</td></tr><tr align="center" style="background-color:#CCCCCC"><td valign="top" rowspan="1" colspan="1"><italic>P. gingivalis</italic></td><td valign="top" rowspan="1" colspan="1">AGGCAGCTTGCCATACTGCG</td><td valign="top" rowspan="1" colspan="1">ACTGTTAGCAACTACCGATGT</td><td valign="top" rowspan="1" colspan="1">59</td><td valign="top" rowspan="1" colspan="1">127</td></tr></tbody></table><table-wrap-foot><fn><p>TA - annealing temperature; bp - base pairs</p></fn></table-wrap-foot></table-wrap><p>Real-time PCR was performed as previously described<sup><xref rid="r20" ref-type="bibr">20</xref></sup> with a MiniOpticon system (Bio-Rad, Hercules, CA,
USA), using SybrGreen MasterMix (Invitrogen Life Technologies, Carlsbad, CA , USA),
specific primers, and 50 ng of DNA in each reaction. The positivity of bacteria
detection in each sample was determined by comparison with positive and negative
controls. The results were analyzed according to the cycle threshold (C<sub>t</sub>)
values. The number of bacteria in each sample and the C<sub>t</sub> values were
compared with a standardized curve composed from bacterial DNA ranging from
10<sup>-3</sup> to 10<sup>9</sup> bacteria.</p></sec><sec><title>Statistical analysis</title><p>Periodontal conditions of test and control groups were compared using an unpaired
<italic>t</italic> -test. The prevalence of <italic>P. gingivalis</italic> and
<italic>A. actinomycetemcomitans</italic> detected by conventional PCR was
evaluated by a chi-squared test, with a 95% confidence level. The quantity of
<italic>P. gingivalis</italic> and <italic>A. actinomycetemcomitans</italic> DNA
quantified by real-time PCR were not normally distributed and were found to be
consistent with a log normal distribution in the case of <italic>P.
gingivalis</italic>, and thus comparisons were made using the Kolmogorov-Smirnov
test. The risk of the occurrence of stroke influenced by periodontal disease was
expressed as an odds ratio (OR), with a 95% confidence level. The correlation of
periodontal parameters and the bacterial DNA levels were analyzed using a Spearman's
rank correlation coefficient test.</p></sec></sec><sec sec-type="results"><title>RESULTS</title><p>In the test group of 20 patients, 7 (35%) patients developed hemorrhagic cerebrovascular
episodes (H-CVE) and 13 (65%) patients developed ischemic cerebrovascular episodes
(I-CVE). Data were obtained from 720 sites in the test group recovering from stroke and
2,158 sites in the control group (<xref ref-type="table" rid="t01">Table 1</xref>depicts the periodontal conditions of the test and control groups). The prevalence of
<italic>P. gingivalis</italic> and <italic>A. actinomycetemcomitans</italic> in the
subgingival microbiota of test and control groups evaluated by conventional PCR
demonstrated that, respectively, 60% and 10% showed the presence of <italic>P.
gingivalis</italic> (chi-squared test, p<0.001, <xref ref-type="fig" rid="f02">Figure 2</xref>). <italic>A. actinomycetemcomitans</italic> DNA was not detected in
any of the groups by conventional or real-time PCR.</p><table-wrap id="t01" orientation="portrait" position="float"><label>Table 1</label><caption><p>Clinical periodontal conditions of test and control group patients (t-test)</p></caption><table frame="hsides" rules="groups"><thead><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1"><bold>Parameter</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>Test Group</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>Control Group</bold></td></tr></thead><tbody><tr><td align="center" valign="top" rowspan="1" colspan="1">Age (years)</td><td align="center" valign="top" rowspan="1" colspan="1">59±13</td><td align="center" valign="top" rowspan="1" colspan="1">48±10</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">PPD (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">2.6±2.4</td><td align="center" valign="top" rowspan="1" colspan="1">2.4±1.5</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">CAL (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">5.1±4.4<xref ref-type="table-fn" rid="t01-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">3.2±2.6</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">BOP (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">1.1±0.2<xref ref-type="table-fn" rid="t01-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">1.7±0.8</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">PLI</td><td align="center" valign="top" rowspan="1" colspan="1">1.0±0.0<xref ref-type="table-fn" rid="t01-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">1.8±0.4</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">Teeth missing</td><td align="center" valign="top" rowspan="1" colspan="1">2.4±1.6<xref ref-type="table-fn" rid="t01-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">1.0±1.2</td></tr></tbody></table><table-wrap-foot><fn><p>PPD - pocket probing depth (mm); CAL - clinical attachment level (mm); BOP -
bleeding on probing (scores: 1 - presence; 2 - absence); PLI – dichotomous
plaque index (scores: 1- presence; 2 - absence). Test and control values are
reported as means±one SEM.</p></fn><fn id="t01-fn01"><label>*</label><p>Significantly different from control, p<0.001</p></fn></table-wrap-foot></table-wrap><fig id="f02" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Detection of <italic>P. gingivalis,</italic> DNA using 2% agarose gel
electrophoresis. The gel shows staining for <italic>P. gingivalis</italic> DNA
amplified by conventional PCR from test group subjects. Lane 1 – contains
the 100 bp molecular weight marker; lanes 2 to 10, 12 to 18, 20 to 21: positive
staining for <italic>P. gingivalis</italic> DNA; columns 11 and 19 - negative
samples for <italic>P. gingivalis</italic></p></caption><graphic xlink:href="jaos-20-01-0104-g01"></graphic></fig><p>The levels of <italic>P. gingivalis</italic> detected by real-time PCR are illustrated
in <xref ref-type="fig" rid="f03">Figure 3</xref>. Kolmogorov-Smirnov test showed a
greater prevalence of <italic>P. gingivalis</italic> in the test group compared to the
control group (p<0.001).</p><fig id="f03" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Quantification of <italic>P. gingivalis </italic>DNA detected in subgingival
plaque samples from test and control group subjects using real-time PCR. These
data were not normally distributed and were found to be consistent with a log
normal distribution, and thus comparisons were made using the Kolmogorov-Smirnov
test and depicted on a log scale using median with the error bars representing a
distribution between the 2.5th percentile and the 97.5th percentile. *D=1.0000
with a corresponding p<0.001 compared to control</p></caption><graphic xlink:href="jaos-20-01-0104-g02"></graphic></fig><p>In this study, periodontal disease was specifically defined by the presence of at least
one site showing a PPD≥4 mm, which resulted in 19 (95%) diseased patients in the test
group and 17 (28.3%) patients in the control group, resulting in an unadjusted odds
ratio of 48.06 (95% confidence interval:5.96 to 387.72, p<0.001).</p><p>The test group included 7 smoking patients (35%), 5 of which developed I-CVE and 2 of
which developed H-CVE (data not shown), while the control group included 17 smoking
patients (28.3%) (<xref ref-type="table" rid="f04">Figure 4</xref>). An analysis showed
that smoking did not have a significant influence on attachment loss in the test group
(chi-squared test, p<0.05), although a significant influence was observed in the
control group with respect to smoking (data not shown).</p><table-wrap id="f04" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Health questionnaire results</p></caption><table frame="box" rules="all"><tbody><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1"><bold>Patient</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>Age</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>Stroke</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>Parameters</bold></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">A</td><td align="center" valign="top" rowspan="1" colspan="1">63</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">B</td><td align="center" valign="top" rowspan="1" colspan="1">52</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">C</td><td align="center" valign="top" rowspan="1" colspan="1">36</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">D</td><td align="center" valign="top" rowspan="1" colspan="1">56</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">E</td><td align="center" valign="top" rowspan="1" colspan="1">55</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">F</td><td align="center" valign="top" rowspan="1" colspan="1">72</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">G</td><td align="center" valign="top" rowspan="1" colspan="1">48</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">H</td><td align="center" valign="top" rowspan="1" colspan="1">61</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">I</td><td align="center" valign="top" rowspan="1" colspan="1">69</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">J</td><td align="center" valign="top" rowspan="1" colspan="1">71</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">K</td><td align="center" valign="top" rowspan="1" colspan="1">59</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">L</td><td align="center" valign="top" rowspan="1" colspan="1">35</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">M</td><td align="center" valign="top" rowspan="1" colspan="1">56</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">N</td><td align="center" valign="top" rowspan="1" colspan="1">78</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">O</td><td align="center" valign="top" rowspan="1" colspan="1">80</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">P</td><td align="center" valign="top" rowspan="1" colspan="1">57</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">Q</td><td align="center" valign="top" rowspan="1" colspan="1">41</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">R</td><td align="center" valign="top" rowspan="1" colspan="1">78</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD, H, S</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">S</td><td align="center" valign="top" rowspan="1" colspan="1">60</td><td align="center" valign="top" rowspan="1" colspan="1">H-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">PD</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">T</td><td align="center" valign="top" rowspan="1" colspan="1">48</td><td align="center" valign="top" rowspan="1" colspan="1">I-CVE</td><td align="center" valign="top" rowspan="1" colspan="1">H</td></tr></tbody></table><table-wrap-foot><fn><p>I-CVE - ischemic cardiovascular episode; H-CVE - hemorrhagic cardiovascular
episode; PD – periodontal disease; H – hypertension; S – smoker</p></fn></table-wrap-foot></table-wrap><p>By separating ischemic (I-CVE, n=13) and hemorrhagic (H-CVE, n=7) patients, increased
PPD and CAL were observed in the I-CVE group, while increased levels of <italic>P.
gingivalis</italic> were detected in the H-CVE group (p<0.05). No significant
differences were observed between subgroups in BOP and number of missing teeth
(p>0.05, <xref ref-type="table" rid="t02">Table 2</xref>). A positive correlation
between PPD and the prevalence of <italic>P. gingivalis</italic> (r=0.60, p=0.03) was
observed in the I-CVE group (<xref ref-type="fig" rid="f05">Figure 5A</xref>); however
this finding was not observed in the H-CVE group (p=0.09, <xref ref-type="fig" rid="f05">Figure 5B</xref>).</p><table-wrap id="t02" orientation="portrait" position="float"><label>Table 2</label><caption><p>Periodontal status and levels of <italic>P. gingivalis</italic> detected by
real-time PCR in ischemic (I-CVE) and hemorrhagic (H-CVE) cardiovascular
episode</p></caption><table frame="hsides" rules="groups"><thead><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1"><bold>Parameter</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>I-CVE</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>H-CVE</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>p-value</bold></td></tr></thead><tbody><tr><td align="center" valign="top" rowspan="1" colspan="1">PPD (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">2.7±2.4<xref ref-type="table-fn" rid="t02-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">2.3±2.4</td><td align="center" valign="top" rowspan="1" colspan="1">0.009</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">CAL (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">5.4±4.4<xref ref-type="table-fn" rid="t02-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">4.4±4.4</td><td align="center" valign="top" rowspan="1" colspan="1">0.005</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">BOP (mm)</td><td align="center" valign="top" rowspan="1" colspan="1">1.1±0.3</td><td align="center" valign="top" rowspan="1" colspan="1">1.0±0.0</td><td align="center" valign="top" rowspan="1" colspan="1">0.47</td></tr><tr style="background-color:#CCCCCC"><td align="center" valign="top" rowspan="1" colspan="1">Teeth missing</td><td align="center" valign="top" rowspan="1" colspan="1">2.8±1.6</td><td align="center" valign="top" rowspan="1" colspan="1">2.3±2.4</td><td align="center" valign="top" rowspan="1" colspan="1">0.12</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"><italic>P. gingivalis</italic></td><td align="center" valign="top" rowspan="1" colspan="1">1.2x10<sup>6</sup>±2.2x10<sup>6</sup><xref ref-type="table-fn" rid="t02-fn01">*</xref></td><td align="center" valign="top" rowspan="1" colspan="1">1.1x10<sup>7</sup>±1.6x10<sup>6</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.036</td></tr></tbody></table><table-wrap-foot><fn><p>PPD - pocket probing depth (mm); CAL - clinical attachment level (mm); BOP -
bleeding on probing (scores: 1 - presence; 2 - absence); PLI- plaque index
(scores: 1 - presence; 2 -absence); <italic>P. gingivalis</italic> - level of
<italic>P. gingivalis</italic>. Test and control values are reported as
means±one SEM.</p></fn><fn id="t02-fn01"><label>*</label><p>Significantly different from control, p<0.05</p></fn></table-wrap-foot></table-wrap><fig id="f05" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Correlation between the quantity of <italic>P. gingivalis</italic> DNA detected in
subgingival plaque samples and pocket probing depth (PPD) from either A) ischemic
cerebrovascular episodes (I-CVA), r=0.60, p=0.03; or B) hemorrhagic
cerebrovascular episodes (H-CVA), r=0.24, p=0.09.</p></caption><graphic xlink:href="jaos-20-01-0104-g03"></graphic></fig></sec><sec sec-type="discussion"><title>DISCUSSION</title><p>This study tested the hypothesis that periodontal disease is a risk factor for the
development of stroke, since patients with this condition show significant increases in
CAL, BOP, PLI and <italic>P. gingivalis</italic> density compared to systemically
healthy patients.</p><p>Some studies<sup><xref rid="r23" ref-type="bibr">23</xref>,<xref rid="r28" ref-type="bibr">28</xref>,<xref rid="r31" ref-type="bibr">31</xref>,<xref rid="r38" ref-type="bibr">38</xref>,<xref rid="r45" ref-type="bibr">45</xref>,<xref rid="r53" ref-type="bibr">53</xref>,<xref rid="r56" ref-type="bibr">56 </xref></sup>identified periodontal disease as a risk factor for the
development of other medical conditions. The association between periodontal disease,
tooth loss, and stroke was evaluated in epidemiological and prospective
studies<sup><xref rid="r18" ref-type="bibr">18</xref>,<xref rid="r23" ref-type="bibr">23</xref>,<xref rid="r31" ref-type="bibr">31</xref>,<xref rid="r38" ref-type="bibr">38</xref>,<xref rid="r52" ref-type="bibr">52</xref>,<xref rid="r53" ref-type="bibr">53</xref>,<xref rid="r56" ref-type="bibr">56</xref></sup>, suggesting an association between both, corroborating
the findings of this study.</p><p>Periodontal disease remains a prevalent condition among many different
populations<sup><xref rid="r02" ref-type="bibr">2</xref>,<xref rid="r29" ref-type="bibr">29</xref></sup>. Generally, more severe cases seem to be concentrated in
20% of the population<sup><xref rid="r02" ref-type="bibr">2</xref></sup>, while
individuals at older age groups seem to present nearly 8% of severe periodontal
disease<sup><xref rid="r29" ref-type="bibr">29</xref></sup>. For the present
study, it was observed that 17 out of 60 patients in the control group and 19 out of 20
patients in the test group presented at least one periodontal pocket ≥4 mm, resulting in
a non-adjusted odds ratio of 48.06 (confidence interval: 5.96 to 387.72, p<0.001). In
brief, the cause-effect relationship between both conditions needs further
investigation, but the findings of this study indicated that patients with stroke showed
more prevalent and severe periodontal lesions than systemically healthy patients.</p><p>Stroke has been associated with an incidence of fever resulting from respiratory tract
infections<sup><xref rid="r35" ref-type="bibr">35</xref>,<xref rid="r38" ref-type="bibr">38</xref></sup>. Also, stroke may play a role in odontogenic
alterations<sup><xref rid="r26" ref-type="bibr">26</xref></sup>, and can be
regarded as a predisposing factor for cerebral conditions linked to bacterial
endocarditis<sup><xref rid="r45" ref-type="bibr">45</xref></sup>. In the present
study, 13 out of 20 patients in the test group developed ischemic stroke and 7 out of 20
patients developed a hemorrhagic cerebrovascular event. Furthermore, bacterial counts
were significantly increased in hemorrhagic versus ischemic stroke, suggesting to that
bacteria can lead not only atheromatous plaque formation<sup><xref rid="r08" ref-type="bibr">8</xref>,<xref rid="r14" ref-type="bibr">14</xref>-<xref rid="r16" ref-type="bibr">16</xref>,<xref rid="r26" ref-type="bibr">26</xref>,<xref rid="r28" ref-type="bibr">28</xref>,<xref rid="r32" ref-type="bibr">32</xref>,<xref rid="r41" ref-type="bibr">41</xref>,<xref rid="r45" ref-type="bibr">45</xref></sup>, but also the invasion of endothelial cells and injury
to blood vessels<sup><xref rid="r23" ref-type="bibr">23</xref>,<xref rid="r35" ref-type="bibr">35</xref>,<xref rid="r38" ref-type="bibr">38</xref></sup>. Some studies
suggested that the traditional role of lipid imbalance in the risk of cardiovascular
diseases represents only one of the pathogenic pathways for CVD. In particular, a second
pathway may be represented by inflammation<sup><xref rid="r25" ref-type="bibr">25</xref></sup>. This inflammation can induce CVD by impairing endothelial function,
promoting plaque formation and favoring plaque rupture by compromising the structural
integrity of atheromatous plaques through the induction of vascular instability, leading
to increased susceptibility for ischemic and hemorrhagic events<sup><xref rid="r25" ref-type="bibr">25</xref></sup>.</p><p>Dental sites with deep pockets harbor a large number of bacteria<sup><xref rid="r49" ref-type="bibr">49</xref></sup>, with a positive correlation between
pocket probing depth and bacterial levels during ischemic stroke in the present study.
Additionally, a greater incidence of ischemic stroke was previously observed in young
patients with periodontal disease, particularly in those with decreased numbers of
remaining teeth, however occurrence of this condition is unusual for younger age
groups<sup><xref rid="r52" ref-type="bibr">52</xref>,<xref rid="r53" ref-type="bibr">53</xref></sup>.</p><p>Some studies have suggested an incidence of stroke in 10% of patients younger than 55
years<sup><xref rid="r39" ref-type="bibr">39</xref></sup> and 3.9% in patients
younger than 45 years<sup><xref rid="r33" ref-type="bibr">33</xref></sup>. The
definition of the age limit for consideration of stroke in young adults is not
established, with some young patients (less than 45 years old) showing and incidence of
stroke from unknown causes. Zétola, et al. in 2001 found that out of 141 young patients
with stroke, 32% had undetermined etiology<sup><xref rid="r58" ref-type="bibr">58</xref></sup>. For these reasons, the minimum and maximum age for inclusion of
patients in the test and control groups was, respectively, 30 and 80 years. However, the
average age of patients in the test group (59±13 years) showed a trend to be older than
the control group (48±10 years), and this trend might suggest that the majority of
patients older than 30 years were developing stroke. In this study, only 2 patients
younger than 40 years of age had stroke.</p><p>Periodontal disease, in general, is quite prevalent in the world population. Estimates
indicate that 20% of the world population have severe cases of periodontal
disease<sup><xref rid="r02" ref-type="bibr">2</xref></sup>. In a sample of 600
individuals aged 20 to 70 years, Hugoson and Jordan<sup><xref rid="r29" ref-type="bibr">29</xref></sup> (1982), found an incidence of about 11% of marginal periodontal
infectious disease in healthy individuals between 30 and 40 years of age<sup><xref rid="r29" ref-type="bibr">29</xref></sup>. This suggests that in the age group of
40 years old there will be approximately 89% of healthy individuals who have gingivitis
or mild periodontal disease, with no signs of bone loss. Only 8% of individuals between
40 and 70 years of age had severe periodontal disease<sup><xref rid="r29" ref-type="bibr">29</xref></sup>.</p><p>Although the number of patients included in the control group was relatively large
compared to the number of patients in the test group yet in proportion, the increased
number of patients in the control group provided more accurate information concerning
periodontal conditions in the otherwise healthy patients. However, increasing the number
of patients included in the plaque sample, especially for the test group, could have
also potentially provided more accurate information for the periodontal conditions for
ischemic or hemorrhagic stroke. Overall, the results obtained in this study were
significantly different between test and control groups (p<0.001), suggesting that
periodontal disease is more prevalent and more severe in stroke than in systemically
healthy patients, which is corroborated by other studies.</p><p>Periodontal examinations were performed by a single experienced periodontist, but a
Kappa test was not performed to determine accuracy of this single examiner. Considering
that periodontal examination of test group patients was performed bedside, time
permitted only the tooth showing the deepest pocket at each sextant to be recorded,
although a whole mouth examination was performed. Other risk factors for stroke were
considered, in particular smoking. The results obtained in this study showed no
differences between smoking and non-smoking patients.</p><p>Progression of periodontal disease is characterized by acute bursts<sup><xref rid="r22" ref-type="bibr">22</xref>,<xref rid="r50" ref-type="bibr">50</xref></sup>, with the conversion of lymphocytes to neutrophils<sup><xref rid="r21" ref-type="bibr">21</xref>,<xref rid="r27" ref-type="bibr">27</xref></sup>. The etiology of periodontal disease is multifactorial, but
primarily related to host response interactions and specific bacterial species,
including <italic>P. gingivalis</italic> and <italic>A. actinomycetemcomitans</italic>(the two bacteria which were investigated in this study)<sup><xref rid="r44" ref-type="bibr">44</xref></sup>. These bacteria have been extensively investigated due
to their pathological properties, which include their capacity for: invading connective
tissue, epithelial and endothelial cells; activating the complement cascade and immune
system; and stimulating the synthesis of cytokines and other inflammatory
mediators<sup><xref rid="r14" ref-type="bibr">14</xref>,<xref rid="r34" ref-type="bibr">34</xref>,<xref rid="r49" ref-type="bibr">49</xref></sup>. Recently,
these species were identified in atheromatous plaques of CVD patients<sup><xref rid="r08" ref-type="bibr">8</xref>,<xref rid="r14" ref-type="bibr">14</xref>,<xref rid="r16" ref-type="bibr">16</xref>,<xref rid="r26" ref-type="bibr">26</xref>,<xref rid="r32" ref-type="bibr">32</xref>,<xref rid="r57" ref-type="bibr">57</xref></sup>, suggesting a possible role for <italic>P.
gingivalis</italic> and <italic>A. actinomycetemcomitans</italic> in the development
of this lesion.</p><p>Both bacteria have their niche in the subgingival region, but they can also be found in
lesser amounts in supragingival plaque samples<sup><xref rid="r24" ref-type="bibr">24</xref>,<xref rid="r49" ref-type="bibr">49</xref></sup>. However, their
prevalence is not observed in all subgingival sites in the oral cavity, since healthy or
inactive sites harbor extremely low populations of these bacteria<sup><xref rid="r24" ref-type="bibr">24</xref>,<xref rid="r51" ref-type="bibr">51</xref></sup>. Correspondingly, both bacteria are infrequently observed in the
general population, but increased population densities are observed in patients with
periodontal disease<sup><xref rid="r24" ref-type="bibr">24</xref>,<xref rid="r51" ref-type="bibr">51</xref></sup>. Although saliva is considered an easy, reliable and
safe method to allow DNA identification by PCR<sup><xref rid="r47" ref-type="bibr">47</xref>,<xref rid="r55" ref-type="bibr">55</xref></sup>, some studies<sup><xref rid="r04" ref-type="bibr">4</xref>,<xref rid="r07" ref-type="bibr">7</xref>,<xref rid="r09" ref-type="bibr">9</xref></sup> have suggested that a higher prevalence
of bacteria is detected from subgingival microbiota, as found in this study.</p><p>In the present study, the presence and quantity of these bacteria in subgingival plaque
samples were investigated by conventional and real-time PCR. The results obtained showed
that <italic>P. gingivalis</italic> was more prevalent in the test group than in the
control group, and that <italic>A. actinomycetemcomitans</italic> could not be detected
in either group. The absence of observable <italic>A. actinomycetemcomitans</italic> is
intriguing and needs further investigation since the primers used in the PCR worked well
for the positive controls (ATCC 29522) and in a previous work by our group to detect
<italic>A. actinomycetemcomitans</italic> from saliva samples of children<sup><xref rid="r47" ref-type="bibr">47</xref></sup>.</p><p>Overall, the findings of this study are in agreement with other reports in the
literature<sup><xref rid="r18" ref-type="bibr">18</xref>,<xref rid="r23" ref-type="bibr">23</xref>,<xref rid="r26" ref-type="bibr">26</xref>,<xref rid="r31" ref-type="bibr">31</xref>,<xref rid="r38" ref-type="bibr">38</xref>,<xref rid="r52" ref-type="bibr">52</xref>,<xref rid="r53" ref-type="bibr">53</xref>,<xref rid="r56" ref-type="bibr">56</xref></sup>, suggesting an
association of periodontal disease and tooth loss with an increased risk of stroke. The
increased levels of <italic>P. gingivalis</italic> in stroke patients could suggest a
role for periodontopathic bacteria in the formation of atheromatous plaque and vascular
lesions, thus increasing the risk of cardiovascular and cerebrovascular diseases.</p><p>Chronic infections, such as periodontal disease, can contribute to atherogenesis by
direct (platelet aggregation, invasion and injury to endothelial cells) or indirect
(synthesis of intracellular adhesion molecules, production of antibodies against
bacterial LPS and an imbalance of the immune system) pathways<sup><xref rid="r03" ref-type="bibr">3</xref>,<xref rid="r19" ref-type="bibr">19</xref></sup>. Namely, it was
observed in this study that the I-CVE group had increased pocket depth and attachment
loss when compared to the H-CVE group, which showed significant increases in the
population density of <italic>P. gingivalis</italic>. The composition of the
subgingival microbiota in patients with periodontal disease provides a significant and
persistent bacterial challenge to the host body, which may gain access through ulcerated
junctional epithelium lining the periodontal pockets<sup><xref rid="r06" ref-type="bibr">6</xref></sup>.</p><p>It was found that atherogenesis and plaque instability can be inferred by increased
levels of plasma markers for inflammation, as ascertained by C-reactive protein, which
may be mediated by periodontal disease. Recent studies have indicated that periodontal
treatment could reduce plasma levels of C-reactive protein and interleukin-6<sup><xref rid="r10" ref-type="bibr">10</xref>,<xref rid="r11" ref-type="bibr">11</xref></sup>, improve endothelial function<sup><xref rid="r17" ref-type="bibr">17</xref>,<xref rid="r37" ref-type="bibr">37</xref>,<xref rid="r48" ref-type="bibr">48</xref>,<xref rid="r54" ref-type="bibr">54</xref></sup> and improve
periodontal health conditions, but without concomitant reduction in systemic levels of
C-reactive protein when compared to the untreated control population.</p><p>Although the findings of the present study seem to be considerably relevant, other
studies are necessary to confirm the role of periodontal pathogens in the development of
atheromatous plaques, to more fully understand the mechanisms linking periodontal
disease with cardiovascular diseases.</p></sec><sec sec-type="conclusions"><title>CONCLUSIONS</title><p>Stroke patients had deeper pockets, more severe attachment loss, increased bleeding on
probing, increased plaque indexes, and their pockets harbored increased levels of
<italic>Porphyromonas gingivalis.</italic> These findings suggest that periodontal
disease is a risk factor for the development of cerebral hemorrhage or infarction. Early
treatment of periodontitis may counteract the development of cerebrovascular
episodes.</p></sec></body><back><ack><sec><title>ACKNOWLEDGEMENTS</title><p>The authors thank Dr. José Roberto Pereira Lauris for his statistical analysis. The
authors also thank FAPESP (The State of São Paulo Research Foundation, process
number: 2006/02376-4) and CAPES (Coordination of Support for Higher Education) for
financially supporting this study.</p></sec></ack><fn-group><fn id="fn01" fn-type="conflict"><p><bold>COMPETING INTERESTS</bold> The authors declare no competing interests.</p></fn></fn-group><ref-list><title>REFERENCES</title><ref id="r01"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ainamo</surname><given-names>J</given-names></name><name><surname>Bay</surname><given-names>I</given-names></name></person-group><article-title>Problems and proposals for recording gingivitis and
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