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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">CC</journal-id>
<journal-id journal-id-type="nlm-ta">Cardiol Croat</journal-id>
<journal-title-group>
<journal-title>Cardiologia Croatica</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Cardiol. Croat.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="ppub">1848-543X</issn>
<issn pub-type="epub">1848-5448</issn>
<publisher><publisher-name>Croatian Cardiac Society</publisher-name></publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">CC_13(7-8)_239</article-id>
<article-id pub-id-type="doi">10.15836/ccar2018.239</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Professional Article</subject></subj-group>
</article-categories>
<title-group>
<article-title>Unique Characteristics of Hypertension in Women and Association with to Target Organ Damage</article-title>
<trans-title-group xml:lang="HR">
<trans-title>Posebnosti arterijske hipertenzije u &#x017E;ena i povezanost s o&#x0161;te&#x0107;enjem ciljnih organa</trans-title>
</trans-title-group>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-5830-7131</contrib-id><name><surname>Prka&#x010D;in</surname><given-names>Ingrid</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8446-6120</contrib-id><name><surname>Lovri&#x0107; Ben&#x010D;i&#x0107;</surname><given-names>Martina</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-9432-6882</contrib-id><name><surname>Markovi&#x0107;</surname><given-names>Domagoj</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib>
<aff id="aff1"><label>1</label>Medicinski fakultet Sveu&#x010D;ili&#x0161;ta u Zagrebu, Zagreb, Hrvatska</aff>
<aff id="aff2"><label>2</label>Klini&#x010D;ka bolnica Merkur, Zagreb, Hrvatska</aff>
<aff id="aff3"><label>3</label>Medicinski fakultet Sveu&#x010D;ili&#x0161;ta u Zagrebu, Klini&#x010D;ki bolni&#x010D;ki centar Zagreb, Zagreb, Hrvatska</aff>
<aff id="aff4"><label>4</label>Klini&#x010D;ki bolni&#x010D;ki centar Split, <addr-line>Split</addr-line>, <country>Croatia</country></aff>
<aff id="aff5"><label>1</label><institution>University of Zagreb School of Medicine</institution>, <addr-line>Zagreb</addr-line>, <country>Croatia</country></aff>
<aff id="aff6"><label>2</label><institution>University Hospital &#x00AB;Merkur&#x00BB;</institution>, <addr-line>Zagreb</addr-line>, <country>Croatia</country></aff>
<aff id="aff7"><label>3</label>University of Zagreb School of Medicine, <institution>University Hospital Centre Zagreb</institution>, <addr-line>Zagreb</addr-line>, <country>Croatia</country></aff>
<aff id="aff8"><label>4</label><institution>University Hospital Centre Split</institution>, <addr-line>Split</addr-line>, <country>Croatia</country></aff>
</contrib-group>
<author-notes>
<corresp id="cor1"><label>*</label>ADDRESS FOR CORRESPONDENCE: Ingrid Prka&#x010D;in, Klini&#x010D;ka bolnica Merkur, Ul. I. Zajca 19, HR-10000 Zagreb, Croatia. / Phone: +385-98-406-218 / E-mail: <email xlink:href="ingrid.prkacin@gmail.com">ingrid.prkacin@gmail.com</email></corresp></author-notes>
<pub-date pub-type="epub-ppub"><month>07</month><year>2018</year></pub-date>
<volume>13</volume>
<issue>7-8</issue>
<fpage>239</fpage>
<lpage>242</lpage>
<history>
<date date-type="received"><day>01</day><month>06</month><year>2018</year></date><date date-type="accepted"><day>15</day><month>06</month><year>2018</year></date>
</history>
<permissions>
<copyright-year>2018</copyright-year>
<copyright-holder>Croatian Cardiac Society</copyright-holder>
</permissions>
<abstract>
<title>Summary</title>
<p>Traditional cardiovascular risk factors for target organ damage are the same in both women and men and include hypertension, hyperlipidemia, diabetes mellitus, smoking, and atrial fibrillation. There are several risk factors that are specific to women, such as differences in sex hormones, exogenous estrogens, and pregnancy. Further investigation into the sex-specific differences in therapeutic utilization and the sex-specific differences in the safety and efficacy of the therapeutic options is required.</p>
</abstract>
<trans-abstract xml:lang="HR">
<title>Sa&#x017E;etak</title>
<p>Tradicionalni &#x010D;imbenici rizika za o&#x0161;te&#x0107;enje ciljnih organa jednaki su za mu&#x0161;karce i &#x017E;ene i uklju&#x010D;uju arterijsku hipertenziju, hiperlipidemiju, &#x0161;e&#x0107;ernu bolest, nikotinizam i fibrilaciju atrija. No postoje i specifi&#x010D;ni rizi&#x010D;ni &#x010D;imbenici prisutni samo u &#x017E;ena koji uklju&#x010D;uju razlike u spolnim hormonima, estrogenskoj dodatnoj terapiji i doba trudno&#x0107;e. Potrebna su daljnja istra&#x017E;ivanja koja &#x0107;e pridonjeti boljem razumijevanju specifi&#x010D;nosti vezanih za zdravlje &#x017E;ena, &#x0161;to &#x0107;e dodatno utjecati na sigurnosti i u&#x010D;inkovitosti primijenjenih terapijskih mogu&#x0107;nosti.</p>
</trans-abstract>
<kwd-group kwd-group-type="translator" xml:lang="HR"><kwd>Klju&#x010D;ne rije&#x010D;i: &#x017E;ene</kwd><kwd>&#x010D;imbenici rizika</kwd><kwd>arterijska hipertenzija</kwd></kwd-group>
<kwd-group kwd-group-type="author"><title>Keywords: </title><kwd>women</kwd><kwd>risk factors</kwd><kwd>hypertension</kwd></kwd-group>
</article-meta>
</front>
<body>
<p>Differences between men and women in hypertension are not recent news. There are well-established differences in prevalence which manifests in age difference (higher prevalence in men up to the fifth decade of life and higher prevalence in women in later ages) as well as higher incidence of white coat hypertension in women; however, the effect of hypertension on target organ damage is less well known, particularly for stroke, which is more common in women than in men (<xref ref-type="bibr" rid="r1"><italic>1</italic></xref>).</p>
<p>Despite a clear biological difference between women and men, there are no guidelines related to the sex differences except for the treatment of hypertension in pregnancy (<xref ref-type="bibr" rid="r1"><italic>1</italic></xref>). Hypertension in a state of endothelial dysfunction of all blood vessels, and obesity represents the most important factor for the development of heart and kidney disease (<xref ref-type="bibr" rid="r2"><italic>2</italic></xref>, <xref ref-type="bibr" rid="r3"><italic>3</italic></xref>). The overall challenges with female patients are especially emphasized in pregnancy, requiring a multidisciplinary approach.</p>
<p>Autoimmune diseases in women, especially systemic lupus types, are often associated with kidney damage, and patients with autoimmune diseases have increased risk of cardiovascular diseases; consequently, the cooperation between different fields of expertise in the treatment of women with autoimmune diseases is especially important (<xref ref-type="bibr" rid="r4"><italic>4</italic></xref>). Heart failure with preserved ejection fraction is more common in women, and the importance of the link between the heart and the brain is well-know (<xref ref-type="bibr" rid="r5"><italic>5</italic></xref>).</p>
<sec sec-type="other1">
<title>The kidney-heart-brain link in women</title>
<p>The guiding principle of arterial hypertension treatment, an omnipresent and current preventable causal factor, is the reduction of total mortality. We often forget that stroke is the third leading cause of death for women in the United States of America and the leading cause of incapacitation (<xref ref-type="bibr" rid="r5"><italic>5</italic></xref>). Beside traditional risk factors for target organ damage that are the same for men and women (arterial hypertension, hyperlipidemia, diabetes, cigarette smoking, atrial fibrillation), there are also specific risk factors present only in women (differences in sex hormones, estrogen supplementation therapy, and pregnancy) (<xref ref-type="bibr" rid="r5"><italic>5</italic></xref>).</p>
<p>Cardiovascular diseases (CVD) are responsible for more than 17 million cases of death per year (<xref ref-type="bibr" rid="r6"><italic>6</italic></xref>). The overall data show that more women than men die of CVD. This group of diseases is responsible for 45% of all deaths in women and 38% of all deaths in men. In 2013, the World Health Organization published findings showing that arterial hypertension is responsible for at least 45% of cases of death due to heart disease and 51% cases of death due to stroke, and that every tenth person also has chronic kidney disease (CKD) (<xref ref-type="bibr" rid="r6"><italic>6</italic></xref>). The risk of development of CKD in women is higher than in men (14% vs. 12%) (<xref ref-type="bibr" rid="r7"><italic>7</italic></xref>). Chronic kidney disease affects approximately 195 million women worldwide and is the 8<sup>th</sup> leading cause of death in women annually, with 600 000 cases of death (<xref ref-type="bibr" rid="r8"><italic>8</italic></xref>). Female sex, arterial hypertension, advanced age, and obesity are characteristic for heart failure with preserved ejection fraction (HFpEF) (<xref ref-type="bibr" rid="r5"><italic>5</italic></xref>, <xref ref-type="bibr" rid="r9"><italic>9</italic></xref>). In everyday practice, patients with heart remodeling due to hypertension with atrial fibrillation are common and require adjustment of oral doses of anticoagulation medication depending on the level of CKD, with an increasing prevalence of women of advanced age among them (<xref ref-type="bibr" rid="r10"><italic>10</italic></xref>). Additionally, HFpEF is often inadequately recognized and managed, and it is associated with numerous comorbid states such as hypertension (60%-80%), ischemic heart disease (35%-70%), diabetes (20%-45%), and atrial fibrillation (15%-40%) (<xref ref-type="bibr" rid="r11"><italic>11</italic></xref>).</p>
<p>Consequently, there have been efforts to raise awareness of the association between CKD, cardiovascular morbidity and mortality, and the possibility of preventive measures recommended by various societies, such as the formation of the Council on Kidney in Cardiovascular Disease as part of the American Heart Association, which approaches the issues of kidney disease as a part of translational medicine with the goal of reducing cardiovascular risk.</p>
</sec>
<sec sec-type="other2">
<title>Obesity, kidney damage, and hypertensive disorders in women</title>
<p>The prevalence of obesity in Europe is between 4-28% in men and 6.2%-36.5% in women. It is incredible that obesity is more common in women than in men. The prevalence of obesity increased with age (25% of persons between 45 and 72 years of age are overweight). What is worrying is the high prevalence of obesity in younger age groups, especially in childhood (8.8%). It is a well-known fact that cardiovascular mortality and morbidity as well as association with uncontrolled hypertension is higher in obese patients (<xref ref-type="bibr" rid="r2"><italic>2</italic></xref>).</p>
<p>The specific characteristic of disorders related to obesity is the mechanism of insulin resistance and ectopic lipid accumulation, which contributes to organ damage in the context of metabolic diseases, indicating that kidney disease associated with obesity is really a state of lipodystrophy and aging process acceleration. The association between lipid-disordered metabolism, insulin resistance, and the activation of inflammatory processes leads to the development of glomerulopathy associated with obesity and heart and vascular remodeling (<xref ref-type="bibr" rid="r2"><italic>2</italic></xref>). Hypertensive disorders have been recognized as an important risk factor for CVD in women (<xref ref-type="bibr" rid="r12"><italic>12</italic></xref>).</p>
<p>It is important to differentiate between several specific states:</p>
<list id="L1" list-type="order"><list-item><p>Women receiving oral contraceptive therapy</p></list-item></list>
<p>Taking oral contraceptives is associated with a small but significant increase in blood pressure (BP) and hypertension in 5% of women receiving oral contraceptive therapy (especially at older ages) (<xref ref-type="bibr" rid="r13"><italic>13</italic></xref>). The incidence of myocardial infarction and ischemic stroke is low in the age group of women using oral contraceptives. Guidelines do not recommend the use of oral contraceptives in women who have uncontrolled hypertension, and the risk of developing hypertension is reduced with the cessation of oral contraceptives (<xref ref-type="bibr" rid="r14"><italic>14</italic></xref>).</p>
<list id="L2" list-type="order"><list-item><p>Women on hormone replacement therapy</p></list-item></list>
<p>There is a low probability of BP rise in menopausal hypertensive women receiving hormone replacement therapy (<xref ref-type="bibr" rid="r15"><italic>15</italic></xref>). Hormone replacement therapy and selective estrogen receptor modulators are not recommended for primary and secondary prevention of CVD.</p>
<list id="L3" list-type="order"><list-item><p>Specific characteristics in women and guidelines for hypertension in pregnancy</p></list-item></list>
<p>There are no specific guidelines for the treatment of arterial hypertension in women except in pregnancy. The ESH/ESC guidelines for the treatment of hypertension from 2013 recommend commencing antihypertensive treatment at BP values &gt;140/90 mmHg in women with gestational diabetes, preexisting hypertension with the manifestation of gestational diabetes, and in those with hypertension with asymptomatic organ damage or symptoms in any period of the pregnancy (<xref ref-type="bibr" rid="r14"><italic>14</italic></xref>). The choice of medication for the treatment of hypertension in pregnancy are methyldopa, labetalol, and nifedipine (long-acting). In emergencies such as severe preeclampsia, the medication of choice is the intravenous application of labetalol (<xref ref-type="bibr" rid="r14"><italic>14</italic></xref>). In women with preeclampsia, the risk of developing hypertension in older age is four times higher in comparison with women who did not have preeclampsia (<xref ref-type="bibr" rid="r16"><italic>16</italic></xref>). The newest literature lists preeclampsia as an early marker of CVD risk. Women who had preeclampsia have double the risk of developing ischemic heart disease, stroke, and thromboembolic diseases in a period of 5-15 years after pregnancy (<xref ref-type="bibr" rid="r17"><italic>17</italic></xref>). Complication associated with pregnancy also increase the risk of kidney disease. Preeclampsia, septic abortion, and inflammatory conditions such as acute or chronic pyelonephritis and autoimmune diseases such as lupus nephritis typically manifest in women and are the leading cause of acute kidney damage in women (<xref ref-type="bibr" rid="r4"><italic>4</italic></xref>).</p>
<list id="L4" list-type="order"><list-item><p>Chronic kidney disease in women</p></list-item></list>
<p>Chronic kidney disease, which is currently reaching increasingly pandemic proportions, is an additional risk factor for reduced fertility and unwanted outcomes in pregnancy, and women with CKD are at increased risk of poor outcomes due to greatly increased incidence of hypertension and preterm births (<xref ref-type="bibr" rid="r18"><italic>18</italic></xref>). The progression of CKD in women, in addition to numerous disorders of other bodily systems, also leads to menstruation disorders, infertility, and early menopause. Women with premature menopause are at higher risk of developing CKD (<xref ref-type="bibr" rid="r19"><italic>19</italic></xref>).</p>
</sec>
<sec sec-type="conclusions">
<title>Conclusion</title>
<p>It is important to note that women are far less represented in a number of cardiovascular studies, especially those related to guidelines (<xref ref-type="bibr" rid="r20"><italic>20</italic></xref>), which begs the question whether the existing guidelines are adequate for the treatment of women, or only for the treatment of men. Women die more often from CVD than men, and the risk of CKD in women is higher than in men. Even in the early stages, CKD has increased cardiovascular risk, and CVD is basically endothelial dysfunction with simultaneous changes in renal and coronary microcirculation. Further studies are needed to contribute to a better understanding of the unique characteristics related to female health, which have an additional influence on the safety and effectiveness of the treatment options being applied.</p>
</sec>
</body>
<back>
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