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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La insuficiencia card&#237;aca &#40;IC&#41; con fracci&#243;n de eyecci&#243;n preservada &#40;ICFEP&#41; es un s&#237;ndrome cl&#237;nico resultante del aumento de la resistencia al llenado del ventr&#237;culo izquierdo durante la di&#225;stole que da lugar a s&#237;ntomas congestivos<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a>&#46; Aunque el conocimiento de su fisiopatolog&#237;a se ha venido ampliando en los &#250;ltimos a&#241;os&#44; a&#250;n se desconocen muchos aspectos de la ICFEP&#44; como la utilidad de marcadores consistentes&#44; su patog&#233;nesis en poblaciones espec&#237;ficas o los tratamientos que demuestren beneficios en estos pacientes&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">La ICFEP se considera un proceso heterog&#233;neo con m&#250;ltiples fenotipos<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">2&#44;3</span></a>&#44; algunos de ellos relacionados con las comorbilidades subyacentes&#46; Entre estas comorbilidades&#44; la diabetes mellitus tipo<span class="elsevierStyleHsp" style=""></span>2 &#40;DM2&#41; es una de las m&#225;s importantes&#59; est&#225; presente en aproximadamente el 45&#37; de estos pacientes&#44; y esta prevalencia se incrementa en los casos de nuevo diagn&#243;stico de ICFEP<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">4</span></a>&#46; Adem&#225;s&#44; la presencia de DM2 se asocia a un incremento del riesgo de morbimortalidad en pacientes con ICFEP&#44; aunque en menor grado que en pacientes con IC y fracci&#243;n de eyecci&#243;n reducida &#40;ICFER&#41;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">5</span></a>&#46; Un problema a&#241;adido es que los pacientes con DM2 e ICFEP presentan a menudo otras comorbilidades&#44; como hipertensi&#243;n arterial&#44; dislipemia&#44; obesidad&#44; enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41; o fibrilaci&#243;n auricular&#44; que tambi&#233;n influyen en el pron&#243;stico<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a>&#46; Se est&#225; tratando de analizar en qu&#233; medida estas comorbilidades influyen en la ICFEP&#44; determinando c&#243;mo se agrupan dichas comorbilidades en diversos fenotipos sobre los que se podr&#237;a intervenir para conseguir una mejor&#237;a cl&#237;nica y pron&#243;stica de estos pacientes<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">2&#44;6&#44;7</span></a>&#46; Sin embargo&#44; las cohortes existentes de pacientes con ICFEP son escasas y la DM2 suele incluirse como una comorbilidad m&#225;s en los an&#225;lisis&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Nuestro objetivo en el presente estudio es describir los diversos fenotipos de comorbilidades asociadas&#44; tanto cardiovasculares como no cardiovasculares&#44; que pueden presentarse en los pacientes con ICFEP y DM2&#46; Nuestra hip&#243;tesis es que la ICFEP con DM2 es una entidad heterog&#233;nea en base a las comorbilidades acompa&#241;antes&#44; sobre la que se pueden establecer diversos conglomerados &#40;clusters&#41; de comorbilidades que sirvan de punto de partida para investigar y tratar de una forma m&#225;s precisa a estos pacientes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todos</span><p id="par0020" class="elsevierStylePara elsevierViewall">Los pacientes se reclutaron a partir del Registro Nacional de Insuficiencia Card&#237;aca &#40;RICA&#41;&#44; perteneciente al Grupo de Trabajo de Insuficiencia Card&#237;aca y Fibrilaci&#243;n Auricular de la Sociedad Espa&#241;ola de Medicina Interna &#40;SEMI&#41;&#46; Este registro es multic&#233;ntrico&#44; prospectivo y se mantiene activo desde el a&#241;o 2008&#46; Incluye&#44; de forma &#250;nica y consecutiva&#44; a pacientes mayores de 50<span class="elsevierStyleHsp" style=""></span>a&#241;os con diagn&#243;stico de IC al alta hospitalaria por IC descompensada o de nueva aparici&#243;n&#44; seg&#250;n las gu&#237;as europeas de Cardiolog&#237;a vigentes en cada momento<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a>&#46; Estos pacientes&#44; una vez incluidos&#44; son seguidos durante un a&#241;o&#46; El presente an&#225;lisis recoge los datos de pacientes incluidos desde mazo de 2008 hasta mayo de 2017&#46; En este tiempo se han publicado diversos an&#225;lisis surgidos desde el registro<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">9&#44;10</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">El protocolo del registro fue aprobado por el comit&#233; &#233;tico del Hospital Universitario Reina Sof&#237;a de C&#243;rdoba&#44; y todos los pacientes han de firmar un consentimiento informado previamente a su inclusi&#243;n en el registro&#46; Los datos se recogen a partir de una p&#225;gina web &#40;<a href="http://www.registrorica.org/">www&#46;registrorica&#46;org</a>&#41; que contiene la base de datos y a la que se accede a trav&#233;s de claves personalizadas&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">En el presente an&#225;lisis se incluyeron de manera exclusiva los pacientes con una fracci&#243;n de eyecci&#243;n del ventr&#237;culo izquierdo &#40;FEVI&#41; mayor o igual al 50&#37;&#44; excluyendo a los pacientes con IC secundaria a valvulopat&#237;as &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Se han utilizado datos procedentes de antecedentes personales&#44; de exploraci&#243;n f&#237;sica &#40;presi&#243;n arterial sist&#243;lica&#44; peso y talla&#41; y anal&#237;ticos &#40;hemoglobina&#44; estimaci&#243;n del filtrado glomerular &#91;eGFR&#93; por la f&#243;rmula MDRD&#44; hemoglobina glucosilada &#91;HbA1c&#93; y p&#233;ptidos natriur&#233;ticos&#41;&#46; La evaluaci&#243;n de la FEVI se realiz&#243; mediante ecocardiograma<span class="elsevierStyleHsp" style=""></span>2D&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">De la muestra total de pacientes con ICFEP se seleccionaron los pacientes con diagn&#243;stico de DM2&#44; bas&#225;ndose en los antecedentes del paciente o si este estaba tomando tratamiento con agentes antidiab&#233;ticos&#46; Se excluyeron del an&#225;lisis los pacientes que no tuvieran completas las variables a estudiar&#44; los que no completaron el seguimiento y los que fallecieron durante la hospitalizaci&#243;n&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Una vez obtenida la muestra final&#44; la poblaci&#243;n se subdividi&#243; en funci&#243;n del n&#250;mero de clusters de comorbilidad obtenidos en el an&#225;lisis estad&#237;stico&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">El objetivo primario del estudio fue describir las caracter&#237;sticas de cada cluster de comorbilidades y las diferencias existentes entre dichos clusters&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">An&#225;lisis estad&#237;stico</span><p id="par0050" class="elsevierStylePara elsevierViewall">Para la obtenci&#243;n de los clusters utilizamos el an&#225;lisis aglomerativo jer&#225;rquico con el m&#233;todo de Ward&#44; usando la funci&#243;n <span class="elsevierStyleItalic">hclust</span> del programa estad&#237;stico<span class="elsevierStyleHsp" style=""></span>R &#40;versi&#243;n 3&#46;5&#46;1&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a>&#46; Este estudio contempla el an&#225;lisis de pacientes que comparten caracter&#237;sticas similares basadas en las variables referidas&#44; que se van agrupando de forma puntual &#40;inicialmente habr&#237;a tantos grupos como individuos&#41;&#44; construyendo progresivamente una jerarqu&#237;a de los grupos&#44; en nuestro caso de una forma ascendente&#44; es decir&#44; cada observaci&#243;n comienza en su propio grupo y los pares de grupos son mezclados mientras uno sube en le jerarqu&#237;a&#46; Esto permite la construcci&#243;n de un &#225;rbol de clasificaci&#243;n &#40;dendrograma&#41;&#46; Las variables pre-especificadas para realizar el an&#225;lisis se han escogido en base a su disponibilidad en el registro&#44; a estudios previos y a la experiencia cl&#237;nica&#44; y fueron&#58; a&#41;<span class="elsevierStyleHsp" style=""></span>variables cualitativas dicot&#243;micas &#40;EPOC&#44; dislipemia&#44; hepatopat&#237;a y demencia&#41;&#44; a las que se adjudic&#243; el valor<span class="elsevierStyleHsp" style=""></span>1 cuando estaban presentes y 0 cuando estaban ausentes&#59; b&#41;<span class="elsevierStyleHsp" style=""></span>variables cualitativas no dicot&#243;micas&#44; como el ictus &#40;ausente<span class="elsevierStyleHsp" style=""></span>0&#44; accidente isqu&#233;mico transitorio &#91;AIT&#93;<span class="elsevierStyleHsp" style=""></span>1&#44; ictus hemorr&#225;gico<span class="elsevierStyleHsp" style=""></span>2&#44; ictus cardioemb&#243;lico<span class="elsevierStyleHsp" style=""></span>3&#44; ictus aterotromb&#243;tico<span class="elsevierStyleHsp" style=""></span>4&#41; y las arritmias &#40;ritmo sinusal<span class="elsevierStyleHsp" style=""></span>0&#44; flutter&#47;fibrilaci&#243;n auricular<span class="elsevierStyleHsp" style=""></span>1&#44; bloqueo auriculoventricular<span class="elsevierStyleHsp" style=""></span>2&#44; otras<span class="elsevierStyleHsp" style=""></span>3&#41;&#44; y c&#41;<span class="elsevierStyleHsp" style=""></span>variables cuantitativas &#40;presi&#243;n arterial sist&#243;lica&#44; &#237;ndice de masa corporal &#91;IMC&#93;&#44; eGFR y hemoglobina&#41;&#44; que se analizaron seg&#250;n su valor num&#233;rico&#46; Se construy&#243; inicialmente una matriz de &#40;di&#41;similaridad entre las observaciones mediante el m&#233;todo de Kendall usando la funci&#243;n <span class="elsevierStyleItalic">factoextra</span> de R&#44; dado que las variables no son param&#233;tricas&#44; siendo el nivel de color proporcional al valor de similaridad entre las observaciones&#58; si es rojo&#44; la distancia entre las variables es<span class="elsevierStyleHsp" style=""></span>0 &#40;alta similaridad&#41;&#59; si es verde&#44; la distancia es alta &#40;baja similaridad&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; Una vez obtenido el dendrograma&#44; para escoger los clusters m&#225;s adecuados se utilizaron t&#233;cnicas de remuestreo mediante bootstrap &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#41; con la funci&#243;n <span class="elsevierStyleItalic">pvclust</span> de R<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a>&#46; Para cada potencial cluster se calcul&#243; el valor de probabilidad del bootstrap &#40;<span class="elsevierStyleItalic">bootstrap probability</span> &#91;BP&#93;&#41;&#44; que se corresponde con la frecuencia con la que el mismo cluster es detectado en los diferentes remuestreos&#46; De la misma forma&#44; para cada cluster se calcularon los valores de probabilidad aproximada sin sesgos &#40;<span class="elsevierStyleItalic">approximately unbiased probability</span> &#91;AU&#93;&#41;&#46; Los clusters con un AU del 95&#37; se consideraron fuertemente respaldados por los datos&#46; Ha sido en base a los mayores valores posibles de BP y AU &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41; que se han escogido los cuatro grupos del presente estudio&#46; Una vez obtenidos los grupos y clasificados los pacientes seg&#250;n los mismos&#44; las variables cualitativas se expresaron mediante el n&#250;mero absoluto y porcentaje y se compararon mediante chi cuadrado&#46; Las variables cuantitativas se expresaron mediante su mediana y rango intercuart&#237;lico&#44; compar&#225;ndose mediante Kruskal-Wallis por ser variables no param&#233;tricas &#40;analizado con Saphiro-Wilk&#41;&#46; Un valor de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se consider&#243; significativo&#46; El an&#225;lisis se realiz&#243; igualmente con el programa<span class="elsevierStyleHsp" style=""></span>R &#40;versi&#243;n 3&#46;5&#46;1&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Resultados</span><p id="par0055" class="elsevierStylePara elsevierViewall">Un total de 1&#46;934 pacientes presentaban ICFEP&#44; de los cuales 907 &#40;46&#44;9&#37;&#41; ten&#237;an DM2 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; La edad media fue de 78&#44;5 &#40;7&#44;7&#41; a&#241;os&#44; con predominio del sexo femenino &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>552&#44; 60&#44;9&#37;&#41;&#46; La FEVI media fue de 61&#44;1 &#40;7&#44;9&#41; &#37; y el eGFR medio fue de 55&#44;6 &#40;26&#44;6&#41; ml&#47;min&#47;1&#44;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Las comorbilidades m&#225;s prevalentes fueron la dislipemia &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>601&#44; 66&#44;3&#37;&#41;&#44; la fibrilaci&#243;n auricular&#47;flutter &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>522&#44; 57&#44;5&#37;&#41; y la EPOC &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>217&#44; 23&#44;9&#37;&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">El dendrograma resultante del an&#225;lisis de clusters se muestra en la <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>B&#46; Se construyeron 4 clusters cuyas caracter&#237;sticas se muestran en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> y en la <a class="elsevierStyleCrossRef" href="#fig0020">figura 4</a>&#46; Como se puede observar&#44; el cluster n&#250;mero<span class="elsevierStyleHsp" style=""></span>1 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>201&#44; 22&#44;2&#37;&#41; inclu&#237;a a pacientes con elevado riesgo cardiovascular sin arritmia &#40;solo un 1&#37; presentaban fibrilaci&#243;n auricular&#47;flutter&#41;&#44; predominando las mujeres con presi&#243;n arterial sist&#243;lica &#40;PAS&#41; elevada&#44; dislipemia y un elevado porcentaje de ictus aterotromb&#243;ticos&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">El cluster n&#250;mero 2 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>303&#44; 33&#44;4&#37;&#41; inclu&#237;a pacientes de mayor edad&#44; igualmente con predominio del sexo femenino&#44; metab&#243;licamente m&#225;s sanos &#40;sin dislipemia y con PAS m&#225;s baja&#41; y con una tasa de fibrilaci&#243;n auricular&#47;flutter superior al 50&#37;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">El cluster n&#250;mero 3 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>140&#44; 15&#44;4&#37;&#41; inclu&#237;a pacientes mayoritariamente varones&#44; con EPOC&#44; dislipemia y hepatopat&#237;a&#46; Aunque la presencia de fibrilaci&#243;n auricular&#47;flutter fue del 58&#44;6&#37;&#44; este cluster registr&#243; la menor tasa de enfermedad cerebrovascular&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Por &#250;ltimo&#44; el cluster n&#250;mero 4 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>263&#44; 29&#44;0&#37;&#41; fue similar al n&#250;mero<span class="elsevierStyleHsp" style=""></span>1&#44; pero con mucha m&#225;s presencia de fibrilaci&#243;n auricular&#47;flutter &#40;93&#44;9&#37;&#41;&#44; de AIT &#40;7&#44;2&#37;&#41; y de ictus cardioemb&#243;licos &#40;3&#44;4&#37;&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Aunque no se encontraron diferencias significativas relacionadas respecto al IMC&#44; los clusters<span class="elsevierStyleHsp" style=""></span>1&#44; 3 y<span class="elsevierStyleHsp" style=""></span>4 inclu&#237;an pacientes obesos &#40;IMC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#44; mientras que el cluster<span class="elsevierStyleHsp" style=""></span>2 inclu&#237;a a pacientes con sobrepeso &#40;IMC entre 25 y 30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discusi&#243;n</span><p id="par0085" class="elsevierStylePara elsevierViewall">Atendiendo a nuestros resultados&#44; definimos cuatro clusters de pacientes con ICFEP y DM2&#44; en base a las comorbilidades asociadas&#46; Existen dos grupos de pacientes &#40;clusters<span class="elsevierStyleHsp" style=""></span>1 y<span class="elsevierStyleHsp" style=""></span>4&#41;&#44; con predominio del sexo femenino&#44; donde predominaban los factores de riesgo vascular&#44; que se diferenciaban entre ellos por la presencia o ausencia de fibrilaci&#243;n&#47;flutter auricular&#46; En un tercer grupo &#40;cluster<span class="elsevierStyleHsp" style=""></span>3&#41;&#44; de predominio masculino&#44; predomin&#243; la enfermedad respiratoria y la afectaci&#243;n hep&#225;tica&#46; Un &#250;ltimo grupo &#40;cluster<span class="elsevierStyleHsp" style=""></span>2&#41; englob&#243; a pacientes de mayor edad&#44; predominantemente mujeres&#44; con una elevada proporci&#243;n de fibrilaci&#243;n&#47;flutter auricular&#46; Un hecho com&#250;n a todos los grupos fue la presencia de sobrepeso u obesidad&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">La identificaci&#243;n de fenotipos de ICFEP y DM2 con diferentes clusters de comorbilidad permitir&#237;a valorar la pertinencia de abordajes diferenciados en estos grupos concretos de pacientes&#44; en aras de obtener un mayor beneficio terap&#233;utico&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Trat&#225;ndose de pacientes con DM2 e IC&#44; la primera opci&#243;n que emerge como tratamiento son los inhibidores del cotransportador SGLT2 &#40;SGLT2i&#41;&#46; Esta familia de f&#225;rmacos ha demostrado reducci&#243;n de la morbimortalidad cardiovascular&#44; con una marcada disminuci&#243;n de las hospitalizaciones por IC y protecci&#243;n renal en pacientes con DM2 de alto riesgo cardiovascular<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a>&#46; Actualmente est&#225;n en marcha ensayos cl&#237;nicos espec&#237;ficos con SGLT2i en pacientes con ICFEP&#46; Aunque las hip&#243;tesis sobre los mecanismos por los que los SGLT2i ejercen su beneficio cardiorrenal permanecen abiertas&#44; se ha propuesto que la mayor disponibilidad de cuerpos cet&#243;nicos utilizables por el coraz&#243;n<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> y su acci&#243;n sobre el intercambiador Na&#47;H&#44; que reducir&#237;a el Na citoplasm&#225;tico y conllevar&#237;a una vasodilataci&#243;n coronaria<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a>&#44; podr&#237;an ser mecanismos implicados&#46; Adem&#225;s&#44; en pacientes con ICFEP los SGLT2i han mostrado tener efectos beneficiosos sobre la funci&#243;n diast&#243;lica y la masa ventricular izquierda<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">16&#44;17</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Por otra parte&#44; respecto a los clusters 1&#44; 3 y<span class="elsevierStyleHsp" style=""></span>4&#44; en los que la obesidad es un denominador com&#250;n&#44; se podr&#237;a plantear la posibilidad de incluir en el tratamiento antidiab&#233;tico un an&#225;logo del receptor del glucag&#243;n-like p&#233;ptido-1 &#40;GLP-1ra&#41;&#46; Estos f&#225;rmacos&#44; adem&#225;s de reducir el peso corporal&#44; han demostrado beneficios a nivel cardiovascular &#40;lo que los har&#237;a recomendables en los clusters<span class="elsevierStyleHsp" style=""></span>1 y<span class="elsevierStyleHsp" style=""></span>4&#41;&#44; y adem&#225;s podr&#237;an ejercer un efecto positivo sobre la enfermedad pulmonar en los pacientes del cluster<span class="elsevierStyleHsp" style=""></span>3&#44; tal como se ha demostrado en modelos animales<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a>&#46; En los ensayos cl&#237;nicos de seguridad cardiovascular los GLP-1ra han mostrado un efecto neutro sobre la IC<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#44;20</span></a>&#44; pero sus efectos sobre el remodelado ventricular&#44; la rigidez arterial y el estr&#233;s oxidativo<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> los hace potencialmente &#250;tiles en el tratamiento de la ICFEP&#46; Aunque en el estudio LIVE&#44; realizado en pacientes con ICFER&#44; con y sin diabetes&#44; el tratamiento con liraglutida&#44; en comparaci&#243;n con placebo&#44; no mostr&#243; beneficios cl&#237;nicos y s&#237; una mayor tendencia a efectos adversos cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a>&#44; en este mismo ensayo se mostr&#243; un descenso significativo en el ratio E&#47;e&#8217; que confirmar&#237;a esta posible utilidad en el caso de la ICFEP&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Los inhibidores de la enzima DPP-4 &#40;iDPP-4&#41; han mostrado efectos dispares sobre la IC&#46; Mientras que sitagliptina y linagliptina en sus respectivos ensayos cl&#237;nicos de seguridad vascular demostraron ser neutros<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">23&#44;24</span></a>&#44; saxagliptina increment&#243; significativamente el riesgo de hospitalizaciones por IC<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">25</span></a>&#44; mientras que alogliptina mostr&#243; un incremento no significativo<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">26</span></a>&#46; Vildagliptina en el estudio VIVIDD<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a> no mostr&#243; modificaciones en la FEVI&#44; aunque se objetivaron incrementos significativos de los vol&#250;menes telediast&#243;lico y sist&#243;lico del ventr&#237;culo izquierdo&#46; Por otra parte&#44; sitagliptina ha mostrado atenuar el empeoramiento de la disfunci&#243;n diast&#243;lica &#40;ratio E&#47;e&#8217;&#41; en pacientes con DM2<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">28</span></a>&#46; Los iDPP-4 ofrecen una buena seguridad en poblaciones m&#225;s ancianas<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">29</span></a>&#44; lo que favorecer&#237;a su uso en el cluster<span class="elsevierStyleHsp" style=""></span>2&#44; que contiene a los pacientes de m&#225;s edad&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Aparte del abordaje de la DM2&#44; estos clusters ofrecen otras oportunidades de personalizaci&#243;n del tratamiento de los pacientes con ICFEP&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Aunque las estatinas son los f&#225;rmacos de elecci&#243;n para el tratamiento de la dislipemia en pacientes con DM2<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">30</span></a>&#44; su papel en la IC resulta controvertido&#46; La inhibici&#243;n de la coenzima Q<span class="elsevierStyleInf">10</span>&#44; el d&#233;ficit de selenio y el aumento de la calcificaci&#243;n arterial son algunos de los posibles mecanismos que podr&#237;an empeorar la IC<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">31</span></a>&#46; En los pacientes de los clusters<span class="elsevierStyleHsp" style=""></span>1 y<span class="elsevierStyleHsp" style=""></span>4&#44; en los que la dislipemia es altamente prevalente&#44; se podr&#237;a considerar el uso de otros f&#225;rmacos hipolipemiantes &#40;ezetimiba o inhibidores de PCSK9&#41; sin esos potenciales efectos adversos&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Por otro lado&#44; se sabe que la frecuencia card&#237;aca elevada es perjudicial para los pacientes con ICFEP en ritmo sinusal<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a>&#46; Sin embargo&#44; existe controversia sobre la eficacia de los betabloqueantes en la ICFEP&#44; independientemente del ritmo cardiaco &#40;sinusal o fibrilaci&#243;n auricular&#41;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a>&#46; Ivabradina&#44; en un ensayo cl&#237;nico en el que el 75&#37; de los pacientes ten&#237;an adem&#225;s betabloqueantes&#44; demostr&#243; mejorar el control de la frecuencia card&#237;aca en pacientes con ICFEP&#44; sin modificar el patr&#243;n diast&#243;lico &#40;E&#47;e&#8217;&#41; ni el test de la marcha de seis minutos a los 8<span class="elsevierStyleHsp" style=""></span>meses de tratamiento<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a>&#46; En un estudio previo&#44; con un menor porcentaje de pacientes con betabloqueantes y un seguimiento m&#225;s corto&#44; ivabradina demostr&#243; mejorar la capacidad de ejercicio y disminuir las presiones de llenado del ventr&#237;culo izquierdo inducidas por ejercicio en pacientes con ICFEP<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">35</span></a>&#46; Por ello&#44; podr&#237;a considerarse un tratamiento preferente de la ivabradina en el cluster<span class="elsevierStyleHsp" style=""></span>3&#44; donde los betabloqueantes podr&#237;an perjudicar la evoluci&#243;n de la EPOC&#46; En este mismo cluster&#44; y en pacientes con fibrilaci&#243;n auricular&#44; se podr&#237;a asimismo valorar la utilidad del diltiazem&#44; que ha demostrado aumentar el volumen telediast&#243;lico en pacientes con miocardiopat&#237;a hipertr&#243;fica<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">El presente estudio tiene&#44; no obstante&#44; algunas limitaciones&#46; Los pacientes incluidos pueden no ajustarse a la definici&#243;n actual de ICFEP&#44; dado que algunos fueron incluidos previamente a la publicaci&#243;n de los actuales criterios diagn&#243;sticos&#44; y por tanto no todos los pacientes disponen de medidas concretas en el ecocardiograma ni de p&#233;ptidos natriur&#233;ticos&#46; No hemos incluido en el an&#225;lisis algunas comorbilidades discordantes de la DM2 &#40;p&#46;ej&#46;&#44; depresi&#243;n&#41; que pueden tener un impacto cl&#237;nico significativo<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a>&#46; Al tratarse de un estudio transversal&#44; no se ha analizado la evoluci&#243;n y las caracter&#237;sticas pron&#243;sticas de cada cluster&#46; Por &#250;ltimo&#44; se trata de un estudio de cohortes&#44; que puede estar sujeto a diferentes sesgos de selecci&#243;n o de aleatorizaci&#243;n&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; el presente an&#225;lisis describe diferentes grupos de pacientes con ICFEP en funci&#243;n de sus comorbilidades&#44; pudiendo ser un punto de partida para futuras investigaciones que ayuden a definir con mayor precisi&#243;n los diferentes clusters de comorbilidad y permitan realizar un abordaje terap&#233;utico m&#225;s integrador y personalizado que mejore el pron&#243;stico de estos pacientes&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicto de intereses</span><p id="par0135" class="elsevierStylePara elsevierViewall">Los autores declaran que no existe conflicto de intereses&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes y objetivos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La heterogeneidad de los pacientes con insuficiencia card&#237;aca y fracci&#243;n de eyecci&#243;n preservada &#40;ICFEP&#41; es elevada&#44; por lo que se tiende a agrupar en fenotipos para intervenir con precisi&#243;n&#46; Dentro de estos&#44; los pacientes con diabetes mellitus &#40;DM&#41; mantienen esta heterogeneidad&#46; Nuestro objetivo es describir grupos de pacientes con ICFEP y DM basados en otras comorbilidades&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los pacientes se reclutan desde el registro nacional de insuficiencia card&#237;aca &#40;RICA&#41;&#46; Se incluyen pacientes con fracci&#243;n de eyecci&#243;n mayor o igual al 50&#37; sin valvulopat&#237;a y con DM&#46; Se realiza un an&#225;lisis aglomerativo jer&#225;rquico con el m&#233;todo de Ward incluyendo las siguientes variables&#58; dislipemia&#44; hepatopat&#237;a&#44; EPOC&#44; demencia&#44; enfermedad cerebrovascular&#44; arritmia&#44; presi&#243;n arterial sist&#243;lica&#44; &#237;ndice de masa corporal &#40;IMC&#41;&#44; estimaci&#243;n del filtrado glomerular y hemoglobina&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se incluyen 1&#46;934 pacientes con ICFEP&#44; de los que 907 &#40;46&#44;9&#37;&#41; ten&#237;an DM&#44; con predominio de mujeres &#40;60&#44;9&#37;&#41; y con un IMC de 31&#44;1 &#40;5&#44;9&#41; kg&#47;m<span class="elsevierStyleSup">2</span>&#46; Se obtienen 4 grupos&#58; dos con elevado riesgo vascular &#40;uno con arritmia y otro no&#41;&#44; con 263 pacientes el primero y 201 el segundo&#44; otro con predominio de EPOC &#40;140 pacientes&#41; y un &#250;ltimo grupo de 303 pacientes con m&#225;s edad pero menos comorbilidad&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">En nuestros pacientes con ICFEP y DM predomina la obesidad y el sexo femenino&#46; Los cuatro grupos ofrecen oportunidades de tratamiento para mejorar su pron&#243;stico no solo basadas en la utilizaci&#243;n de nuevos f&#225;rmacos antidiab&#233;ticos sino por otras opciones que pueden suponer un punto de partida para nuevas investigaciones&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aim</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">The heterogeneity of patients with heart failure and preserved ejection fraction &#40;HFpEF&#41; is high&#44; thusthis entity tends to be grouped into phenotypes to act with precision&#46; Within these groups&#44; patients with type 2 diabetes mellitus &#40;T2DM&#41; hold this heterogeneity&#46; Our aim is to describe subgroups of patients with HFpEF and T2DM based on other comorbidities&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and Methods</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Patients were recruited from the national registry of heart failure &#40;RCIA&#41;&#46; Patients with ejection fraction greater than or equal to 50&#37; without valvular disease and with T2DM were included&#46; A hierarchical agglomerative analysis was performed with Ward&#39;s method including the following variables&#58; dyslipidemia&#44; liver disease&#44; Chronic obstructive pulmonary disease &#40;COPD&#41;&#44; dementia&#44; cerebrovascular disease&#44; arrhythmia&#44; systolic blood pressure&#44; body mass index &#40;BMI&#41;&#44; estimation of glomerular filtration and hemoglobin&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">1934 patients with ICFEP were included&#44; of which 907 &#40;46&#46;9&#37;&#41; had T2DM with a predominance of women &#40;60&#46;9&#37;&#41; and with a BMI of 31&#46;1 &#40;5&#46;9&#41; Kg &#47; m2&#46; Four groups were obtained&#44; two with high vascular risk &#40;one with arrhythmia and the other without it&#41; with 263 patients the first and 201 the second&#46; A third group had a predominance of COPD &#40;140 patients&#41; and a last group with 303 patients older but with less comorbidity&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">In our patients with ICFEP and T2DM&#44; obesity and female sex predominated&#46; All four groups offered treatment chances to improve their prognosis not only based on the use of new antidiabetic drugs but also on other options that may be a starting point for further research&#46;</p></span>"
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          0 => array:4 [
            "apendice" => "<p id="par0145" class="elsevierStylePara elsevierViewall">&#193;lvarez Rocha P&#46;&#44; Anarte L&#46;&#44; Ar&#233;valo-Lorido J&#46;C&#46;&#44; Cabanes Hern&#225;ndez Y&#46;&#44; Carrascosa S&#46;&#44; Carretero G&#243;mez J&#46;&#44; Cepeda J&#46;M&#46;&#44; Conde-Martel A&#46;&#44; D&#225;vila Ramos M&#46;F&#46;&#44; D&#237;az de Castellv&#237; S&#46;&#44; Epelde F&#46;&#44; Formiga F&#46;&#44; Garc&#237;a Escriv&#225; D&#46;&#44; G&#243;mez Huelgas R&#46;&#44; Gonz&#225;lez Franco A&#46;&#44; Josa Laorden C&#46;&#44; Le&#243;n A&#46;&#44; Ll&#224;cer P&#46;&#44; L&#243;pez-Castellanos G&#46;&#44; Lorente Furi&#243; O&#46;&#44; Manzano L&#46;&#44; Mart&#237;nez Fern&#225;ndez R&#46;&#44; Montero-P&#233;rez-Barquero M&#46;&#44; Ormaechea G&#46;&#44; P&#233;rez-Silvestre J&#46;&#44; Quir&#243;s L&#243;pez R&#46;&#44; Rodr&#237;guez &#193;vila E&#46;E&#46;&#44; Romero Requena J&#46;M&#46;&#44; Rubio Gracia J&#46;&#44; Rugeles Ni&#241;o J&#46;P&#46;&#44; Ruiz Laiglesia F&#46;&#44; Ruiz Ortega R&#46;&#44; Salamanca Bautista M&#46;P&#46;&#44; Serrado Iglesias A&#46;&#44; Soler Rangel M&#46;L&#46;&#44; Su&#225;rez-Pedreira I&#46;&#44; Trull&#224;s J&#46;C&#46;</p>"
            "etiqueta" => "Anexo"
            "titulo" => "Miembros del Registro RICA"
            "identificador" => "sec0035"
          ]
        ]
      ]
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          "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Dendrograma resultante del an&#225;lisis aglomerativo jer&#225;rquico&#46; A&#41;<span class="elsevierStyleHsp" style=""></span>Dendrograma esquematizado resultante&#44; con los grados de significaci&#243;n por comorbilidades&#46; En verde&#44; BP <span class="elsevierStyleItalic">&#40;bootstrap probability&#41;</span>&#59; en rojo&#44; AU <span class="elsevierStyleItalic">&#40;approximately unbiased probability&#41;</span>&#46; B&#41;<span class="elsevierStyleHsp" style=""></span>Dendrograma resultante del an&#225;lisis&#46; En colores se marcan los cluster escogidos&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">eGFR&#58; estimaci&#243;n del filtrado glomerular&#59; HB&#58; hemoglobina&#59; IMC&#58; &#237;ndice de masa corporal&#59; PAS&#58; presi&#243;n arterial sist&#243;lica&#46;</p>"
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        "etiqueta" => "Figura 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Esquema descriptivo de los clusters resultantes&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">AIT&#58; accidente isqu&#233;mico transitorio&#59; Bloqueo AV&#58; bloqueo auriculoventricular&#59; eGFR&#58; estimaci&#243;n por la f&#243;rmula MDRD del filtrado glomerular&#59; EPOC&#58; enfermedad pulmonar obstructiva cr&#243;nica&#59; FA&#47;flutter&#58; fibrilaci&#243;n o flutter auricular&#59; FEVI&#58; fracci&#243;n de eyecci&#243;n del ventr&#237;culo izquierdo&#59; HbA1c&#58; hemoglobina glucosilada&#59; IMC&#58; &#237;ndice de masa corporal&#59; NT-ProBNP&#58; prohormona N-terminal del p&#233;ptido natriur&#233;tico cerebral&#59; PAS&#58; presi&#243;n arterial sist&#243;lica&#46;</p>"
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hemorr&#225;gico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;0&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cardioemb&#243;lico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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