Aortic stenosis as the final phase of calcified aortic valve disease: The tip of the iceberg

de Diego, O.; Andrea, R.

doi:10.1016/j.rceng.2020.03.003

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Andrea" "autores" => array:2 [ 0 => array:2 [ "nombre" => "O." "apellidos" => "de Diego" ] 1 => array:4 [ "nombre" => "R." "apellidos" => "Andrea" "email" => array:1 [ 0 => "randrea@clinic.cat" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Instituto Clínico Cardiovascular, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estenosis aórtica como fase final de la enfermedad valvular aórtica calcificada: la punta del iceberg" ] ] "textoCompleto" => "Calcific aortic valve disease (CAVD) encompasses a wide range of aortic valve involvement. This includes initial phases with cellular involvement, without macroscopic changes, and evolves to progressive calcification of the leaflets without affecting valve functionality (aortic sclerosis), and up through the onset of aortic transvalvular flow obstruction (aortic stenosis).Aortic stenosis (AS) is the primary valvular heart disease that most often determines the need for surgery or catheter intervention.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In addition, according to current prevalence rates and demographic forecasts, the number of patients with AS >70 or >75 years of age could double or triple over the next 50 years in developed countries, as it is a disease with massive epidemiological relevance.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>It is understandable that severe AS attracts the majority of medical interest within the big picture of this disease. This illness directly produces multiple clinical manifestations (typically dyspnoea, angina and syncope, but also sudden death in some cases), as well as extracardiac manifestations (such as gastrointestinal bleeding due to angiodysplasia or Heyde’s syndrome, whose pathogenesis involves impaired platelet function and acquired von Willebrand factor depletion due to the shear stress on the blood as it passes though the stenotic valve).<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Nevertheless, patients with AS represent only 0.4% of the general population and 1.7% of the population >65 years. On the contrary, the prevalence of aortic sclerosis is estimated to be 25% of the population >65 years and almost 50% of the population >85 in developed countries.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>The current issue of Revista Clínica Española features a study by Gracia-Baena et al.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>, which aims to determine the association between different cardiovascular risk factors and comorbidities with severe symptomatic aortic stenosis. In the study, they select as case subjects patients >65 years of age referred to a tertiary referral centre for valve intervention assessment (n = 102) and, as controls, age-matched subjects ± five years and sex, without known AS and from the same health care area as the case subjects (n = 221).The applied logistic regression model determines the variables of age, high blood pressure, smoking, hypercholesterolemia, and low HDL levels to be factors associated with severe symptomatic AS. Regarding comorbidities, those associated with the disease are: history of cerebrovascular accident (CVA), carotid artery disease (CAD), history of chronic kidney disease (CKD) and low haemoglobin levels.These results coincide significantly with those obtained in previous studies.<a class="elsevierStyleCrossRefs" href="#bib0025">5-9</a>Factors that have been mentioned in the literature as associated with the risk of presenting with CAVD significantly overlap with those associated with atherosclerosis and include: age, male sex, high blood pressure, smoking, hypercholesterolemia, obesity, metabolic syndrome, diabetes, and high levels of lipoprotein (a).<a class="elsevierStyleCrossRefs" href="#bib0010">2,10</a>The current observational study describes an association between the history of CVA, CAD, and CKD and severe symptomatic AS. As the researchers point out, such associations are likely more justified because all these diseases share common risk factors and represent different manifestations of cardiovascular disease, rather than because there is a real causal association between them.On the other hand, the association found between severe symptomatic AS and anaemia deserves special attention. There are various mechanisms through which AS could cause anaemia, such as bleeding due to gastrointestinal angiodysplasias or impaired iron absorption due to heart failure and chronic disease; however, beyond being able to explain its presence in patients with severe AS, anaemia is a severity marker in these patients and determines a worse prognosis.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>This study confirms the results of others in the reference population and once again underscores the importance of cardiovascular risk factor control and the study of comorbidities for the development of cardiovascular disease. Nevertheless, as explained, severe symptomatic AS is just the tip of the iceberg of CAVD, a multifactorial disease that involves inflammation, lipoprotein infiltration, oxidation, local angiotensin II overexpression, and complex mineralisation and osteogenesis mechanisms with osteoblastic differentiation of valvular interstitial cells<a class="elsevierStyleCrossRefs" href="#bib0010">2,10</a>; and while this disease is often considered a dichotomy (severe AS/non-severe AS) from the clinical perspective due to the significant repercussion of end-stage CAVD, understanding it as a continuum broadens the possibilities for preventing and detecting it and slowing down its progression. Therefore, the fact that the Gracia-Baena<a class="elsevierStyleCrossRef" href="#bib0020">4</a> study establishes a comparison between patients with severe AS and patients for whom, while they did not have known AS, it was unknown whether they could have some degree of valvular sclerosis, this limits the comparison or extrapolation of the results to patients with a lower degree of CAVD.Currently, the investigative challenge that this disease presents has shifted to the genetic field, where various alterations related to CAVD have been determined and which would also contribute to explaining its heterogeneous geographic distribution.<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a> In terms of preventing disease development, after various studies have failed in their attempts to demonstrate the efficacy of statin therapy<a class="elsevierStyleCrossRef" href="#bib0070">14</a> to reduce the progression of CAVD, current lines of research include as treatment targets lipoprotein (a) and the renin-angiotensin system, among others.<a class="elsevierStyleCrossRefs" href="#bib0010">2,15,16</a>However, to date there is no effective treatment to prevent or reduce CAVD progression. Its diagnosis should be founded on clinical suspicion based on a detailed medical history, careful auscultation and subsequent confirmation via echocardiogram. Knowledge of CAVD risk factors could help clinicians by facilitating early detection and anticipating the diagnosis prior to the onset of symptoms resulting from severe AS to support intervention at the indicated time and thereby modify the prognosis." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: de Diego O, Andrea R. Estenosis aórtica como fase final de la enfermedad valvular aórtica calcificada: la punta del iceberg. 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as it is a disease with massive epidemiological relevance&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It is understandable that severe AS attracts the majority of medical interest within the big picture of this disease&#46; This illness directly produces multiple clinical manifestations &#40;typically dyspnoea&#44; angina and syncope&#44; but also sudden death in some cases&#41;&#44; as well as extracardiac manifestations &#40;such as gastrointestinal bleeding due to angiodysplasia or Heyde&#8217;s syndrome&#44; whose pathogenesis involves impaired platelet function and acquired von Willebrand factor depletion due to the shear stress on the blood as it passes though the stenotic valve&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Nevertheless&#44; patients with AS represent only 0&#46;4&#37; of the general population and 1&#46;7&#37; of the population &#62;65 years&#46; On the contrary&#44; the prevalence of aortic sclerosis is estimated to be 25&#37; of the population &#62;65 years and almost 50&#37; of the population &#62;85 in developed countries&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The current issue of <span class="elsevierStyleItalic">Revista Cl&#237;nica Espa&#241;ola</span> features a study by Gracia-Baena et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; which aims to determine the association between different cardiovascular risk factors and comorbidities with severe symptomatic aortic stenosis&#46; In the study&#44; they select as case subjects patients &#62;65 years of age referred to a tertiary referral centre for valve intervention assessment &#40;n&#8239;&#61;&#8239;102&#41; and&#44; as controls&#44; age-matched subjects&#8239;&#177;&#8239;five years and sex&#44; without known AS and from the same health care area as the case subjects &#40;n&#8239;&#61;&#8239;221&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The applied logistic regression model determines the variables of age&#44; high blood pressure&#44; smoking&#44; hypercholesterolemia&#44; and low HDL levels to be factors associated with severe symptomatic AS&#46; Regarding comorbidities&#44; those associated with the disease are&#58; history of cerebrovascular accident &#40;CVA&#41;&#44; carotid artery disease &#40;CAD&#41;&#44; history of chronic kidney disease &#40;CKD&#41; and low haemoglobin levels&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">These results coincide significantly with those obtained in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5-9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Factors that have been mentioned in the literature as associated with the risk of presenting with CAVD significantly overlap with those associated with atherosclerosis and include&#58; age&#44; male sex&#44; high blood pressure&#44; smoking&#44; hypercholesterolemia&#44; obesity&#44; metabolic syndrome&#44; diabetes&#44; and high levels of lipoprotein &#40;a&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The current observational study describes an association between the history of CVA&#44; CAD&#44; and CKD and severe symptomatic AS&#46; As the researchers point out&#44; such associations are likely more justified because all these diseases share common risk factors and represent different manifestations of cardiovascular disease&#44; rather than because there is a real causal association between them&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">On the other hand&#44; the association found between severe symptomatic AS and anaemia deserves special attention&#46; There are various mechanisms through which AS could cause anaemia&#44; such as bleeding due to gastrointestinal angiodysplasias or impaired iron absorption due to heart failure and chronic disease&#59; however&#44; beyond being able to explain its presence in patients with severe AS&#44; anaemia is a severity marker in these patients and determines a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">This study confirms the results of others in the reference population and once again underscores the importance of cardiovascular risk factor control and the study of comorbidities for the development of cardiovascular disease&#46; Nevertheless&#44; as explained&#44; severe symptomatic AS is just the tip of the iceberg of CAVD&#44; a multifactorial disease that involves inflammation&#44; lipoprotein infiltration&#44; oxidation&#44; local angiotensin II overexpression&#44; and complex mineralisation and osteogenesis mechanisms with osteoblastic differentiation of valvular interstitial cells<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10</span></a>&#59; and while this disease is often considered a dichotomy &#40;severe AS&#47;non-severe AS&#41; from the clinical perspective due to the significant repercussion of end-stage CAVD&#44; understanding it as a continuum broadens the possibilities for preventing and detecting it and slowing down its progression&#46; Therefore&#44; the fact that the Gracia-Baena<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> study establishes a comparison between patients with severe AS and patients for whom&#44; while they did not have known AS&#44; it was unknown whether they could have some degree of valvular sclerosis&#44; this limits the comparison or extrapolation of the results to patients with a lower degree of CAVD&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Currently&#44; the investigative challenge that this disease presents has shifted to the genetic field&#44; where various alterations related to CAVD have been determined and which would also contribute to explaining its heterogeneous geographic distribution&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a> In terms of preventing disease development&#44; after various studies have failed in their attempts to demonstrate the efficacy of statin therapy<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> to reduce the progression of CAVD&#44; current lines of research include as treatment targets lipoprotein &#40;a&#41; and the renin-angiotensin system&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;15&#44;16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">However&#44; to date there is no effective treatment to prevent or reduce CAVD progression&#46; Its diagnosis should be founded on clinical suspicion based on a detailed medical history&#44; careful auscultation and subsequent confirmation via echocardiogram&#46; Knowledge of CAVD risk factors could help clinicians by facilitating early detection and anticipating the diagnosis prior to the onset of symptoms resulting from severe AS to support intervention at the indicated time and thereby modify the prognosis&#46;</p></span>"
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