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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq Bras Cardiol</journal-id>
      <journal-title-group>
        <journal-title>Arquivos Brasileiros de Cardiologia</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Arq. Bras. Cardiol.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">0066-782X</issn>
      <issn pub-type="epub">1678-4170</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">WFXN5SgMvp4mPfJNYcKmgJs</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2015000300002</article-id>
      <article-id pub-id-type="other">00002</article-id>
      <article-id pub-id-type="publisher-id" specific-use="previous-pid">S0066-782X201400504018</article-id>
      <article-id pub-id-type="doi">10.5935/abc.20140187</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original Articles</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Serum Potassium Levels Inversely Correlate with D-Dimer In Patients with
               Acute-Onset Atrial Fibrillation</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Cervellin</surname>
            <given-names>Gianfranco</given-names>
          </name>
          <xref ref-type="corresp" rid="c01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Bonfanti</surname>
            <given-names>Laura</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Picanza</surname>
            <given-names>Alessandra</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lippi</surname>
            <given-names>Giuseppe</given-names>
          </name>
        </contrib>
      </contrib-group>
      <aff id="aff01">
        <label>1</label>
        <institution content-type="orgname">Academic Hospital of Parma</institution>
        <country>Italy</country>
        <institution content-type="original">Academic Hospital of Parma, Italy</institution>
      </aff>
      <author-notes>
        <corresp id="c01"><bold>Mailing Address: Gianfranco Cervellin,</bold> Via Marocchi 5,
               Parma. Postal Code 43126, Parma &#8211; Italy. Email: <email>gcervellin@ao.pr.it</email>;
                  <email>gianfranco.cervellin@gmail.com</email></corresp>
        <fn fn-type="con">
          <p>
            <bold>Author contributions</bold>
          </p>
          <p>Conception and design of the research: Cervellin G, Acquisition of data, Analysis
                  and interpretation of the data, Writing of the manuscript and Critical revision of
                  the manuscript for intellectual content: Cervellin G, Picanza A, Lippi G;
                  Statistical analysis: Bonfanti L, Picanza A.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potential Conflict of Interest</bold>
          </p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub">
        <day>09</day>
        <month>12</month>
        <year>2014</year>
      </pub-date>
      <pub-date pub-type="collection">
        <month>03</month>
        <year>2015</year>
      </pub-date>
      <volume>104</volume>
      <issue>3</issue>
      <fpage>181</fpage>
      <lpage>184</lpage>
      <history>
        <date date-type="received">
          <day>04</day>
          <month>08</month>
          <year>2014</year>
        </date>
        <date date-type="rev-recd">
          <day>06</day>
          <month>10</month>
          <year>2014</year>
        </date>
        <date date-type="accepted">
          <day>06</day>
          <month>10</month>
          <year>2014</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>Background:</title>
          <p>D-dimer values are frequently increased in patients with atrial fibrillation (AF)
                  compared to subjects in sinus rhythm. Hypokalemia plays a role in several
                  cardiovascular diseases, but little is known about the association with AF.</p>
        </sec>
        <sec>
          <title>Objective:</title>
          <p>D-dimer values are frequently increased in patients with atrial fibrillation (AF)
                  compared with subjects in sinus rhythm. Hypokalemia plays a role in several
                  cardiovascular diseases, but little is known about the association with AF. The
                  aim of this study was to investigate correlations between D-dimer and serum
                  potassium in acute-onset AF (AAF).</p>
        </sec>
        <sec>
          <title>Methods:</title>
          <p>To investigate the potential correlation between the values of serum potassium and
                  D-dimer in patients with AAF, we retrospectively reviewed clinical and laboratory
                  data of all emergency department visits for AAF in 2013.</p>
        </sec>
        <sec>
          <title>Results:</title>
          <p>Among 271 consecutive AAF patients with D-dimer assessments, those with
                  hypokalemia (n = 98) had significantly higher D-dimer values than normokalemic
                  patients (139 versus 114 ng/mL, p = 0.004). The rate of patients with D-dimer
                  values exceeding the diagnostic cut-off was higher in the group of patients with
                  hypokalemia than in those with normal serum potassium (26.5% versus 16.2%; p =
                  0.029). An inverse and highly significant correlation was found between serum
                  potassium and D-dimer (r = &#8722;0.21; p &lt; 0.001), even after adjustments for age
                  and sex (beta coefficient &#8722;94.8; p = 0.001). The relative risk for a positive
                  D-dimer value attributed to hypokalemia was 1.64 (95% CI, 1.02 to 2.63; p =
                  0.040). The correlation remained statistically significant in patients free from
                  antihypertensive drugs (r = &#8722;0.25; p = 0.018), but not in those taking
                  angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, or
                  diuretics.</p>
        </sec>
        <sec>
          <title>Conclusions:</title>
          <p>The inverse correlation between values of potassium and D-dimer in patients with
                  AAF provides important and complementary information about the thromboembolic risk
                  of these patients.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <kwd>Atrial Fibrillation</kwd>
        <kwd>Hypokalemia</kwd>
        <kwd>Fibrinogen / metabolism</kwd>
        <kwd>Tromboembolism</kwd>
        <kwd>Potassium</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="2"/>
        <equation-count count="0"/>
        <ref-count count="23"/>
        <page-count count="4"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introduction</title>
      <p>It is well established that atrial fibrillation (AF) carries a significant risk of
            mortality and morbidity in the general population, and the high propensity of clotting
            in the left atrial appendage represents the leading clinical concern for these
               patients<xref ref-type="bibr" rid="B01">1</xref>. Hence, it was recently emphasized
            that the presence of AF increases the risk of cerebrovascular accidents by 2.6-fold to
            4.5-fold throughout all classes of age<xref ref-type="bibr" rid="B02">2</xref>.</p>
      <p>The association between AF and hypercoagulability has been recognized for a long
               while<xref ref-type="bibr" rid="B03">3</xref>, but only recently have scientists
            focused on biomarkers associated with thromboembolism in patients with AF. D-dimer, a
            circulating biomarker of both thrombogenesis and thrombus turnover, is considered the
            gold standard in this field<xref ref-type="bibr" rid="B04">4</xref>. Several studies
            showed that D-dimer levels are higher in AF patients compared with matched controls in
            sinus rhythm<xref ref-type="bibr" rid="B05">5</xref><sup>-</sup><xref ref-type="bibr" rid="B07">7</xref> and that patients with paroxysmal AF have intermediate levels of
            D-dimer compared with patients with chronic AF and controls in sinus rhythm, correlating
            with intermediate risk of thromboembolism<xref ref-type="bibr" rid="B05">5</xref>. In a
            previous study<xref ref-type="bibr" rid="B08">8</xref>, it was demonstrated that AF
            represents one of the leading causes of D-dimer elevation in a large number of patients
            seeking emergency department (ED) treatment for suspected venous thromboembolism.</p>
      <p>Although it is generally acknowledged that hypokalemia represents a common and
            reversible factor in the natural history of cardiovascular disease, little information
            is available about the association between serum potassium concentration and atrial
               arrhythmias<xref ref-type="bibr" rid="B09">9</xref>. Myocardiocyte repolarization
            depends on potassium influx, and hypokalemia lengthens the action potential and
            increases QT dispersion, thus reflecting electrical dishomogeneity<xref ref-type="bibr" rid="B10">10</xref><sup>,</sup><xref ref-type="bibr" rid="B11">11</xref>.
            Pre-treatment with intravenous magnesium and potassium solution is effective in lowering
            energy levels in external electrical cardioversion for persistent AF<xref ref-type="bibr" rid="B12">12</xref><sup>,</sup><xref ref-type="bibr" rid="B13">13</xref>. Only recently the association between serum potassium levels and the
            incidence of AF has been demonstrated in a group of Danish patients<xref ref-type="bibr" rid="B14">14</xref>, despite the elusive underlining mechanisms. Therefore, a
            retrospective investigation was performed to assess the potential correlation between
            serum potassium and D-dimer levels in patients with acute-onset atrial fibrillation
            (AAF).</p>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <p>This study included all episodes of AAF recorded in a large urban ED (90.000 visits per
            year, serving an area with a population of approximately 435.000) in 2013, which were
            retrospectively reviewed from the hospital&#8217;s electronic database. The analysis was
            limited to cases with onset of AF recorded within 48 hours from an ED visit and for whom
            D-dimer assessment was requested by an emergency physician in order to exclude an
            underlying cause of AAF (namely a pulmonary embolus, based mainly on a Gestalt
            perception). Only in a minority of instances was this the case.</p>
      <p>According to currently available guidelines, the definition of AAF included both
            first-diagnosed AF and paroxysmal AF (PAF)<xref ref-type="bibr" rid="B01">1</xref>.</p>
      <p>In all patients, the concentration of D-dimer was measured using HemosIL D-dimer HS for
            ACL TOP (Instrumentation Laboratory, Bedford, MA), a latex-enhanced turbidimetric
            immunoassay characterized by a total imprecision lower than 6.6%, a detection limit of
            21 ng/mL, and a diagnostic cut-off of 243 ng/mL. Serum potassium was assessed with
            indirect ion selective electrode (ISE), on a Beckman Coulter AU 5800 (Beckman Coulter
            Inc., Brea CA, USA). According to a local and validated practice, hemolyzed specimens
            displaying a concentration of cell-free hemoglobin &gt; 0.5 g/L are systematically
            rejected, so spurious hyperkaliemic samples were not included in this study. The quality
            of laboratory data was validated throughout the study period by regular internal quality
            control (IQC) procedures and participation in an External Quality Assessment Scheme
            (EQAS).</p>
      <p>Results of testing were finally expressed as median and interquartile range (IQR). The
            significance of differences was evaluated by the Mann-Whitney-Wilcoxon Test (for
            continuous variables) and the chi-squared test with Yates&#8217;s correction for continuity
            (for categorical variables), using Analyse-it (Analyse-it Software, Ltd, Leeds, UK).
            Simple linear and multivariate regression analyses were also used to identify factors
            potentially associated with D-dimer values (included as a continuous variable). The
            Relative Risk (RR) was calculated using MedCalc Version 12.3.0 (MedCalc.</p>
      <p>Software, Mariakerke, Belgium). The investigation was performed in accordance with the
            Declaration of Helsinki and under the terms of all relevant local legislation.</p>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <p>Overall, 474 cases of AAF were recorded in the ED in 2013, 271 (134 males and 137
            females; mean age 67 &#177; 12 years) with a D-dimer measurement available upon admission.
            The 98 patients with hypokalemia (i.e., serum potassium levels &lt;4.0 mmol/L) had
            significantly higher D-dimer values than those with serum potassium &#8805; 4.0 mmol/L (139
            ng/mL, IQR 70-270 ng/mL versus 114 ng/mL, IQR 58-195 ng/mL; p = 0.004) (<xref ref-type="table" rid="t01">Table 1</xref>). The percentage of patients with D-dimer
            values exceeding the diagnostic cut-off of the method (i.e., 243 ng/mL) was also
            significantly higher in the group of AAF patients with hypokalemia (26/98; 26.5%) than
            in those with serum potassium &#8805; 4.0 mmol/L (28/173; 16.2%; p = 0.029). An inverse and
            highly significant correlation was found between serum potassium and D-dimer values (r =
            &#8722;0.21; p &lt; 0.001), which remained statistically significant after adjustment for age
            and sex (beta coefficient&#8211;94.8; p = 0.001). The RR for positive D-dimer attributable to
            hypokalemia was 1.64 (95% CI, 1.02 to 2.63; p = 0.040).</p>
      <table-wrap id="t01">
        <label>Table 1</label>
        <caption>
          <title>Demographical and laboratory data (median and interquartile range) of the
                  study population</title>
        </caption>
        <table frame="hsides" rules="groups">
          <thead>
            <tr style="border-bottom-width:thin;border-bottom-style:solid">
              <th>&#160;</th>
              <th colspan="2" align="center">Serum potassium</th>
              <th align="center">&#160;</th>
            </tr>
            <tr>
              <th>&#160;</th>
              <th align="center">&lt; 4 mmol/L</th>
              <th align="center">&#8805; 4 mmol/L</th>
              <th align="center">p</th>
            </tr>
          </thead>
          <tbody>
            <tr>
              <td>N</td>
              <td align="center">98</td>
              <td align="center">173</td>
              <td align="center">&#160;</td>
            </tr>
            <tr>
              <td>Age (years)</td>
              <td align="center">69 (58-76)</td>
              <td align="center">68 (58-75)</td>
              <td align="center">0.35</td>
            </tr>
            <tr>
              <td>Sex (M/F)</td>
              <td align="center">43/55</td>
              <td align="center">91/82</td>
              <td align="center">0.21</td>
            </tr>
            <tr>
              <td>
                <bold>D-dimer </bold>
              </td>
              <td align="center">&#160;</td>
              <td align="center">&#160;</td>
              <td align="center">&#160;</td>
            </tr>
            <tr>
              <td>- Value (ng/mL)</td>
              <td align="center">139 (77-270)</td>
              <td align="center">114 (58-195)</td>
              <td align="center">0.004</td>
            </tr>
            <tr>
              <td>- Value &gt; cut-off</td>
              <td align="center">26/98</td>
              <td align="center">28/173</td>
              <td align="center">0.029</td>
            </tr>
          </tbody>
        </table>
      </table-wrap>
      <p>The patients were subsequently classified according to the pharmacologic treatment used
            at the time of ED presentation. A total of 147 patients were free from antihypertensive
            drugs, whereas 60 were taking angiotensin receptor blockers (ARBs), 54 were taking
            angiotensin-converting enzyme inhibitors (ACE-Is), and 54 were taking diuretics (37 took
            thyazides, 14 took loop diuretics, 9 took spironolactone; and 6 patients took an
            association of thyazide and spironolactone). Forty-one patients were administered double
            therapy and 3 patients triple therapy. Interestingly, the correlation between serum
            potassium and D-dimer values remained statistically significant in patients free from
            antihypertensive drugs (r = &#8722;0.25; p = 0.018), but not in those taking ARBs (r = &#8722;0.06;
            p = 0.76), ACE-Is (r = &#8722;0.16; p = 0.39) or diuretics (r = &#8722;0.17; p = 0.21).</p>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <p>Humans have lived for millennia eating a potassiumrich, sodium-poor diet (i.e., a
            potassium-to-sodium intake ratio ranging from 3 to 10), so that biological systems have
            developed in a "sodium-retaining and potassium-wasting" environment<xref ref-type="bibr" rid="B15">15</xref><sup>,</sup><xref ref-type="bibr" rid="B16">16</xref>. The human
            genetic code has also evolved accordingly, and the cardio-reno-vascular system has
            undergone a gradual adaptation for successful living in these ancestral conditions. The
            remarkable changes that have occurred in dietary habits throughout past centuries are
            mostly characterized by a shift towards a sodium-rich diet (i.e., a potassium-to-sodium
            intake ratio usually &lt; 0.4), and have also been associated with a marked trend
            towards sodium overload and potassium depletion<xref ref-type="bibr" rid="B17">17</xref>
            with significant adverse cardiovascular effects<xref ref-type="bibr" rid="B18">18</xref>.</p>
      <p>The risk of developing AF constantly increases with age, and is mostly associated with
            hypertension in Western countries<xref ref-type="bibr" rid="B19">19</xref>. Although the
            risk of AF has also been associated with a variety of genetic<xref ref-type="bibr" rid="B20">20</xref>, infectious (i.e., namely rheumatic heart disease)<xref ref-type="bibr" rid="B21">21</xref>, and environmental<xref ref-type="bibr" rid="B22">22</xref> factors, no information is available regarding the potential association
            between serum potassium concentration, the risk of developing AF, or the thromboembolic
            tendency in patients with established AF.</p>
      <p>Recent evidence from hypertension and heart failure clinical trials show that drugs
            acting on the renin-angiotensin system (i.e., angiotensin-converting enzyme inhibitors
            and angiotensin receptor blockers) are effective in the primary preventer of AF,
            although this benefit seems to be limited to patients with systolic left ventricular
            dysfunction or left ventricular hypertrophy, and is not clearly related to their
            potassium-sparing effect<xref ref-type="bibr" rid="B22">22</xref>.</p>
      <p>The results of this retrospective analysis of 271 cases of AAF demonstrate for the first
            time that a significant negative correlation exists between values of serum potassium
            and D-dimer, which is a well-established biomarker of thrombosis and fibrinolysis<xref ref-type="bibr" rid="B04">4</xref>. This finding may have significant clinical
            implications. Due to a substantially increased risk of cardiovascular mortality and
            morbidity, AF requires early and appropriate management. Specifically, AAF is a frequent
            reason for ED evaluation so that the appropriate management strategy should encompass
            accurate risk assessment of stroke, bleeding, and cardiovascular morbidity. Along with
            conventional risk assessment tools such as CHA<sub>2</sub>DS<sub>2</sub>-VASc and
            HAS-BLED scores, and troponin<xref ref-type="bibr" rid="B01">1</xref>, D-dimer and
            potassium levels may hence provide important complementary information about the
            thromboembolic risk and prognosis of these patients, especially in those free from
            antihypertensive drugs. It is also noteworthy that the greater risk of
            hypercoagulability that we have observed in AAF patients with hypokalemia, as mirrored
            by the remarkably higher rate of increased D-dimer values, may provide a reliable
            foundation for planning interventional trials aimed at establishing whether correction
            of hypokalemia, or even the modest elevation of serum potassium value within the
            physiological range, may be effective in lowering the risk of thromboembolic
            complications in these patients. This is also supported by experimental data suggesting
            that an increase of potassium concentration in blood is associated with a number of
            antithrombotic effects such as inhibition of free radical generation, reduction of
            platelet hyperaggregability and an overall decrease of the endogenous prothrombotic
               potential<xref ref-type="bibr" rid="B23">23</xref>.</p>
      <p>Potential limitations of the study are represented by the retrospective nature of it,
            and its monocentric design.</p>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclusions</title>
      <p>The inverse correlation between values of potassium and D-dimer in patients with AAF may
            provide, when added to conventional risk assessment tools such as
               CHA<sub>2</sub>DS<sub>2</sub>&#8209;VASc and HAS-BLED scores, and troponin, important and
            complementary information about the thromboembolic risk and the prognosis of these
            patients, especially in those free from antihypertensive drugs.</p>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="financial-disclosure">
        <p>
          <bold>Sources of Funding</bold>
        </p>
        <p>There were no external funding sources for this study.</p>
      </fn>
      <fn fn-type="other">
        <p>
          <bold>Study Association</bold>
        </p>
        <p>This study is not associated with any thesis or dissertation work.</p>
      </fn>
    </fn-group>
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              <surname>Garfinkle</surname>
              <given-names>M</given-names>
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              <surname>Yusuf</surname>
              <given-names>S</given-names>
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              <surname>Connolly</surname>
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          <source>J Am Coll Cardiol</source>
          <year>2005</year>
          <volume>45</volume>
          <issue>11</issue>
          <fpage>1832</fpage>
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        <mixed-citation>Young DB, Lin H, McCabe RD. Potassium's cardiovascular protective
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              <surname>Young</surname>
              <given-names>DB</given-names>
            </name>
            <name>
              <surname>Lin</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>McCabe</surname>
              <given-names>RD</given-names>
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          <article-title xml:lang="en">Potassium's cardiovascular protective
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          <source>Am J Physiol</source>
          <year>1995</year>
          <volume>268</volume>
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      </ref>
    </ref-list>
  </back>
  <sub-article article-type="translation" id="SA1" xml:lang="pt">
    <front-stub>
      <title-group>
        <article-title>Concentra&#231;&#245;es S&#233;ricas de Pot&#225;ssio Encontram-se Inversamente
               Correlacionadas aos N&#237;veis de D-D&#237;mero em Pacientes com Fibrila&#231;&#227;o Atrial
               Aguda</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Cervellin</surname>
            <given-names>Gianfranco</given-names>
          </name>
          <xref ref-type="corresp" rid="c02"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Bonfanti</surname>
            <given-names>Laura</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Picanza</surname>
            <given-names>Alessandra</given-names>
          </name>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lippi</surname>
            <given-names>Giuseppe</given-names>
          </name>
        </contrib>
      </contrib-group>
      <aff id="aff02">
        <institution content-type="orgname">Academic Hospital of Parma</institution>
        <country>It&#225;lia</country>
        <institution content-type="original">Academic Hospital of Parma, It&#225;lia</institution>
      </aff>
      <author-notes>
        <corresp id="c02"><bold>Mailing Address: Gianfranco Cervellin,</bold> Via Marocchi 5,
               Parma. Postal Code 43126, Parma &#8211; It&#225;lia. Email: <email>gcervellin@ao.pr.it</email>;
                  <email>gianfranco.cervellin@gmail.com</email></corresp>
        <fn fn-type="con">
          <p>
            <bold>Contribui&#231;&#227;o dos autores</bold>
          </p>
          <p>Concep&#231;&#227;o e desenho da pesquisa: Cervellin G; Obten&#231;&#227;o de dados, An&#225;lise e
                  interpreta&#231;&#227;o dos dados, Reda&#231;&#227;o do manuscrito e Revis&#227;o cr&#237;tica do manuscrito
                  quanto ao conte&#250;do intelectual importante: Cervellin G, Picanza A, Lippi G;
                  An&#225;lise estat&#237;stica: Bonfanti L, Picanza A.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potencial conflito de interesse</bold>
          </p>
          <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
        </fn>
      </author-notes>
      <abstract>
        <sec>
          <title>Fundamento:</title>
          <p> Valores de D-d&#237;mero s&#227;o frequentemente aumentada em pacientes com fibrila&#231;&#227;o
                  atrial (FA) em compara&#231;&#227;o com indiv&#237;duos em ritmo sinusal. A hipocalemia
                  desempenha um papel em v&#225;rias doen&#231;as cardiovasculares, mas pouco se sabe sobre a
                  associa&#231;&#227;o com FA.</p>
        </sec>
        <sec>
          <title>Objetivo:</title>
          <p>As concentra&#231;&#245;es de D-d&#237;mero encontram-se frequentemente aumentadas em pacientes
                  com FA, quando comparados com indiv&#237;duos em ritmo sinusal. A hipopotassemia
                  desempenha um papel importante nas doen&#231;as cardiovasculares, por&#233;m, pouco &#233;
                  conhecido sobre sua associa&#231;&#227;o com a FA. O objetivo deste estudo foi investigar a
                  correla&#231;&#227;o entre os n&#237;veis s&#233;ricos de D-d&#237;mero e pot&#225;ssio na FA aguda (FAA).</p>
        </sec>
        <sec>
          <title>M&#233;todos:</title>
          <p>Para investigar a exist&#234;ncia de uma potencial correla&#231;&#227;o entre os n&#237;veis s&#233;ricos
                  de pot&#225;ssio e D-d&#237;mero em pacientes com FAA, realizamos uma revis&#227;o retrospectiva
                  de dados cl&#237;nicos e laboratoriais relacionados a todas as visitas ao departamento
                  de emerg&#234;ncia devido &#224; FAA, no ano de 2013.</p>
        </sec>
        <sec>
          <title>Resultados:</title>
          <p>Entre os 271 pacientes com FAA, aqueles com hipopotassemia (n = 98) mostraram
                  aumento significativo nos n&#237;veis de D-d&#237;mero, quando comparados com pacientes com
                  concentra&#231;&#245;es normais de pot&#225;ssio (139 versus 114 ng/mL, p = 0,004). A taxa de
                  pacientes com n&#237;veis de D-d&#237;mero excedendo o valor limiar de diagn&#243;stico foi maior
                  no grupo de pacientes com hipopotassemia, quando comparado com o grupo de
                  pacientes com concentra&#231;&#245;es normais de pot&#225;ssio (26,5% versus 16,2%; p = 0,029).
                  Detectamos uma correla&#231;&#227;o inversa e altamente significativa entre os n&#237;veis
                  s&#233;ricos de pot&#225;ssio e D-d&#237;mero (r = -0,21; p &lt; 0,001), at&#233; mesmo ap&#243;s ajuste
                  para idade e sexo (coeficiente beta &#8211;94,8; p = 0,001). O risco relativo de um
                  valor positivo de D-d&#237;mero estar relacionado &#224; hipopotassemia foi de 1,64 (95% CI,
                  1,02 to 2,63; p = 0,040). A correla&#231;&#227;o permaneceu estatisticamente significativa
                  em pacientes livres de medicamentos hipertensivos (r = -0,25; p = 0,018), por&#233;m
                  n&#227;o nos pacientes em tratamento com bloqueadores do receptor de angiotensina,
                  inibidores da enzima conversora de angiotensina e diur&#233;ticos.</p>
        </sec>
        <sec>
          <title>Conclus&#245;es:</title>
          <p>A correla&#231;&#227;o inversa existente entre os n&#237;veis s&#233;ricos de pot&#225;ssio e D-d&#237;mero em
                  pacientes com FAA fornece informa&#231;&#245;es importantes sobre o risco de tromboembolismo
                  nestes pacientes.</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="pt">
        <kwd>Fibrila&#231;&#227;o Atrial</kwd>
        <kwd>Hipopotassemia</kwd>
        <kwd>Fibrinog&#234;nio / metabolismo</kwd>
        <kwd>Tromboembolia</kwd>
        <kwd>Potassio</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <sec sec-type="intro">
        <title>Introdu&#231;&#227;o</title>
        <p>Sabe-se que a fibrila&#231;&#227;o atrial (FA) est&#225; relacionada a um aumento do risco de
               mortalidade e morbidade na popula&#231;&#227;o em geral e que a maior propens&#227;o a forma&#231;&#227;o de
               trombos no ap&#234;ndice atrial esquerdo representa a principal preocupa&#231;&#227;o cl&#237;nica nestes
                  pacientes<xref ref-type="bibr" rid="B01">1</xref>. Recentemente foi enfatizado que
               a presen&#231;a de FA eleva o risco de acidente cerebrovascular de 2,6 para 4,5 vezes,
               independente da faixa et&#225;ria<xref ref-type="bibr" rid="B02">2</xref>.</p>
        <p>A associa&#231;&#227;o entre FA e hipercoagulabilidade &#233; aceita h&#225; tempos<xref ref-type="bibr" rid="B03">3</xref>, por&#233;m, s&#243; recentemente cientistas v&#234;m focando em biomarcadores
               associados ao tromboembolismo em pacientes com FA. O D-d&#237;mero &#233; considerado o
               biomarcador s&#233;rico mais confi&#225;vel para se determinar a presen&#231;a de trombog&#234;nese e de
               turnover de trombos<xref ref-type="bibr" rid="B04">4</xref>. V&#225;rios estudos mostraram
               que os n&#237;veis de D-d&#237;mero encontram-se elevados em pacientes com FA, quando
               comparados com indiv&#237;duos em em ritmo sinusal<xref ref-type="bibr" rid="B05">5</xref><sup>-</sup><xref ref-type="bibr" rid="B07">7</xref>. Al&#233;m disso, sabe-se
               que pacientes com FA parox&#237;stica t&#234;m n&#237;veis intermedi&#225;rios de D-d&#237;mero, quando
               comparados com pacientes com FA cr&#244;nica e indiv&#237;duos em ritmo sinusal, de acordo com
               o risco intermedi&#225;rio de tromboembolismo nestes pacientes<xref ref-type="bibr" rid="B05">5</xref>. Em um estudo anterior<xref ref-type="bibr" rid="B08">8</xref>,
               mostramos que a FA representa uma das principais causas de eleva&#231;&#227;o dos n&#237;veis de
               D-d&#237;mero em um grupo de pacientes presentes no departamento de emerg&#234;ncia por
               suspeita de tromboembolismo venoso.</p>
        <p>Apesar do fato da hipopotassemia representar um fator comum e revers&#237;vel na hist&#243;ria
               natural da doen&#231;a cardiovascular, pouco se sabe a respeito da associa&#231;&#227;o entre as
               concentra&#231;&#245;es s&#233;ricas de pot&#225;ssio e arritmias atriais<xref ref-type="bibr" rid="B09">9</xref>. A repolariza&#231;&#227;o de cardiomi&#243;citos depende do influxo de pot&#225;ssio e a
               hipopotassemia aumenta o potencial de a&#231;&#227;o e a dispers&#227;o do intervalo QT, refletindo
               assim, quebra de homogeneidade el&#233;trica<xref ref-type="bibr" rid="B10">10</xref><sup>,</sup><xref ref-type="bibr" rid="B11">11</xref>. O pr&#233;-tratamento
               intravenoso com solu&#231;&#245;es de magn&#233;sio e pot&#225;ssio &#233; efetivo em diminuir os n&#237;veis de
               energia para a cardiovers&#227;o el&#233;trica externa usada na FA persistente<xref ref-type="bibr" rid="B12">12</xref><sup>,</sup><xref ref-type="bibr" rid="B13">13</xref>. S&#243; recentemente a associa&#231;&#227;o entre os n&#237;veis de pot&#225;ssio e a
               incid&#234;ncia de FA foram demonstrados em um grupo de pacientes dinamarqueses<xref ref-type="bibr" rid="B14">14</xref>, apesar dos mecanismos respons&#225;veis
               permanecerem desconhecidos. Portanto, realizamos uma an&#225;lise retrospectiva para
               avaliar a exist&#234;ncia de uma potencial correla&#231;&#227;o entre os n&#237;veis s&#233;ricos de pot&#225;ssio
               e D-d&#237;mero em pacientes com FA aguda (FAA).</p>
      </sec>
      <sec sec-type="methods">
        <title>M&#233;todos</title>
        <p>Este estudo foi planejado para incluir todos os epis&#243;dios de FAA registrados em um
               grande departamento de emerg&#234;ncia urbano (90.000 visitas por ano, servindo uma &#225;rea
               com uma popula&#231;&#227;o de aproximadamente 435.000 habitantes) no ano de 2013. Estes foram
               revisados retrospectivamente da base de dados do hospital. A an&#225;lise foi limitada aos
               casos em que o in&#237;cio da FA foi registrado dentro de 48 horas a partir da entrada no
               hospital. Al&#233;m disso, somente foram inclu&#237;dos os pacientes que tiveram a an&#225;lise de
               D-d&#237;mero requerida pelo m&#233;dico, na tentativa de excluir a causa fundamental da FAA,
               ou seja, a presen&#231;a de um &#234;mbolo pulmonar, baseado principalmente no ensaio de
               Gestalt, e somente na minoria dos casos no escore revisado de Genebra.</p>
        <p>De acordo com as diretrizes atuais, a defini&#231;&#227;o de FAA inclui tanto FA rec&#233;m
               diagnosticada como FA parox&#237;stica (FAP)<xref ref-type="bibr" rid="B01">1</xref>.</p>
        <p>Em todos os pacientes, a concentra&#231;&#227;o de D-d&#237;mero foi avaliada usando o HemosIL
               D-d&#237;mero HS for ACL TOP (Instrumentation Laboratory, Bedford, MA), um imunoensaio
               turbidim&#233;trico caracterizado pela alta precis&#227;o (94%), um limite de detec&#231;&#227;o de 21
               ng/mL e um limiar de diagn&#243;stico de 243 ng/mL. Os n&#237;veis de pot&#225;ssio s&#233;rico foram
               determinados com um eletrodo seletivo de &#237;ons (ESI) da Beckman Coulter AU 5800
               (Beckman Coulter Inc., Brea CA, USA). De acordo com a pr&#225;tica local, esp&#233;cimens
               hemolisados contendo hemoglobina livre em uma concentra&#231;&#227;o de &gt; 0,5 g/L foram
               sistematicamente rejeitados, assim amostras hipopotass&#234;micas devido a artefato n&#227;o
               foram inclu&#237;das no estudo. A qualidade dos dados laboratoriais foi validada durante o
               per&#237;odo de estudo por procedimentos de controles de qualidade internos regulares
               (CQI) e participa&#231;&#227;o em um esquema de controle de qualidade externo (CQE).</p>
        <p>Os resultados dos testes foram expressos como mediana e intervalo interquartil (IIQ).
               A signific&#226;ncia foi avaliada pelo teste de Mann-Whitney-Wilcoxon (para vari&#225;veis
               cont&#237;nuas) e teste do qui-quadrado com corre&#231;&#227;o de Yates para continuidade (para
               vari&#225;veis categ&#243;ricas) usando o software Analyse-it (Analyse-it Software Ltd, Leeds,
               UK). Regress&#227;o linear simples e multivariada tamb&#233;m foram utilizadas para identificar
               fatores associados aos valores de D-d&#237;mero (inclu&#237;do como uma vari&#225;vel cont&#237;nua). O
               risco relativo (RR) foi calculado usando MedCalc Vers&#227;o 12.3.0 (MedCalc Software,
               Mariakerke, Belgium). A investiga&#231;&#227;o foi conduzida de acordo com a declara&#231;&#227;o de
               Helsinque e dentro da legisla&#231;&#227;o local.</p>
      </sec>
      <sec sec-type="results">
        <title>Resultados</title>
        <p>No ano de 2013, 474 casos de FAA foram registrados no departamento de emerg&#234;ncia.
               Destes, 271 (134 homens e 137 mulheres; idade m&#233;dia de 67&#177;12 anos) foram avaliados
               quanto aos n&#237;veis de D-d&#237;mero. Os 98 pacientes com hipopotassemia (i. e., n&#237;veis
               s&#233;ricos de pot&#225;ssio &lt; 4,0 mmol/L) mostraram concentra&#231;&#245;es de D-d&#237;mero
               significativamente maiores que os pacientes com n&#237;veis de pot&#225;ssio s&#233;rico &#8805; 4,0
               mmol/L (139 ng/mL, IIQ 70&#8209;270 ng/mL versus 114 ng/mL, IIQ 58-195 ng/mL; p = 0,004)
                  (<xref ref-type="table" rid="t02">Tabela 1</xref>). A porcentagem de pacientes com
               n&#237;veis de D-d&#237;mero excedendo o valor limiar do m&#233;todo (i.e., 243 ng/mL) tamb&#233;m foi
               significativamente maior no grupo dos pacientes com FAA e hipopotassemia (26/98;
               26,5%) do que naqueles com concentra&#231;&#245;es de pot&#225;ssio &#8805; 4,0 mmol/L (28/173; 16,2%; p =
               0,029). Uma correla&#231;&#227;o inversa e altamente significativa foi encontrada entre os
               valores s&#233;ricos de pot&#225;ssio e D-d&#237;mero (r = -0,21; p &lt; 0,001), a qual permaneceu
               estatisticamente significativa ap&#243;s ajuste para idade e sexo (coeficiente beta &#8211;94,8;
               p = 0,001). O RR de D-d&#237;mero positivo atribu&#237;do &#224; hipopotassemia foi de 1,64 (95% CI,
               1,02 a 2,63; p= 0,040).</p>
        <table-wrap id="t02">
          <label>Tabela 1</label>
          <caption>
            <title>Dados demogr&#225;ficos e laboratoriais (mediana e intervalo interquartil) da
                     popula&#231;&#227;o em estudo</title>
          </caption>
          <table frame="hsides" rules="groups">
            <thead>
              <tr style="border-bottom-width:thin;border-bottom-style:solid">
                <th>&#160;</th>
                <th colspan="2" align="center">Pot&#225;ssio s&#233;rico</th>
                <th align="center">&#160;</th>
              </tr>
              <tr>
                <th>&#160;</th>
                <th align="center">&lt; 4 mmol/L</th>
                <th align="center">&#8805; 4 mmol/L</th>
                <th align="center">p</th>
              </tr>
            </thead>
            <tbody>
              <tr>
                <td>n</td>
                <td align="center">98</td>
                <td align="center">173</td>
                <td align="center">&#160;</td>
              </tr>
              <tr>
                <td>Idade (anos)</td>
                <td align="center">69 (58-76)</td>
                <td align="center">68 (58-75)</td>
                <td align="center">0,35</td>
              </tr>
              <tr>
                <td>Sexo (M/F)</td>
                <td align="center">43/55</td>
                <td align="center">91/82</td>
                <td align="center">0,21</td>
              </tr>
              <tr>
                <td>
                  <bold>D-d&#237;mero</bold>
                </td>
                <td align="center">&#160;</td>
                <td align="center">&#160;</td>
                <td align="center">&#160;</td>
              </tr>
              <tr>
                <td>- Valor (ng/mL)</td>
                <td align="center">139 (77-270)</td>
                <td align="center">114 (58-195)</td>
                <td align="center">0,004</td>
              </tr>
              <tr>
                <td>- Valor &gt; limiar</td>
                <td align="center">26/98</td>
                <td align="center">28/173</td>
                <td align="center">0,029</td>
              </tr>
            </tbody>
          </table>
        </table-wrap>
        <p>Os pacientes foram subsequentemente classificados de acordo com o tratamento
               farmacol&#243;gico usado no momento da entrada no departamento de emerg&#234;ncia. Um total de
               147 pacientes encontravam-se livres de medicamentos anti-hipertensivos, dos quais 60
               faziam uso de bloqueadores do receptor de angiotensina, 54 de inibidores da enzima
               conversora de angiotensina (ECA), 54 de diur&#233;ticos (37 tiazidas, 14 diur&#233;ticos de
               alca, 9 espironolactona; 6 associa&#231;&#227;o de tiazida e espironolactona). Um total de 41
               pacientes encontravam-se em terapia dupla e 3 pacientes em terapia tripla.
               Interessante notar que a correla&#231;&#227;o entre os n&#237;veis de pot&#225;ssio s&#233;rico e D-d&#237;mero
               permaneceram estatisticamente significativa em pacientes livres de medicamentos
               anti&#8209;hipertensivos (r = -0,25; p = 0,018), mas n&#227;o naqueles fazendo uso de
               bloqueadores do receptor de angiotensina (r = -0,06; p = 0,76), inibidores de ECA (r
               = -0,16; p = 0,39) ou diur&#233;ticos (r = -0,17; p = 0,21).</p>
      </sec>
      <sec sec-type="discussion">
        <title>Discuss&#227;o</title>
        <p>A ra&#231;a humana passou milhares de anos alimentando-se com uma dieta rica em pot&#225;ssio e
               pobre em s&#243;dio (i.e., rela&#231;&#227;o de ingest&#227;o pot&#225;ssio/s&#243;dio em um intervalo de 3 para
               10), assim os sistemas biol&#243;gicos desenvolveram uma condi&#231;&#227;o de reten&#231;&#227;o de s&#243;dio e
               libera&#231;&#227;o de pot&#225;ssio<xref ref-type="bibr" rid="B15">15</xref><sup>,</sup><xref ref-type="bibr" rid="B16">16</xref>. O c&#243;digo gen&#233;tico humano tamb&#233;m evoluiu neste
               campo e os sistemas card&#237;aco e renal sofreram adapta&#231;&#245;es graduais para ter sucesso de
               sobreviv&#234;ncia nestas condi&#231;&#245;es ancestrais. As not&#225;veis mudan&#231;as ocorridas nos h&#225;bitos
               alimentares durante os &#250;ltimo s&#233;culos, principalmente caracterizadas por uma troca
               para dietas ricas em s&#243;dio (i.e., rela&#231;&#227;o de ingest&#227;o pot&#225;ssio/s&#243;dio em geralmente
               &lt; 0,4), t&#234;m sido associadas &#224; uma tend&#234;ncia de sobrecarga de s&#243;dio e esgotamento
               de pot&#225;ssio<xref ref-type="bibr" rid="B17">17</xref>, com eventos cardiovasculares
               adversos importantes<xref ref-type="bibr" rid="B09">9</xref>.</p>
        <p>O risco de desenvolver FA aumenta concomitantemente com a idade e nos pa&#237;ses
               ocidentais, est&#225; associado com hipertens&#227;o<xref ref-type="bibr" rid="B18">18</xref>.
               Apesar do risco de FA estar associado a uma variedade de fatores gen&#233;ticos<xref ref-type="bibr" rid="B19">19</xref>, infecciosos (i.e., doen&#231;a reum&#225;tica)20 e
               ambientais, nada se conhece sobre uma potencial associa&#231;&#227;o entre a concentra&#231;&#227;o de
               pot&#225;ssio s&#233;rico, o risco de desenvolver FA ou o risco de tromboembolismo em pacientes
               com FA j&#225; estabelecida<xref ref-type="bibr" rid="B21">21</xref>.</p>
        <p>Evid&#234;ncias recentes de ensaios cl&#237;nicos em hipertens&#227;o e falha card&#237;aca mostram que
               medicamentos atuando no sistema renina-angiotensina (i.e., inibidores de ECA e
               bloqueadores do receptor de angiotensina) s&#227;o efetivos na preven&#231;&#227;o da FA, apesar dos
               benef&#237;cios parecerem limitados a pacientes com disfun&#231;&#227;o sist&#243;lica ventricular
               esquerda ou hipertrofia ventricular esquerda. Al&#233;m disso, estes efeitos n&#227;o est&#227;o
               claramente relacionados ao pot&#225;ssio<xref ref-type="bibr" rid="B22">22</xref>.</p>
        <p>O resultado esta an&#225;lise retrospectiva de 271 casos de FAA demonstra pela primeira
               vez que existe uma correla&#231;&#227;o inversa significativa entre os valores de pot&#225;ssio
               s&#233;rico e D-d&#237;mero, o qual &#233; um biomarcador bem estabelecido para trombose e
                  fibrin&#243;lise<xref ref-type="bibr" rid="B04">4</xref>. Este achado possui
               implica&#231;&#245;es cl&#237;nicas importantes. Devido ao elevado risco de mortalidade e morbidade
               cardiovascular, a FA requere cuidados urgentes e apropriados. Mais especificamente, a
               FAA representa motivo frequente para visitas ao departamento de emerg&#234;ncia. Assim,
               estrat&#233;gias de cuidado adequadas devem incluir an&#225;lise de risco de infarto,
               sangramento e morbidade cardiovascular. Juntamente &#224;s ferramentas de an&#225;lise de risco
               convencionais como escores CHA2DS2-VASc e HAS-BLED e troponina<xref ref-type="bibr" rid="B01">1</xref>, os n&#237;veis de D-d&#237;mero e pot&#225;ssio podem fornecer informa&#231;&#245;es
               importantes sobre o risco tromb&#243;tico e prognose destes pacientes, especialmente
               naqueles livres de medicamentos anti-hipertensivos. Tamb&#233;m &#233; digno de nota que o
               maior risco de hipercoagulabilidade observado nos pacientes com FAA e hipopotassemia,
               como evidenciado pela maior taxa de valores aumentados de D-d&#237;mero, pode fornecer uma
               base segura para o planejamento de estudos cl&#237;nicos intervencionais para estabelecer
               se a corre&#231;&#227;o da hipopotassemia ou mesmo a eleva&#231;&#227;o moderada dos n&#237;veis de pot&#225;ssio
               s&#233;rico, seriam efetivas na diminui&#231;&#227;o do risco de complica&#231;&#245;es tromboemb&#243;licas nestes
               pacientes. Isto tamb&#233;m &#233; apoiado por dados experimentais que sugerem que o aumento
               das concentra&#231;&#245;es de pot&#225;ssio no sangue est&#225; associado a uma variedade de efeitos
               anti-tromb&#243;ticos como a inibi&#231;&#227;o da gera&#231;&#227;o de radicais livres, redu&#231;&#227;o da
               hiper-agregabilidade plaquet&#225;ria e uma diminui&#231;&#227;o do potencial pro-tromb&#243;tico
                  end&#243;geno<xref ref-type="bibr" rid="B23">23</xref>.</p>
        <p>Limita&#231;&#245;es potenciais deste estudo est&#227;o representadas pelo car&#225;ter retrospectivo
               deste e seu design monoc&#234;ntrico.</p>
      </sec>
      <sec sec-type="conclusions">
        <title>Conclus&#245;es</title>
        <p>A correla&#231;&#227;o inversa existente entre os n&#237;veis s&#233;ricos de pot&#225;ssio e D-d&#237;mero em
               pacientes com FAA fornece (quando analisada juntamente com ferramentas convencionais
               de an&#225;lise de risco como escores de CHA2DS2-VASc e HAS-BLED e troponina) informa&#231;&#245;es
               importantes sobre o risco de tromboembolismo e prognose destes pacientes,
               especialmente nos pacientes livres de medicamentos anti-hipertensivos.</p>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="financial-disclosure">
          <p>
            <bold>Fontes de financiamento</bold>
          </p>
          <p>O presente estudo n&#227;o teve fontes de financiamento externas.</p>
        </fn>
        <fn fn-type="other">
          <p>
            <bold>Vincula&#231;&#227;o acad&#234;mica</bold>
          </p>
          <p>N&#227;o h&#225; vincula&#231;&#227;o deste estudo a programas de p&#243;s&#8209;gradua&#231;&#227;o.</p>
        </fn>
      </fn-group>
    </back>
  </sub-article>
</article>
