Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is a strong independent predictor of cardiovascular morbidity and mortality, while its regression is associated with an improved clinical prognosis. It is, therefore, vital to elucidate and fully comprehend the mechanisms that contribute to LVH development and to identify markers that indicate a strong predisposition to the development of severe cardiac hypertrophy, before its occurrence. Hypertrophic cardiomyopathy (HCM) serves as a model to investigate LVH development. This primary cardiac disease is characterised by LVH in the absence of increased external loading conditions and is caused by defective sarcomeric proteins, as a result of mutations within the genes encoding these proteins. However, the hypertrophic phenotype of HCM is largely complex, as we see strong variability in the extent and distribution of LVH in HCM, even in individuals with the same disease-causing mutation from the same family; this points toward the involvement of additional genetic and environmental modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) influence LVH indirectly, through their key role in blood pressure regulation, but also directly, due to the direct cellular hypertrophic effects of some RAAS components. Previous genetic association studies aimed at investigating the contribution of RAAS variants to LVH were largely centred on a subset of polymorphisms within the genes encoding the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor genes, while the renin section and RAAS components downstream from ACE remained largely neglected. In addition, most previous studies have reported relatively small individual effects for a small subset of RAAS variants on LVH. In the present study we, therefore, employ a family-based genetic association analysis approach to investigate the contribution of the entire RAAS to this complex hypertrophic phenotype by exploring both the individual as well as the compound effects of 84 variants within 22 RAAS genes, in a cohort of 388 individuals from 27 HCM families, in which either of three HCM-founder mutations segregate. During the course of this explorative study, we identified a number of RAAS variants that had significant effects on hypertrophy in HCM, whether alone or within the context of a multi-variant haplotype. Through single variant association analyses, we identified variants within the genes encoding angiotensinogen, renin-binding protein, the mannose-6-phosphate receptor, ACE, ACE2, angiotensin receptors 1 and 2, the mineralocorticoid receptor, as well as the epithelial sodium channel and the Na+/K+-ATPase β-subunits, that contribute to hypertrophy in HCM. Using haplotype-based association analyses, we were able to identify haplotypes within the genes encoding for renin, the mannose-6-phosphate receptor, angiotensin receptor 1, the mineralocorticoid receptor, epithelial sodium channel and Na+/K+-ATPase α- and β subunits, as well as the CYP11B1/B2 locus, that contribute significantly to LVH. In addition, we found that some RAAS variants and haplotypes had statistically significantly different effects in the three HCM founder mutation groups. Finally, we used stepwise selection to identify a set of nine risk-alleles that together predicted a 127.80 g increase in left ventricular mass, as well as a 13.97 mm increase in maximum interventricular septal thickness and a 14.67 mm increase in maximum left ventricular wall thickness in the present cohort. In contrast, we show that a set of previously identified “pro-LVH” polymorphisms rather poorly predicted LVH in the present South African cohort. This is the first RAAS investigation, to our knowledge, to provide clear quantitative effects for a subset of RAAS variants indicative of a risk for LVH development that are representative of the entire pathway. Our findings suggest that the eventual hypertrophic phenotype of HCM is modulated by the compound effect of a number of RAAS modifier loci, where each polymorphism makes a modest contribution towards the eventual phenotype. Research such as that presented here provides a basis on which future studies can build improved risk profiles for LVH development within the context of HCM, and ultimately in all patients with a risk of cardiac hypertrophy. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is 'n sterk onafhanklike voorspeller van kardiovaskulêre morbiditeit en mortaliteit, terwyl LVH regressie verband hou met ‘n verbeterde kliniese voorspelling. Dit is dus noodsaaklik om die meganismes wat bydra to LVH ontwikkeling ten volle te verstaan en merkers wat 'n sterk geneigdheid tot die ontwikkeling van ernstige kardiale hipertrofie te identifiseer, voordat dit voorkom. Hipertrofiese kardiomiopatie (HKM) dien as 'n model om LVH ontwikkeling te ondersoek. Hierdie primêre hartsiekte word gekenmerk deur LVH en word meestal veroorsaak deur foutiewe sarkomeer proteïene as gevolg van mutasies binne die gene wat kodeer vir hierdie proteïene. Die hipertrofiese fenotipe van HKM is egter grootliks kompleks; ons sien, by voorbeeld, sterk veranderlikheid in die omvang en die verspreiding van LVH in HKM, selfs in individue met dieselfde siekte-veroorsakende mutasie binne dieselfde gesin, wat dui op die betrokkenheid van addisionele genetiese en omgewing modifiseerders. Komponente van die renien-angiotensien-aldosteroon sisteem (RAAS) beïnvloed LVH indirek, deur middel van hul belangrike rol in bloeddruk regulasie, maar ook direk, as gevolg van die direkte sellulêre hipertrofiese gevolge van sommige RAAS komponente. Vorige genetiese assosiasie studies wat daarop gemik was om die bydrae van RAAS variante LVH te ondersoek, was hoofsaaklik gesentreer op 'n groepie polimorfismes binne die gene wat kodeer vir die “angiotensin converting enzyme” (ACE) en angiotensien II tipe 1-reseptor gene, terwyl die renien gedeelte en RAAS komponente stroomaf van ACE meestal nie ondersoek was nie. Daarbenewens het die meeste vorige studies relatief klein individuele gevolge gerapporteer vir 'n klein groepie RAAS variante op LVH. In die huidige studie het ons dus 'n familie-gebaseerde genetiese assosiasie-analise benadering gebruik om die bydrae van die hele RAAS tot hierdie komplekse hipertrofiese fenotipe te ondersoek deur 'n studie van die individuele-, sowel as die saamgestelde effekte van 84 variante binne 22 RAAS gene, in 'n groep van 388 individue vanaf 27 HKM families, waarin een van drie HCM-stigter mutasies seggregeer. Gedurende die loop van hierdie studie het ons 'n aantal RAAS variante wat ‘n beduidende uitwerking op HKM hipertrofie geïdentifiseer, hetsy alleen of binne die konteks van' n multi-variant haplotipe. Deur middel van enkele variant assosiasie toetsing het ons variante geïdentifiseer binne die gene wat kodeer vir angiotensinogen, renien-bindende proteïen, die mannose-6-fosfaat reseptor, ACE, ACE2, angiotensien reseptore 1 en 2, die mineralokortikoïd reseptor, sowel as die epiteel natrium kanaal en Na+/ K+-ATPase β-subeenhede, wat bydra tot HKM hipertrofie. Deur die gebruik van haplotipe-gebaseerde assosiasie ontleding was ons in staat om haplotipes te identifiseer binne die gene wat kodeer vir renien, die mannose-6-fosfaat reseptor angiotensien reseptor 1, die mineralokortikoïd reseptor, epiteel natrium kanaal en die Na+/ K+-ATPase α-en β subeenhede, sowel as die CYP11B1/B2 lokus, wat aansienlik bydra tot LVH. Verder het ons bevind dat sommige RAAS variante en haplotipes statisties beduidende verskillende effekte gehad het in die drie HKM stigter mutasie groepe. Laastens, het ons stapsgewyse seleksie gebruik om 'n stel van nege risiko-allele wat saam' n toename van 127.80 g in linker ventrikulêre massa, sowel as 'n 13.97 mm toename in maksimum ventrikulêre septale dikte, en' n 14.67 mm verhoging in maksimum linker ventrikulêre wanddikte voorspel, te identifiseer in die huidige kohort. In teenstelling hiermee wys ons dat 'n stel van voorheen geïdentifiseerde "pro-LVH" polimorfismes swakker gevaar het as LVH-voorspellers in die huidige Suid-Afrikaanse kohort. Hierdie is die eerste RAAS ondersoek, tot ons kennis, wat ‘n duidelike kwantitatiewe gevolge vir 'n stel RAAS variante wat ‘n verhoogde risiko tot LVH ontwikkeling aandui, wat verteenwoordigend is van die hele RAAS. Ons bevindinge dui daarop dat die uiteindelike hipertrofiese fenotipe van HKM gemoduleer word deur die saamgestelde effek van 'n aantal RAAS wysiger loki, waar elke polimorfisme ' n beskeie bydrae maak tot die uiteindelike fenotipe. Navorsing soos dié wat hier aangebied word dien as 'n basis waarop toekomstige studies kan bou vir ‘n verbeterde risiko-profiel vir LVH ontwikkeling binne die konteks van die HKM, en uiteindelik in alle pasiënte met' n verhoogde risiko vir kardiale hipertrofie.

Made available in DSpace on 2016-08-19T17:47:09Z (GMT). No. of bitstreams: 1 Arnaldo Muniz Garcia.pdf: 655892 bytes, checksum: f9f5eda07bd90764780889b563437e7f (MD5) Previous issue date: 2004-01-28 / A cohort prospective study was carried with 350 dogs of various ages at localities Vila Nova and Bom Viver in the municipality of Raposa-MA, from March of 2002 to December of 2003. The objective is to avaluate the behavior of L. (L.) chagasi infection. The chosen areas are a result of the disordered occupation process, contributing with 60% of LVH and LVC cases that were notified by the municipal district. At first, the procedure was made by doing the populational inquiry the two places by means of canine census. The study was processed in two phases, with interval of 7 months among the same ones. In the first phase, 350 dogs participated of the study and by a visiting process a questionnaire with epidemiological, demographical, clinical and behavioral data about the dogs was applied. The testing of Montenegro intradermoreaction (IDRM) was made with the antigen of L. (L.) amazonensis and adapted for dogs, serological examination testing Enzyme Linked Immunsorbent Assay (ELISA), clinical e parasitical were also made in positive animals to IDRM and/or ELISA tests. Starting from clinical and immunological parameters already referred in literature, were defined four diagnoses categories, classifying the dogs according to its evolutionary course in not infected dogs (195), infected (100), Oligosymptomatic sick (41) and polysymptomatic sick (14). The second phase was accomplished with application of the same tests of the first phase with 230 dogs, that reduction was due in function of the losses (36,28%) caused by death, address change and missing. The positive dogs for an or both tests were accompanied bimonthly with reevaluation of the clinical exams. The initial and final prevalence and incidence of the infection were 8,57%, 6,52% and 8% for IDRM; by ELISA 39,71%, 32,6% and 16%; for ELISA and IDRM 44,29%, 37,39% and 21,6% respectively. In what the clinical form refers, the dogs were classified in the following way: infected (28,57%), oligosymptomatic sick (11,71%) and polysymptomatic sick (4%). in agreement with the statistical analyses not adjusted and adjusted, the variable age, race, secondary lesion, physical condition and place were associated the infection for L. (L.) chagasi. The infection for L. (L.) chagasi was present in 52,97% of the canine population of Vila Bom Viver and 34,55% in Vila Nova, demonstrating that in endemic area happens the intense and active circulation of Leishmania. / Realizou-se um estudo de coorte prospectivo com 350 cães com idades variadas nas localidades de Vila Nova e Bom Viver no município da Raposa-MA no período de março de 2002 a dezembro de 2003, com o objetivo de avaliar o comportamento da infecção por L. (L.) chagasi. As áreas escolhidas são resultantes do processo de ocupação desordenada, contribuindo em média com 60% dos casos de LVH e LVC notificados pelo município. Procedeu-se inicialmente com o inquérito populacional nas duas localidades por meio do censo canino. O estudo processou-se em duas fases, com intervalo de 7 meses entre as mesmas. Na primeira fase participaram do estudo 350 cães, e por meio de visita casa/casa aplicou-se um questionário com dados epidemiológicos, demográficos, clínicos e comportamentais dos cães. Realizou-se o teste de intradermorreação de Montenegro (IDRM) com antígeno de L. amazonensis e adequado para cães, teste sorológico Enzyme Linked Immunsorbent Assay (ELISA), clínico e parasitológico dos animais positivos para os testes IDRM e/ou ELISA. A partir de parâmetros clínico e imunológico já referidos na literatura, foram definidas quatro categorias de diagnóstico, classificando os cães segundo o seu curso evolutivo em cães não infectados (195), infectados (100), doente oligossintomático (41) e doente polissintomático (14). A segunda fase foi realizada com aplicação dos mesmos testes da primeira fase com 230 cães, essa redução deveu-se em função das perdas (36,28%) ocasionadas por óbitos, mudança de endereço e desaparecidos. Os cães positivos para um ou ambos os testes foram acompanhados bimestralmente com reavaliação dos exames clínicos. A prevalência inicial, final e incidência da infecção foram 8,57%, 6,52% e 8% por IDRM; por ELISA 39,71%, 32,6% e 16%; por ELISA e IDRM 44,29%, 37,39% e 21,6% respectivamente. No que se refere a forma clinica, os cães foram classificados da seguinte forma: infectados (28,57%), doente oligossintomático (11,71%) e doente polissintomático (4%). De acordo com as análises estatísticas não ajustada e ajustada, as variáveis idade, raça, lesão secundária, condição física e localidade foram associadas a infecção por L. (L.) chagasi. A infecção por L. (L.) chagasi estava presente 52,97% da população canina de Vila Bom Viver e 34,55% em Vila Nova, demonstrando que em área endêmica ocorre a intensa e ativa circulação da Leishmania.

Hypertension is associated with end organ damage (EOD). Since EOD is a risk factor for cardio- and cerebrovascular complications, it is a major requirement for these to be detected, prevented and treated. A total of 147 consecutive patients with newly-diagnosed essential hypertension and attending the outpatient clinic were included in this study based on a set of inclusion and exclusion criteria (patients with co-morbid illnesses were excluded from the investigation). Among them, 86% (70 male (M) and 56 female (F)) had one or more EODs, an observation which was very close to statistically significance (P=0.054). The presence of one or more EODs in newly-detected hypertension indicates widespread vascular damage which carries the high risk for cardio- and cerebrovascular morbidity and mortality. Although thyroid dysfunctions exert significant effects on blood pressure (BP), published literature available has revealed contradictory data. Objective of our study was to explore the inter-relationships between selected thyroid dysfunctional status (hyper and hypothyroid) and established biomarkers [thyroid stimulating hormone (TSH) and thyroxine (T4)]; and BP components [specifically Systolic BP (SBP), Diastolic BP (DBP), and Mean Arterial Pressure (MAP), and uniquely SBP:DBP ratio]. We followed rigid criteria in order to select adults with hyperthyroidism (n=71) and hypothyroidism (n=300), together with healthy age-matched controls (n =300), and applied a series of statistical analyses on the datasets acquired. We have observed thyroid dysfunctional status is associated with elevated BP, and increasing BP is positively-correlated with elevated serum thyroid biomarkers, hyper and hypothyroid disorders should be recognized and treated early in order to avoid critical hazards presented by high BP. Also, we have studied awareness among public and physicians in managing hypertension. Overall, the levels of knowledge and awareness among both groups are sub-optimal. Hence there is an urgent need for empowerment among both groups to enhance awareness and to bring effective standard of care.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular morbidity and allcause mortality. Significantly, it is considered a modifiable cardiovascular risk factor as its regression increases overall survival and reduces the frequency of adverse cardiac events. A clear understanding of LVH pathogenesis is thus imperative to facilitate improved risk stratification and therapeutic intervention. Hypertrophic cardiomyopathy (HCM), an inherited cardiac disorder, is a model disease for elucidating the molecular mechanisms underlying LVH development. LVH, in the absence of increased external loading conditions, is its quintessential clinical feature, resulting from mutations in genes encoding sarcomeric proteins. The LVH phenotype in HCM exhibits marked variability even amongst family members who carry the same disease-causing mutation. Phenotypic expression is thus determined by the causal mutation and additional determinants including the environment, epigenetics and modifier genes. Thus far, factors investigated as potential hypertrophy modifiers in HCM have been relatively removed from the primary stimulus for LVH; and the few studies that have been replicated yielded inconsistent results. We hypothesized that the factors that closely interact with the primary stimulus of faulty sarcomeric functioning, have a greater capacity to modulate it, and ultimately the LVH phenotype in HCM. Plausible candidate modifiers would include factors relating to the structure or function of the sarcomere, including known HCM-causal genes; and the enzymes that function in sarcomere-based energetics. Indeed, the literature highlights the relevance of sarcomeric proteins, Ca2+-handling and myocardial energetics in the development of LVH in HCM. This study, therefore, set out to evaluate the hypertrophy-modifying capacity of such factors by means of family-based genetic association testing in 27 South African HCM families in which one of three unique HCM-causing founder mutations segregates. Moreover, the single and combined effects of 76 variants within 26 candidate genes encoding sarcomeric or sarcomere-associated proteins were investigated. The study identified a modifying role in the development of hypertrophy in HCM for each of the candidate genes investigated with the exception of the metabolic protein-encoding gene, PRKAG1. More specifically, single variant association analyses identified a modifying role for variants within the genes MYH7, TPM1 and MYL2, which encode proteins of the sarcomere, as well as the genes CPT1B, CKM, ALDOA and PRKAB2, which encode metabolic proteins. Haplotype-based association analyses identified combined modifying effects for variants within the genes ACTC, TPM1, MYL2, MYL3 and MYBPC3, which encode proteins of the sarcomere, as well as the genes CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A, PRKAA2, PRKAG2 and PRKAG3, which encode metabolic proteins. Moreover, a number of variants and haplotypes showed statistically significant differences in effect amongst the three HCM founder mutation groups. The HCM-modifier genes identified were prioritised for future studies according to the number of significant results obtained for the four tests of association performed. The genes TPM1 and MYBPC3, which encode sarcomeric proteins, as well as the genes PFKM and PRKAG2, which encode metabolic proteins, were identified as stronger candidates for future studies as they delivered multiple significant results for various statistical tests. This study makes a novel contribution to the field of hypertrophy research as it tested the hypothesis that structural or energy-related factors located within the sarcomere may act as modifiers of cardiac hypertrophy in HCM, and succeeded in identifying a modifying role for many of the candidate genes selected. The significant results include substantial single and within-genecontext variant effects; and identified sizeable variation in the risk of developing LVH owing to the compound effect of the modifier and the individual founder mutations. Collectively, these findings enhance the current understanding of genotype/phenotype correlations and may, as consequence, improve patient risk stratification and choice of treatment. Moreover, these findings emphasize the potential for modulation of disease by further elucidation of some of the avenues identified. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is ‘n onafhanklike voorspeller van kardiovaskulêre morbiditeit en van mortaliteit weens alle oorsake. Van belang is dat dit ‘n wysigbare kardiovaskulêre risiko faktor is, aangesien die afname daarvan algehele oorlewing verhoog en die frekwensie van nadelige kardiale voorvalle verlaag. ‘n Duidelike begrip van LVH patogenese is dus noodsaaklik om verbeterde risiko stratifikasie en terapeutiese intervensie te fasiliteer. Hipertrofiese kardiomiopatie (HKM), ‘n oorerflike hart-siekte, is ‘n model-siekte vir die uitpluis van die molekulêre meganismes onderliggend aan die ontwikkeling van LVH. LVH, in die afwesigheid van verhoogde eksterne lading, is die kern kliniese simptoom van HKM en die gevolg van mutasies in die gene wat kodeer vir sarkomeriese proteïene. Die LVH fenotiepe in HKM toon merkbare veranderlikheid selfs in familie-lede wat dieselfde siekte-veroorsakende mutasie dra. Die fenotiepe word dus bepaal deur die siekte-veroorsakende mutasie asook addisionele determinante insluitend die omgewing, epigenetika en modifiserende gene. Potensiële hipertrofie-modifiseerders wat tot dusver bestudeer is, is betreklik verwyder van die primêre stimulus vir LVH en die paar studies wat gerepliseer is, het teenstrydige resultate gelewer. Ons hipoteseer dat die faktore wat in noue interaksie met die primêre stimulus van foutiewe sarkomeriese funksionering is, ‘n groter kapasitieit het om dit en uiteindelik die LVH fenotiepe in HKM, te moduleer. Aanneemlike kandidaat-modifiseerders sou insluit faktore wat betrekking het tot die struktuur en funksie van die sarkomeer insluitend HKM-oorsaaklike gene en die ensieme wat funksioneer in sarkomeer-gebaseerde energetika. Die literatuur beklemtoon inderdaad die relevansie van sarkomeriese proteïene, Ca2+-hantering en miokardiese energetika in die ontwikkeling van LVM in HKM. Hierdie studie het beoog om die hipertrofie-modifiserende kapasiteit van sulke faktore te evalueer deur middel van familie-gebaseerde genetiese assosiasie toetse in 27 Suid-Afrikaanse HKM families waarin een van drie unieke HKM-stigter mutasies segregeer. Verder was die enkel en gekombineerde effekte van 76 variante binne 26 kandidaat gene wat kodeer vir sarkomeer en sarkomeer-geassosieerde proteïene, ondersoek. Hierdie studie het ‘n modifiserende rol in die ontwikkeling van hipertrofie in HKM geïdentifiseer vir elk van die kandidaat gene wat ondersoek is, met uitsluiting van die PRKAG1, wat kodeer vir ‘n metaboliese proteïen. Meer spesifiek, enkel variant assosiasie analises het ‘n modifiserende rol geïdentifiseer vir variante in die gene MYH7, TPM1 en MYL2, wat kodeer vir sarkomeriese proteïene, asook die gene CPT1B, CKM, ALDOA en PRKAB2, wat kodeer vir metabolise proteïene. Haplotipe-gebaseerde assosiasie-analises het gekombineerde modifiserende effekte geïdentifiseer vir variante in die gene ACTC, TPM1, MYL2, MYL3 en MYBPC3, wat kodeer vir strukturele proteïene van die sarkomeer asook die gene CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A, PRKAA2, PRKAG2 en PRKAG3, wat kodeer vir metabolise proteïene. Verder het ‘n aantal variante en haplotipes statisties betekenisvolle verskille in effek tussen die drie HKM-stigter mutasie groepe getoon. Die HKM-modifiserende gene wat geïdentifiseer is, is verder geprioritiseer vir toekomstige studies volgens die aantal beduidende resultate wat vir die vier assosiasie toetse verkry is. Die gene TPM1 and MYBPC3, wat kodeer vir sarkomeriese proteïene, asook die gene PFKM and PRKAG2, wat kodeer vir metaboliese proteïene, is geïdentifiseer as sterker kandidate vir verdere studies omdat veelvuldige beduidende resultate vir die verskeie statistiese toetse deur hulle gelewer is. Hierdie studie maak ‘n nuwe bydrae tot die veld van hipertrofie navorsing omdat dit die hipotese dat strukturele en energie-verwante faktore, wat binne die sarkomeer geposisioneer is, potensieel as modifiseerders van kardiale hipertropfie in HKM kan optree, ondersoek het. Dit slaag ook daarin om ‘n modifiserende rol vir baie van die geselekteerde kandidaatgene te identifiseer. Die beduidende resultate sluit in aansienlike enkel en binne-geen-konteks variant-effekte en aansienlike variasie in die risiko vir LVH ontwikkeling verskuldig aan die gekombineerde effek van modifiseerder en individuele stigter mutasies. Gesamentlik verbeter hierdie bevindinge die huidige begrip van genotipe/fenotipe korrelasies en dit mag tot gevolg hê verbeterde pasiënt risiko stratifikasie en keuse van behandeling. Verder beklemtoon hierdie bevindinge die potensiaal vir siekte modulering deur verdere uitpluis van sekere van hierdie geïdentifiseerde navorsingsrigtings. / National Research Foundation / Dr. Paul van Helden / Stellenbosch University

Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.

Short summary: Background: High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD. Aim: We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4. Methods: In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2-4 for an average study period of 36±10...

Short summary: Background: High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD. Aim: We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4. Methods: In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2-4 for an average study period of 36±10...