Editorial comment
Homocysteinemia and vascular disease: Where we stand in 2022
Homocisteinemia e doença vascular: Onde nos encontramos em 2022
R. Palma Reis
New Medical School and CHLN, Hospital Pulido Valente, Lisboa, Portugal
Lido
3153
Vezesque se leu este artigo
828
Total PDF
2325
Total HTML
Compartilhar estatísticas
array:24 [ "pii" => "S0870255122002670" "issn" => "08702551" "doi" => "10.1016/j.repc.2022.06.005" "estado" => "S300" "fechaPublicacion" => "2022-10-01" "aid" => "1987" "copyright" => "Sociedade Portuguesa de Cardiologia" "copyrightAnyo" => "2022" "documento" => "simple-article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "dis" "cita" => "Rev Port Cardiol. 2022;41:821-2" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S0870255122002554" "issn" => "08702551" "doi" => "10.1016/j.repc.2021.06.021" "estado" => "S300" "fechaPublicacion" => "2022-10-01" "aid" => "1975" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2022;41:823-30" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Impact of the withdrawal of renin-angiotensin-aldosterone inhibitors on mortality in COVID-19 patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "823" "paginaFinal" => "830" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Impacto da retirada dos inibidores do sistema renina-angiotensina-aldosterona na mortalidade dos doentes com Covid-19" ] ] "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" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1186 "Ancho" => 1675 "Tamanyo" => 110918 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival analysis among all patients with RAASi treatment. Patients discontinuing both an angiotensin converting enzyme inhibitors/angiotensin receptor blockers plus a mineralocorticoid receptor antagonists showed the worst prognosis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan Caro-Codón, Juan R. Rey, Angel M. Iniesta, Sandra O. Rosillo, Sergio Castrejon-Castrejon, Laura Rodriguez-Sotelo, Jose M. Garcia-Veas, Irene Marco, Luis A. Martinez, Lorena Martin-Polo, Carlos Merino, Marcel Martinez-Cossiani, Antonio Buño, Luis Gonzalez-Valle, Alicia Herrero, Esteban López-de-Sá, Jose L. Merino" "autores" => array:18 [ 0 => array:2 [ "nombre" => "Juan" "apellidos" => "Caro-Codón" ] 1 => array:2 [ "nombre" => "Juan R." "apellidos" => "Rey" ] 2 => array:2 [ "nombre" => "Angel M." "apellidos" => "Iniesta" ] 3 => array:2 [ "nombre" => "Sandra O." "apellidos" => "Rosillo" ] 4 => array:2 [ "nombre" => "Sergio" "apellidos" => "Castrejon-Castrejon" ] 5 => array:2 [ "nombre" => "Laura" "apellidos" => "Rodriguez-Sotelo" ] 6 => array:2 [ "nombre" => "Jose M." "apellidos" => "Garcia-Veas" ] 7 => array:2 [ "nombre" => "Irene" "apellidos" => "Marco" ] 8 => array:2 [ "nombre" => "Luis A." "apellidos" => "Martinez" ] 9 => array:2 [ "nombre" => "Lorena" "apellidos" => "Martin-Polo" ] 10 => array:2 [ "nombre" => "Carlos" "apellidos" => "Merino" ] 11 => array:2 [ "nombre" => "Marcel" "apellidos" => "Martinez-Cossiani" ] 12 => array:2 [ "nombre" => "Antonio" "apellidos" => "Buño" ] 13 => array:2 [ "nombre" => "Luis" "apellidos" => "Gonzalez-Valle" ] 14 => array:2 [ "nombre" => "Alicia" "apellidos" => "Herrero" ] 15 => array:2 [ "nombre" => "Esteban" "apellidos" => "López-de-Sá" ] 16 => array:2 [ "nombre" => "Jose L." "apellidos" => "Merino" ] 17 => array:1 [ "colaborador" => "on behalf of the CARD-COVID Investigators (Appendix)" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122002554?idApp=UINPBA00004E" "url" => "/08702551/0000004100000010/v1_202210061538/S0870255122002554/v1_202210061538/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0870255122002542" "issn" => "08702551" "doi" => "10.1016/j.repc.2021.12.011" "estado" => "S300" "fechaPublicacion" => "2022-10-01" "aid" => "1974" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2022;41:813-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Pirfenidone alleviates vascular intima injury caused by hyperhomocysteinemia" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "813" "paginaFinal" => "819" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "A pirfenidona reduz a lesão da íntima vascular causada pela hiperhomocisteinemia" ] ] "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" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1838 "Ancho" => 2508 "Tamanyo" => 404680 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Intimal hyperplasia of each group at 14 weeks of arterial injury. Forty magnification photomicrographs (hematoxylin and eosin and Van Gieson elastin stain) of arterial sections from control group (A), model group (B), and PFD group (C). Note thicker intimal in model group. (D), Bar graph shows neointima formation of each group. (E), Bar graph shows the ratio between neointimal and media area of each group. The scale bar=1 mm. Values are represented as mean±SD (n=10). p<0.05 indicates a significant difference. *p<0.05, compared with control group. <span class="elsevierStyleSup">#</span>p<0.05, compared with model group. N, intimal, M, media.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Junying Kong, Ying Deng" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Junying" "apellidos" => "Kong" ] 1 => array:2 [ "nombre" => "Ying" "apellidos" => "Deng" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122002542?idApp=UINPBA00004E" "url" => "/08702551/0000004100000010/v1_202210061538/S0870255122002542/v1_202210061538/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "Homocysteinemia and vascular disease: Where we stand in 2022" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "821" "paginaFinal" => "822" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "R. Palma Reis" "autores" => array:1 [ 0 => array:3 [ "nombre" => "R." "apellidos" => "Palma Reis" "email" => array:1 [ 0 => "palma.reis@nms.unl.pt" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "New Medical School and CHLN, Hospital Pulido Valente, Lisboa, Portugal" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Homocisteinemia e doença vascular: Onde nos encontramos em 2022" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The increased vascular risk of homocystinuria, a rare genetic disease that affects young children, is widely acknowledged. In the first description of the disease, referring to a intellectually disabled child who died at the age of eight due to a stroke, the autopsy described an occlusive vascular pathology that “would only be seen in an elderly person”.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> The international collaborative study on the natural history of homocystinuria, involving 629 patients with homocystinuria, defined thromboembolic complications as the main cause of death in these patients.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">McCully's theory of arteriosclerosis by homocysteinemia brought with it a new concept: the moderate elevation of homocysteine, such as that found in heterozygotes for homocystinuria, can result in an increased risk of vascular disease.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">3–5</span></a> With moderate elevations of homocysteine, either homocystine, a large molecule that filters in the kidney and appears in the urine, composed of two linked molecules of homocysteine, or homocystinuria will not appear, and vascular disease should affect young adults, not children.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The homocysteine theory of atherosclerosis was studied in depth and proved at the end of the last century. Various national and international studies, involving thousands of patients, have shown that:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">In a normal population, homocysteinemia is higher in men than in women, and increases after menopause. In these circumstances, it can partially explain the gender differences in cardiovascular risk, as well as the increased vascular risk after menopause.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">6</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">Homocysteinemia (Hcy) is higher in smokers, than in non-smokers.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">7</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">Hyperhomocysteinemia (HHcy) is linked to myocardial infarction,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">8,9</span></a> stroke<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> and peripheral vascular disease.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">The high prevalence of high Hcy levels in normal persons, as well as in vascular patients, excludes the heterozygosity for homocystinuria, a rare disease, as the cause of most of Hcy elevations.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">Vitamin B deficiencies, in particular B6, B12 and folic acid, co-factors of methionine/homocysteine metabolism, were associated with an increase in Hcy levels.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">12,13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">The large COMAC study on homocysteinemia confirmed that Hcy risk is independent of conventional risk factors and enhances the risk.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">High levels of Hcy are associated with worse prognosis after myocardial infarction.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a></p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">After defining Hcy risk, the control of Hcy plasma levels with B vitamin supplements is easy and possible. Folic acid can decrease HC levels by approximately 42%, B6 by 5% and B12 by 15%. The three elements together decrease Hcy levels by about 50%.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">16</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Much more difficult to prove is the clinical benefit of reducing Hcy levels. We will need a large interventional study with thousands of patients at high cardiovascular risk (for example, patients with myocardial infarction) followed during a long period of 5 to 10 years. The high costs of the study, including the insurance policy, to support the use of generic and cheep medications (vitamins), mean that the study is not of interest to the pharmaceutical industry.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In fact, from several studies by research groups, with different protocols and inclusion criteria, it has emerged that Hcy-lowering interventions with B vitamin supplements have failed to demonstrate clinical benefits in myocardial infarction patients, and presented a dubious or modest benefit in stroke patients.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The lack of clinical benefit of B vitamin supplements can be explained by multiple arguments: clinical study selection based on the atherosclerotic disease are not adequate, inclusion criteria should be guided by the high levels of Hcy. Folic acid is already abundant in western diets, particularly in cereal enrichment with B vitamins and general supplementation is not useful. Folic acid can contribute to increasing the built-up of arterial plaque and folic acid and B12 can methylate vascular cell genes, which may also accelerate plaque growth.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Whatever the reason, the lack of clinical benefit from B vitamin treatment in HHcy led to a decrease in the enthusiasm for Hcy as a vascular risk factor. Consequently, world preventive efforts on atherosclerosis prevention were targeted toward more intense investment in known risk factors, with clearly proven efficacy of intervention, such as smoking cessation, lipid control, hypertension, diabetes, or physical activity.</p><p id="par0080" class="elsevierStylePara elsevierViewall">With this in mind, the current issue of this journal presents a paper on the influence of pirfenidone (PFD) on vascular intimal injury caused by hyperhomocysteinemia.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">18</span></a> Knowing that Hcy induces vascular intimal oxidative and inflammatory lesions, the authors tested an anti-fibrotic agent, PFD, to decrease these inflammatory alterations. In an animal study, comparing normally fed rabbits with rabbits fed with a methionine (precursor of Hcy) rich diet, the authors proved that Hcy induces significant alterations of endothelium, increasing neointimal area, with macrophage infiltration. The administration of PFD concomitantly with a methionine rich diet, decreased macrophage infiltration without changes in blood lipids or HC levels. The authors conclude that PDF can alleviate intimal hyperplasia and proliferation, by inhibiting inflammatory and Hcy-induced oxidative stress.</p><p id="par0085" class="elsevierStylePara elsevierViewall">After the disappointment of Hcy treatment with B vitamin supplements, based on the rational of decreasing Hcy levels, this paper opens a potential new way to reduce Hhcy-associated vascular risk by decreasing the inflammatory effects of Hcy. The journey from animal to human studies is a long one, but the potential preventive effect of this kind of molecules is in existence.</p><p id="par0090" class="elsevierStylePara elsevierViewall">In conclusion, high Hcy levels are at the very least a risk marker for atherosclerosis in different territories and increase atherosclerosis risk in primary and secondary prevention. Proving Hcy risk reversibility, Hcy will be an atherosclerotic risk factor.</p><p id="par0095" class="elsevierStylePara elsevierViewall">A general vitamin supplement approach can effectively lower Hcy but failed to demonstrate this in clinical results. In these circumstances, vitamin supplementation can be reserved for a small population of patients with high levels of Hcy but after strict control of conventional risk factors, and which leads to indisputable clinical benefits.</p><p id="par0100" class="elsevierStylePara elsevierViewall">New approaches to Hcy vascular risk are seductive but there is a long journey ahead between concept and animal effectiveness to human clinical randomized interventional trials confirming their safety and efficacy. This paper represents the first step on that long journey.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0095" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Case records of the Massachussets General Hospital. Case 19471. Marked cerebral symptoms following a limp of three months duration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T. Mallory" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1933" "volumen" => "209" "paginaInicial" => "1063" "paginaFinal" => "1066" "itemHostRev" => array:3 [ "pii" => "S0015028217304296" "estado" => "S300" "issn" => "00150282" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0100" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The natural history of homocystinuria due to cystatione B-sinthase deficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "S.H. Mudd" 1 => "F. Skovby" 2 => "H.L. Levy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Hum Genet" "fecha" => "1985" "volumen" => "37" "paginaInicial" => "1" "paginaFinal" => "31" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3872065" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0105" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homocysteine theory of arteriosclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.S. McCully" 1 => "R.B. Wilson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0021-9150(75)90004-0" "Revista" => array:6 [ "tituloSerie" => "Atherosclerosis" "fecha" => "1975" "volumen" => "22" "paginaInicial" => "215" "paginaFinal" => "227" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1191372" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0110" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.E.L. Wilcken" 1 => "S.G. Reddy" 2 => "V.A. Gupta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0026-0495(83)90045-8" "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "1983" "volumen" => "32" "paginaInicial" => "363" "paginaFinal" => "370" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6684724" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0115" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G. Boers" 1 => "A. Smals" 2 => "F.J. Trijbels" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198509193131201" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1985" "volumen" => "313" "paginaInicial" => "709" "paginaFinal" => "715" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4033695" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0120" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influência do sexo e da menopausa nos níveis de homocisteinemia basal e após sobrecarga com metionina" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "1999" "volumen" => "18" "paginaInicial" => "155" "paginaFinal" => "159" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0125" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influência do tabagismo na homocisteinemia basal e após sobrecarga" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "2000" "volumen" => "19" "paginaInicial" => "471" "paginaFinal" => "474" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0130" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A homocisteinemia como factor de risco de enfarte do miocárdio precoce - estudo de casos e controlos" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "1994" "volumen" => "13" "paginaInicial" => "119" "paginaFinal" => "124" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0135" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homocisteinemia como factor de risco de enfarte do miocárdio - importância da idade e dos níveis da homocisteinemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "1995" "volumen" => "14" "paginaInicial" => "713" "paginaFinal" => "716" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0140" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A homocisteinemia como factor de risco de doença cerebrovascular precoce" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Acta Méd Portuguesa" "fecha" => "1994" "volumen" => "7" "paginaInicial" => "285" "paginaFinal" => "289" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0145" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homocysteinemia after a methionine overload as a coronary artery disease risk factor - Importance of age and homocysteinemia levels" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Coronary Artery Dis" "fecha" => "1995" "volumen" => "6" "paginaInicial" => "851" "paginaFinal" => "856" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0150" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influência dos níveis de B6, B12 e ácido fólico nos valores de homocisteinemia basal e após sobrecarga com metionina" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "1998" "volumen" => "17" "paginaInicial" => "57" "paginaFinal" => "61" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0155" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low circulating folate and vitamin B6: risk factors for stroke, peripheral vascular disease and coronary artery disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "Killian Robinson" 1 => "Kristopher Arheart" 2 => "Helga Refsum" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.cir.97.5.437" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "1998" "volumen" => "97" "paginaInicial" => "437" "paginaFinal" => "443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9490237" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0160" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "I. Graham" 1 => "L. Daly" 2 => "H. Refsum" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Am Med Assoc" "fecha" => "1997" "volumen" => "227" "paginaInicial" => "1775" "paginaFinal" => "1781" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0165" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Significado prognóstico da homocisteinemia após enfarte do miocárdio" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Palma Reis" 1 => "J. Azinheira" 2 => "H. Palma Reis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Card" "fecha" => "2000" "volumen" => "19" "paginaInicial" => "581" "paginaFinal" => "585" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0170" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin requirements for the treatment of hyperhomocysteinemia in humans" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.B. Ubbink" 1 => "W.J.H Vermaak" 2 => "A. Merwe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jn/124.10.1927" "Revista" => array:6 [ "tituloSerie" => "J Nutr" "fecha" => "1994" "volumen" => "124" "paginaInicial" => "1927" "paginaFinal" => "1933" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7931701" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0175" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homocysteine-lowering interventions for preventing cardiovascular events" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "A.J. Martí-Carvajal" 1 => "I. Solà" 2 => "D. Lathyris" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/14651858.CD006612.pub5" "Revista" => array:5 [ "tituloSerie" => "Cochrane Database Syst Rev" "fecha" => "2017" "volumen" => "8" "paginaInicial" => "CD006612" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28816346" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0180" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pirfenidone alleviates vascular intima injury caused by hyperhomocysteinemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Kong" 1 => "Y. Deng" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Cardiol" "fecha" => "2022" "volumen" => "41" "paginaInicial" => "813" "paginaFinal" => "819" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08702551/0000004100000010/v1_202210061538/S0870255122002670/v1_202210061538/en/main.assets" "Apartado" => array:4 [ "identificador" => "92834" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/08702551/0000004100000010/v1_202210061538/S0870255122002670/v1_202210061538/en/main.pdf?idApp=UINPBA00004E&text.app=https://revportcardiol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122002670?idApp=UINPBA00004E" ]
| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 12 | 8 | 20 |
| 2024 Outubro | 54 | 37 | 91 |
| 2024 Setembro | 76 | 31 | 107 |
| 2024 Agosto | 81 | 43 | 124 |
| 2024 Julho | 74 | 42 | 116 |
| 2024 Junho | 55 | 32 | 87 |
| 2024 Maio | 85 | 27 | 112 |
| 2024 Abril | 82 | 39 | 121 |
| 2024 Maro | 59 | 29 | 88 |
| 2024 Fevereiro | 50 | 20 | 70 |
| 2024 Janeiro | 77 | 21 | 98 |
| 2023 Dezembro | 78 | 24 | 102 |
| 2023 Novembro | 76 | 35 | 111 |
| 2023 Outubro | 65 | 22 | 87 |
| 2023 Setembro | 54 | 19 | 73 |
| 2023 Agosto | 55 | 14 | 69 |
| 2023 Julho | 62 | 9 | 71 |
| 2023 Junho | 37 | 13 | 50 |
| 2023 Maio | 57 | 24 | 81 |
| 2023 Abril | 87 | 11 | 98 |
| 2023 Maro | 158 | 20 | 178 |
| 2023 Fevereiro | 110 | 24 | 134 |
| 2023 Janeiro | 168 | 14 | 182 |
| 2022 Dezembro | 112 | 26 | 138 |
| 2022 Novembro | 146 | 50 | 196 |
| 2022 Outubro | 180 | 90 | 270 |
| 2022 Setembro | 113 | 41 | 154 |
| 2022 Agosto | 40 | 42 | 82 |
| 2022 Julho | 22 | 21 | 43 |
Mostrar tudo
