Original Article
Procollagen type III amino terminal peptide and myocardial fibrosis: A study in hypertensive patients with and without left ventricular hypertrophy
Concentração sérica de procolágeno tipo III e fibrose miocárdica - Estudo em doentes hipertensos com e sem hipertrofia ventricular esquerda
Carlos dos Santos Moreiraa,
, Fátima Serejob, Paula Alcântaraa, Vítor Ramalhinhoa, J. Braz Nogueiraa
Corresponding author
a Cadeira de Medicina I/Faculdade de Medicina de Lisboa, Serviço de Medicina I – Centro Hospitalar Lisboa Norte – Hospital S. Maria, Lisboa, Portugal
b Cadeira de Medicina II/Faculdade de Medicina de Lisboa, Serviço de Medicina II – Centro Hospitalar Lisboa Norte – Hospital S. Maria, Lisboa, Portugal
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A realidade nacional" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1028 "Ancho" => 3132 "Tamanyo" => 134858 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival curves for mortality in the three groups over a one-year follow-up according to GRACE score risk categories.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Davide Moreira, Bruno Marmelo, Anne Delgado, Luís Nunes, João Pipa, Oliveira Santos" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Davide" "apellidos" => "Moreira" ] 1 => array:2 [ "nombre" => "Bruno" "apellidos" => "Marmelo" ] 2 => array:2 [ "nombre" => "Anne" "apellidos" => "Delgado" ] 3 => array:2 [ "nombre" => "Luís" "apellidos" => "Nunes" ] 4 => array:2 [ "nombre" => "João" "apellidos" => "Pipa" ] 5 => array:2 [ "nombre" => "Oliveira" "apellidos" => "Santos" ] 6 => array:1 [ "colaborador" => "on behalf of researchers from the National Registry of Acute Coronary Syndromes" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S0870255115000360" "doi" => "10.1016/j.repc.2014.10.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255115000360?idApp=UINPBA00004E" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204915000732?idApp=UINPBA00004E" "url" => "/21742049/0000003400000005/v1_201506091454/S2174204915000732/v1_201506091454/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Procollagen type III amino terminal peptide and myocardial fibrosis: A study in hypertensive patients with and without left ventricular hypertrophy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "309" "paginaFinal" => "314" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carlos dos Santos Moreira, Fátima Serejo, Paula Alcântara, Vítor Ramalhinho, J. Braz Nogueira" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Carlos" "apellidos" => "dos Santos Moreira" "email" => array:1 [ 0 => "csmoreira2012@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Fátima" "apellidos" => "Serejo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Paula" "apellidos" => "Alcântara" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Vítor" "apellidos" => "Ramalhinho" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "J." "apellidos" => "Braz Nogueira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Cadeira de Medicina I/Faculdade de Medicina de Lisboa, Serviço de Medicina I – Centro Hospitalar Lisboa Norte – Hospital S. Maria, Lisboa, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Cadeira de Medicina II/Faculdade de Medicina de Lisboa, Serviço de Medicina II – Centro Hospitalar Lisboa Norte – Hospital S. Maria, Lisboa, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Concentração sérica de procolágeno tipo III e fibrose miocárdica - Estudo em doentes hipertensos com e sem hipertrofia ventricular esquerda" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 776 "Ancho" => 1000 "Tamanyo" => 65784 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Scatterplot shows inverse correlation between serum concentrations of procollagen type III amino terminal peptide (PIIIP) and the ratio between maximal early late transmitral flow velocity measured during diastole (V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span>) all patients.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The myocardium contains types I and III collagen as major fibrillar collagens. These collagens are constantly synthesized and secreted as procollagens in the interstitial space. Increased collagen turnover has been associated with myocardial fibrosis and plays an important role in determining the functional properties of the arterial vasculature and ventricular myocardium. An exaggerated accumulation of type I and type III fibrillar collagens occurs throughout the free wall and interventricular septum of patients with primary hypertension<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">1,2</span></a> and left ventricular (LV) hypertrophy (LVH).<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Types I and III collagen are synthesized as procollagens with a small amino terminal and a larger carboxy terminal propeptide. Once secreted into the extracellular space, the propeptides are removed by specific endopeptidases, thus allowing integration of the rigid collagen triple helix into the growing fibril.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">4</span></a> The three-amino acid procollagen type III amino terminal peptide (PIIIP) formed during this process is released into the blood. The serum concentration of PIIIP has been proposed as a useful marker of type III collagen synthesis.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">5</span></a> This is supported by a variety of clinical observations demonstrating that high serum levels of the peptide reflect on-going tissue fibrosis.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">6</span></a> Other authors have shown that serum PIIIP concentration is abnormally increased in a small group of patients with essential hypertension,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">7</span></a> thus suggesting that type III collagen turnover is also increased in this condition.</p><p id="par0015" class="elsevierStylePara elsevierViewall">It has been proposed that the excess of myocardial collagen seen in hypertension is the result of both increased collagen synthesis and unchanged or decreased collagen degradation. The development of LVH depends not only on the renin-angiotensin system generating angiotensin II,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">8</span></a> but also on mechanical stress, which activates the protein kinase cascade of phosphorylation in cardiac myocytes.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In the present study serum PIIIP concentration was measured to assess more accurately the intensity of the fibrogenic process in patients with essential hypertension. In addition, the relation between serum PIIIP concentrations and various parameters of LV anatomy and function were analyzed to determine the value of this peptide as a potential marker of ventricular fibrosis in hypertensive patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study population consisted of patients with never-treated mild to moderate essential hypertension and 30 normotensive control subjects. All subjects gave their informed consent and the local human research ethics committee approved the study protocol.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Blood pressure was measured in the morning, after 10 min in the supine position, using a mercury column sphygmomanometer. Phases I and V of the Korotkoff sounds were used; three measurements were obtained on each occasion, at 5-min intervals, and averaged. Hypertension was defined as present if systolic and diastolic blood pressure were ≥140 and 90 mmHg, respectively. All patients underwent appropriate clinical and laboratory assessment to exclude hypertension secondary to the following: renal disorders, renal artery abnormalities, adrenocortical disorders, pheochromocytoma, and iatrogenic causes. Conditions associated with elevated serum PIIIP concentrations (chronic liver disease, pulmonary fibrosis, rheumatoid arthritis, extensive wounds and acute myocardial infarction) were excluded after complete medical examination. We also excluded patients with overt coronary artery disease or other organic heart disease as shown by clinical, ECG, and echocardiographic criteria. None of the women were pregnant or taking oral contraceptives. The control group consisted of 30 subjects with blood pressure <140/90 mmHg in repeated measurements, referred to our center for suspected hypertension. None of the control subjects had echocardiographic evidence of cardiac disturbances.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Echocardiographic study</span><p id="par0035" class="elsevierStylePara elsevierViewall">Two-dimensional, targeted M-mode and Doppler ultrasound recordings were obtained in each patient. M-mode measurements were taken according to the guidelines laid down by the American Society of Echocardiography.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> LV mass was calculated using the formula validated by Devereux and Reichek.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a> LV mass index (LVMI) was obtained by dividing LV mass by body surface area. Relative wall thickness (RWT) was measured at end-diastole as 2×(posterior wall thickness/internal dimensions). The presence of LVH was established either when LVMI was >111 g/m<span class="elsevierStyleSup">2</span> for men and >106 g/m<span class="elsevierStyleSup">2</span> for women or when RWT was >0.44.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">12</span></a> LV fractional shortening and ejection fraction were calculated according to Quinones et al.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">13</span></a> The following pulsed Doppler measurements were obtained: maximal early transmitral velocity in diastole (V<span class="elsevierStyleInf">E</span>) and maximal late transmitral velocity in diastole (V<span class="elsevierStyleInf">A</span>). A diagnosis of diastolic dysfunction was established when the V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio was <1.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Biochemical measurements</span><p id="par0040" class="elsevierStylePara elsevierViewall">The general biochemical assessment included plasma glucose concentration and serum lipid profile and measurement of serum potassium and serum and urine creatinine. Blood samples were drawn in a fasting state. Biochemical parameters were measured by routine laboratory methods. Renal creatinine clearance was calculated as the product of urine flow rate and urine creatinine concentration divided by serum creatinine concentration.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Serum samples to determine PIIIP and procollagen type I amino terminal peptide (PIP) were taken at the time of the clinical studies and stored at −40<span class="elsevierStyleHsp" style=""></span>°C for up to six months. The six-month follow-up samples were analyzed together with samples from the initial setup. No changes were observed in samples analyzed twice.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Serum PIIIP was determined by a coated-tube radioimmunoassay as previously described by Risteli et al.,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> using commercial antisera specifically directed against the terminal amino terminal peptide (RIA-gnost Procollagen-III-Peptide, Behringwerke, Marburg, Germany). The inter- and intra-assay variations for determining PIIIP were both <10%. The sensitivity (lower detection limit) was 1.5 ng PIIIP/ml.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Values are expressed as mean ± SEM. The one-way ANOVA test was used to assess the statistical significance of differences between control subjects and patients with and without LVH. The correlation between continuously distributed variables was tested by univariate regression analysis. A two-tailed p value of <0.05 was considered significant.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0060" class="elsevierStylePara elsevierViewall">Baseline demographic, biochemical, ambulatory blood pressure monitoring, and echocardiographic parameters are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. As expected, blood pressure levels were higher in hypertensive patients, especially those with LVH, than in normotensive patients.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Values are expressed as mean (range), mean ± SEM, or number of subjects.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Heart rate and body mass index were higher in hypertensive patients compared with normotensive patients. No other differences in clinical and biochemical parameters were found between the three groups.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Posterior wall thickness was increased in hypertensive patients compared with normotensive controls, and calculated LV mass and LVMI were also increased in the hypertensive groups, particularly in those with LVH. The V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio was lower in the hypertensive patients, particularly in those with LVH, than in normotensive controls. Parameters of systolic function were within normal limits in all patients studied.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Considering all patients in the model, it can be seen that there is an inverse correlation between PIIIP and the V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>) and a direct correlation between serum PIIIP concentrations and LVMI (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Like other authors,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> we found increased serum PIIIP concentrations in patients with essential hypertension.</p><p id="par0090" class="elsevierStylePara elsevierViewall">PIIIP, like PIP,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a> is eliminated from the blood by the liver. Considering that none of the patients studied showed impaired liver function, it could be assumed that the elevated serum PIIIP concentrations in hypertensive patients represent increased production of the peptide in the hypertensive heart, related to LVH. The half-life of collagen in hypertrophic myocardium is 17 days, compared to 80–120 days in normal myocardium. Furthermore, fibroblast proliferation may also contribute to increased collagen synthesis. This remodeling of collagen structure has been reported in hypertension,<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">17,18</span></a> heart failure,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a> stunned myocardium<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">20</span></a> and myocardial infarction. In the present study, hypertensive patients with liver disease, lung disease, and diabetes were excluded because these conditions are also causes of elevated PIIIP.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Although serum PIIIP has been proposed as a useful marker of fibrogenesis,<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">5,21</span></a> it should be noted that this peptide is not completely removed from its procollagen precursor during the extracellular processing of type III collagen.<span class="elsevierStyleSup">24</span></p><p id="par0100" class="elsevierStylePara elsevierViewall">Serum PIIIP concentrations in hypertensive patients with LVH in this study were increased relative to the normal serum range of 0.25–0.7 U/ml and to patients without LVH. This finding was expected, since in vivo studies have shown that chronic elevation of circulating angiotensin II or aldosterone cause myocardial accumulation of fibrillar collagen. In vitro, effector hormones of the renin-angiotensin-aldosterone system have been shown to directly enhance collagen synthesis in rat fibroblasts. This may be of particular interest to explain the increased synthesis of type III collagen, since a direct correlation has been reported<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a> between serum PIIIP and plasma renin activity in hypertensive patients.</p><p id="par0105" class="elsevierStylePara elsevierViewall">A variety of experimental and clinical findings indicate that cardiac collagen accumulation adversely influences diastolic relaxation and LV stiffness. We found that serum PIIIP concentrations are inversely correlated with the V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio, suggesting that myocardial accumulation of type III collagen plays a role in diastolic dysfunction in patients with essential hypertension.</p><p id="par0110" class="elsevierStylePara elsevierViewall">The findings presented here show an increase in serum PIIIP concentrations in patients with essential hypertension, which may be a marker of increased type III collagen in these patients. On the other hand, the relation observed between serum PIIIP and parameters of LV mass and diastolic function lead us to propose that circulating procollagen-derived peptides may reflect ongoing myocardial fibrosis in essential hypertension.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The correlations found demonstrate that in LVH there is collagen deposition and that this deposition is related to LV diastolic function and LVMI.</p><p id="par0120" class="elsevierStylePara elsevierViewall">To summarize, an increase in serum PIIIP concentration indicates that type III collagen synthesis increases in hypertensive patients, particularly in those with LVE. Therefore, alterations in the heart in hypertension are the result not solely of hypertrophied LV muscle, but also of increased collagen deposition within the ventricular wall and around the coronary vessels. The results of these hemodynamic and structural LV alterations are usually recognized as electrocardiographic and echocardiographic LVH, which may be manifested clinically by angina pectoris and cardiac failure as well as silent ischemia, myocardial infarction and, of course, sudden death.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Measurement of serum PIIIP could therefore be a practical and useful tool in the non-invasive assessment of myocardial remodeling in hypertension. In particular, it may have clinical importance in documenting the extent of collagen accumulation and in evaluating pharmacological measures to prevent or even reverse this accumulation.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Nevertheless, because of the limitations of this investigation, we are aware that further large studies are necessary to validate this approach.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Study limitations</span><p id="par0135" class="elsevierStylePara elsevierViewall">Due to its cross-sectional nature, this study should be considered hypothesis-generating at best, and no causal inferences can be drawn regarding pathophysiological mechanisms. Cardiac hypertrophy is a complex process that involves not only collagen turnover (both synthesis and degradation) but also degradation and formation of elastin and formation of collagen cross-links, as well as other spatial and mechanical alterations involving integrins, collagen and smooth muscle cells, regulated by a variety of cytokines and growth factors. This study was not designed to provide a comprehensive analysis of this plethora of regulatory factors. A study reporting serial changes in LVMI and PIIIP might provide better delineation of the temporal relationship between these two entities, providing crucial insights into the precise ways in which they modulate each other. Nevertheless, these findings provide a framework around which future investigations could be planned.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">This study demonstrates that an increase in serum PIIIP concentration indicates that type III collagen synthesis increases in hypertensive patients, particularly in those with LVE. Alterations in the heart in hypertension are thus the result not solely of hypertrophy of LV muscle, but also of increased collagen deposition within the ventricular wall and around the coronary vessels. The study also shows that there a relationship between PIIIP levels and LVMI.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Our results support a possible role for altered circulating collagen markers such as PIIIP that are associated with LVH, which in turn is an important correlate of ventricular mass in hypertensive patients.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Myocardial fibrosis may lead to relaxation abnormalities of the myocardium secondary to impairment of the relengthening of cardiomyocytes during the relaxation phase of the cardiac cycle. A reduced V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio reveals impaired relaxation. Accumulation of collagen fibers within the myocardium is mainly responsible for an increase in intrinsic myocardial stiffness and a decrease in ventricular distensibility. We observed an inverse correlation between myocardial fibrosis and values for this parameter in all hypertensive patients.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The results of these hemodynamic and structural alterations affecting the LV are usually recognized as electrocardiographic and echocardiographic LVH, which may be manifested clinically by angina pectoris, cardiac failure, silent ischemia, myocardial infarction and, of course, sudden death.</p><p id="par0160" class="elsevierStylePara elsevierViewall">Measurement of serum PIIIP could therefore be a practical and useful tool in the non-invasive assessment of myocardial remodeling in hypertension. In particular, it may have clinical importance in documenting the extent of collagen accumulation and in evaluating pharmacological measures to prevent or even reverse this accumulation. Future mechanistic studies could examine whether pharmacologic agents that reduce circulating collagen biomarkers in hypertensive patients also reduce the degree of LVH in this population.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Changes in PIIIP concentrations may be a valuable tool to assess the ability of antihypertensive treatment to regress myocardial fibrosis in hypertensive patients.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Nevertheless, because of the limitations of this investigation, we are aware that further large studies are necessary to definitively validate this approach.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethical disclosures</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Protection of human and animal subjects</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Confidentiality of data</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Right to privacy and informed consent</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres521186" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec541747" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres521187" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução e objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec541748" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Echocardiographic study" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Biochemical measurements" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Study limitations" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:3 [ "identificador" => "sec0050" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Right to privacy and informed consent" ] ] ] 11 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-08-04" "fechaAceptado" => "2014-11-15" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec541747" "palabras" => array:5 [ 0 => "Collagen" 1 => "Hypertension" 2 => "Hypertrophy" 3 => "Myocardium" 4 => "Peptides" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec541748" "palabras" => array:5 [ 0 => "Colagénio" 1 => "Hipertensão" 2 => "Hipertrofia" 3 => "Miocárdio" 4 => "Peptídeos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">An exaggerated accumulation of type I and type III fibrillar collagens occurs throughout the free wall and interventricular septum of patients with primary hypertension and left ventricular hypertrophy (LVH). In the present study the serum concentration of procollagen type III amino terminal peptide (PIIIP) was measured to determine the value of this peptide as a potential marker of ventricular fibrosis in hypertensive patients, particularly those with LVH.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The study population consisted of patients with never-treated mild to moderate essential hypertension and 30 normotensive control subjects. Clinical, echocardiographic, electrocardiographic and biochemical parameters were assessed in all patients.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Heart rate, body mass index and levels of blood pressure were increased in hypertensives, particularly those with LVH, compared to normotensive controls. Posterior wall thickness, left ventricular (LV) mass and LV mass index, and serum PIIIP concentration were also increased in hypertensives, with significant differences between the two hypertensive groups. The ratio between maximal early and late transmitral flow velocity measured during diastole was lower in hypertensives, particularly those with LVH, than in normotensive controls.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The increase in PIIIP indicates that type III collagen synthesis increases in hypertensives, particularly those with LVH, implying that alterations in the heart in hypertension are the result not solely of hypertrophied LV muscle, but also of increased collagen deposition within the ventricular wall and around the coronary vessels.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Thus, measurement of serum PIIIP could be a practical and useful tool in the non-invasive assessment of myocardial remodeling in hypertension.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdução e objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nos doentes com hipertensão arterial (HT) ocorre uma acumulação exagerada de fibras de colagénio tipo I e III quer a nível da parede livre, quer ao longo do septo interventricular do ventrículo esquerdo. Esta acumulação é mais marcada nos HT que apresentam hipertrofia ventricular esquerda. O objetivo do presente estudo, foi a determinação da importância da concentração sérica de procolágeno tipo III, como marcador de fibrose miocárdica, nos hipertensos, principalmente com hipertrofia ventricular esquerda.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A população estudada era composta por pacientes com ligeira a moderada hipertensão essencial nunca tratados (HT) e por 30 pacientes normotensos. Os parâmetros clínicos, ecocardiográficos, eletrocardiográficos e bioquímicos foram avaliados em todos os pacientes.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Os hipertensos apresentavam valores de pressão arterial, frequência cardíaca e índice de massa corporal aumentados quando comparados com os normotensos. Os hipertensos apresentavam valores mais elevados de índice de massa do ventrículo esquerdo e de concentração sérica de PIIIP, e menor relação entre as velocidades de fluxo mitral máxima precoce e a máxima final avaliadas durante a diástole. Os HT com hipertrofia ventricular esquerda apresentavam diferenças significativas destes parâmetros em relação aos HT e normotensos sem hipertrofia ventricular esquerda.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusão</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A concentração sérica PIIIP no soro poderá ser um marcador útil e prático para avaliar de forma não invasiva a remodelação miocárdica, bem como um índice do colagénio depositado nestes pacientes hipertensos, podendo apoiar na escolha criteriosa do tratamento mais eficaz da hipertensão arterial.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução e objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 776 "Ancho" => 1000 "Tamanyo" => 65784 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Scatterplot shows inverse correlation between serum concentrations of procollagen type III amino terminal peptide (PIIIP) and the ratio between maximal early late transmitral flow velocity measured during diastole (V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span>) all patients.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 764 "Ancho" => 998 "Tamanyo" => 71797 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Scatterplot shows direct correlation between serum concentrations of procollagen type III carboxy terminal peptide (PIIIP) and left ventricular mass index (LVMI) in all patients.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">BMI: body mass index; bpm: beats per minute; CCR: creatinine clearance; DBP: diastolic blood pressure; EF: ejection fraction; HR: heart rate; K<span class="elsevierStyleSup">+</span>: potassium; LVH: left ventricular hypertrophy; LVMI: left ventricular mass index; PIIIP: procollagen type III amino terminal peptide; PWT: posterior wall thickness; SBP: systolic blood pressure; ST: septal thickness; V<span class="elsevierStyleInf">E</span>: maximal early transmitral velocity in diastole; V<span class="elsevierStyleInf">A</span>: maximal late transmitral velocity in diastole.</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Values are expressed as mean (range), mean ± SEM, or number of subjects.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normotensive patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hypertensive patients without LVH \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hypertensive patients with LVH \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age, years (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">57 (45–76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59 (34–68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">58 (29–78) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gender, male:female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15:15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19:21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18:22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">SBP, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">125.1±6.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">154.2±23.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">161.4±26.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">DBP, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80.2±4.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98±11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">102±13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HR, bpm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72.2±6.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82.1±15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">87.1±13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BMI, kg/m<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27.1±1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28.4±1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29.2±1.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Blood glucose, mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">93.2±3.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">89.2±5.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">95.2±8.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cholesterol, mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">218.6±15.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">214.5±14.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">225.2±13.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Triglycerides, mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">110.5±16.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">135.2±14.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">136.2±12.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CCR, ml/min×1.73 m<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">101.5±10.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">105.3±11.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">105.7±12.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ST, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.4±0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.9±0.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.1±0.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PWT, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.5±0.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.45±0.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.43±0.24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LVMI, g/m<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">89.6±2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96.2±4.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">115.8±7.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">V<span class="elsevierStyleInf">E</span>/V<span class="elsevierStyleInf">A</span> ratio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.48±0.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.03±0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.89±0.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EF, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67±5.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">69.7±6.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72±4.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PIIIP, ng/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.94±0.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.25±0.76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13.94±0.85 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab841615.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Baseline demographic, biochemical, ambulatory blood pressure monitoring, and echocardiographic parameters.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0115" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypertensive heart disease: cardioreparation by reversal of interstitial collagen in patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" 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| 2024 March | 30 | 15 | 45 |
| 2024 February | 40 | 25 | 65 |
| 2024 January | 27 | 28 | 55 |
| 2023 December | 27 | 21 | 48 |
| 2023 November | 32 | 25 | 57 |
| 2023 October | 34 | 15 | 49 |
| 2023 September | 22 | 21 | 43 |
| 2023 August | 18 | 14 | 32 |
| 2023 July | 21 | 5 | 26 |
| 2023 June | 21 | 8 | 29 |
| 2023 May | 33 | 27 | 60 |
| 2023 April | 23 | 3 | 26 |
| 2023 March | 26 | 19 | 45 |
| 2023 February | 30 | 22 | 52 |
| 2023 January | 31 | 15 | 46 |
| 2022 December | 26 | 19 | 45 |
| 2022 November | 36 | 28 | 64 |
| 2022 October | 23 | 20 | 43 |
| 2022 September | 32 | 30 | 62 |
| 2022 August | 42 | 32 | 74 |
| 2022 July | 25 | 32 | 57 |
| 2022 June | 22 | 15 | 37 |
| 2022 May | 18 | 31 | 49 |
| 2022 April | 21 | 22 | 43 |
| 2022 March | 32 | 23 | 55 |
| 2022 February | 25 | 27 | 52 |
| 2022 January | 28 | 22 | 50 |
| 2021 December | 20 | 31 | 51 |
| 2021 November | 26 | 28 | 54 |
| 2021 October | 27 | 35 | 62 |
| 2021 September | 21 | 25 | 46 |
| 2021 August | 23 | 29 | 52 |
| 2021 July | 20 | 31 | 51 |
| 2021 June | 15 | 13 | 28 |
| 2021 May | 28 | 34 | 62 |
| 2021 April | 52 | 23 | 75 |
| 2021 March | 48 | 14 | 62 |
| 2021 February | 61 | 12 | 73 |
| 2021 January | 33 | 15 | 48 |
| 2020 December | 33 | 6 | 39 |
| 2020 November | 23 | 8 | 31 |
| 2020 October | 10 | 6 | 16 |
| 2020 September | 35 | 8 | 43 |
| 2020 August | 14 | 7 | 21 |
| 2020 July | 32 | 4 | 36 |
| 2020 June | 39 | 3 | 42 |
| 2020 May | 43 | 7 | 50 |
| 2020 April | 38 | 10 | 48 |
| 2020 March | 32 | 9 | 41 |
| 2020 February | 80 | 34 | 114 |
| 2020 January | 29 | 7 | 36 |
| 2019 December | 30 | 6 | 36 |
| 2019 November | 28 | 4 | 32 |
| 2019 October | 36 | 5 | 41 |
| 2019 September | 24 | 10 | 34 |
| 2019 August | 31 | 4 | 35 |
| 2019 July | 32 | 9 | 41 |
| 2019 June | 32 | 10 | 42 |
| 2019 May | 50 | 10 | 60 |
| 2019 April | 24 | 15 | 39 |
| 2019 March | 116 | 9 | 125 |
| 2019 February | 64 | 13 | 77 |
| 2019 January | 31 | 7 | 38 |
| 2018 December | 67 | 10 | 77 |
| 2018 November | 183 | 9 | 192 |
| 2018 October | 445 | 11 | 456 |
| 2018 September | 109 | 14 | 123 |
| 2018 August | 51 | 13 | 64 |
| 2018 July | 19 | 5 | 24 |
| 2018 June | 21 | 10 | 31 |
| 2018 May | 28 | 6 | 34 |
| 2018 April | 30 | 7 | 37 |
| 2018 March | 36 | 8 | 44 |
| 2018 February | 16 | 0 | 16 |
| 2018 January | 28 | 9 | 37 |
| 2017 December | 39 | 9 | 48 |
| 2017 November | 26 | 9 | 35 |
| 2017 October | 36 | 13 | 49 |
| 2017 September | 33 | 12 | 45 |
| 2017 August | 33 | 12 | 45 |
| 2017 July | 25 | 11 | 36 |
| 2017 June | 43 | 19 | 62 |
| 2017 May | 51 | 15 | 66 |
| 2017 April | 25 | 17 | 42 |
| 2017 March | 26 | 6 | 32 |
| 2017 February | 29 | 9 | 38 |
| 2017 January | 37 | 3 | 40 |
| 2016 December | 46 | 9 | 55 |
| 2016 November | 21 | 3 | 24 |
| 2016 October | 42 | 5 | 47 |
| 2016 September | 46 | 5 | 51 |
| 2016 August | 6 | 0 | 6 |
| 2016 July | 8 | 4 | 12 |
| 2016 June | 12 | 2 | 14 |
| 2016 May | 12 | 2 | 14 |
| 2016 April | 16 | 1 | 17 |
| 2016 March | 22 | 8 | 30 |
| 2016 February | 37 | 14 | 51 |
| 2016 January | 25 | 6 | 31 |
| 2015 December | 42 | 7 | 49 |
| 2015 November | 27 | 7 | 34 |
| 2015 October | 35 | 9 | 44 |
| 2015 September | 43 | 6 | 49 |
| 2015 August | 27 | 12 | 39 |
| 2015 July | 14 | 6 | 20 |
| 2015 June | 39 | 10 | 49 |
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