Original Article doi: 10.1111/joim.12232
The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk S. Masson1, N. Agabiti2, T. Vago3, M. Miceli4, F. Mayer2, T. Letizia3, U. Wienhues-Thelen5, G. F. Mureddu6, M. Davoli2, A. Boccanelli6, R. Latini1 & on behalf of the Investigators of the PREDICTOR study From the 1Department of Cardiovascular Research, IRCCS–Istituto di Ricerche Farmacologiche “Mario Negri”, Milan; 2Lazio Regional Health Service, Rome; 3Laboratory of Endocrinology, Ospedale Luigi Sacco, Milan; 4ASL Roma D, Rome, Italy; 5Roche Diagnostics, Penzberg, Germany; and 6Department of Cardiovascular Diseases, S. Giovanni-Addolorata Hospital, Rome, Italy
Abstract. Masson S, Agabiti N, Vago T, Miceli M, Mayer F, Letizia T, Wienhues-Thelen U, Mureddu GF, Davoli M, Boccanelli A, Latini R. The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk. J Intern Med 2015; 277: 318–330. Objectives. Fibroblast growth factor-23 (FGF-23) and vitamin D are hormones involved in phosphate homoeostasis. They also directly influence cardiomyocyte hypertrophy. We examined whether the relationships between levels of vitamin D or FGF23, cardiac phenotype and outcome were independent of established cardiac biomarkers in a large cohort of community-dwelling elderly subjects. Design and Setting. Plasma levels of FGF-23 and vitamin D were measured in 1851 men and women (65–84 years) resident in the Lazio region of Italy. Participants were referred to eight cardiology centres for clinical examination, electrocardiography, comprehensive Doppler echocardiography and blood sampling. All-cause mortality or hospitalizations were available after a median follow-up of 47 months with record linkage of administrative data. Results. Vitamin D deficiency (115 g m 2 in men [27]. Data sources Data were obtained from the health information system databases of the Lazio region (>5.7 million inhabitants). The Hospital Information System (HIS) provides information on patients’ demographic data (sex, age, place of birth, place of residence), dates of admission and discharge, discharge diagnoses (up to six) and medical procedures or surgical interventions (up to six) according to International Classification of Disease (9th revision), Clinical Modification (ICD-9-CM) status upon discharge (alive, dead, transferred to another hospital),ward(s) of stay, date(s) of in-hospital transfer) and a regional code corresponding to the admitting facility for patients discharged from all public and private hospitals in the Lazio region. The Out-of-Region Hospitalization System (ORS) collects information on all hospitalizations of residents in the Lazio region which occur in Italian regions other than Lazio. The Regional Registry of Causes of Death (ReNCaM) lists the causes of death coded according to the International Classification of Diseases (9th revision) for all deaths of residents of the region. Data from different sources can be linked through standardized methods based on a unique, anonymous, personal 15-digit identifier, as reported elsewhere [28, 29]. Outcomes and follow-up The PREDICTOR clinical database was linked to the HIS, ORS, and the Mortality Register 2007– 2012. Different outcomes were defined: (i) total mortality (ICD-9 codes 001-999), (ii) cardiovascular mortality (ICD-9 codes 390-459) identified through ReNCaM, and (iii) hospital admissions with a main diagnosis of cardiovascular diseases (ICD-9-CM codes 390-459) identified through the HIS. In the case of multiple admissions, the first admission was considered. Individual follow-up was based on the start date of the clinical examination. The observation period was considered terminated at the end of the study period (31 December 2012) or on the date of an outcome or emigration, whichever occurred first. Consequently, the potential observation period varied 320
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2015, 277; 318–330
FGF-23 and vitamin D in the elderly
between 4 days and 5.4 years with a mean followup of 3.8 years. Statistical analyses Categorical variables are presented as proportions. Continuous variables are expressed as mean ( SEM) or median (Q1–Q3) values. The relationship between circulating levels of biomarkers and demographic, clinical or echocardiographic variables were investigated with the chi-square test for categorical variables. Continuous variables were compared by the analysis of variance or by the nonparametric Kruskal–Wallis test for non-normally distributed data. Multiple linear or logistic regression models were used to identify the variables independently associated with higher levels of log-transformed FGF-23 or deficient vitamin D (
The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk S. Masson1, N. Agabiti2, T. Vago3, M. Miceli4, F. Mayer2, T. Letizia3, U. Wienhues-Thelen5, G. F. Mureddu6, M. Davoli2, A. Boccanelli6, R. Latini1 & on behalf of the Investigators of the PREDICTOR study From the 1Department of Cardiovascular Research, IRCCS–Istituto di Ricerche Farmacologiche “Mario Negri”, Milan; 2Lazio Regional Health Service, Rome; 3Laboratory of Endocrinology, Ospedale Luigi Sacco, Milan; 4ASL Roma D, Rome, Italy; 5Roche Diagnostics, Penzberg, Germany; and 6Department of Cardiovascular Diseases, S. Giovanni-Addolorata Hospital, Rome, Italy
Abstract. Masson S, Agabiti N, Vago T, Miceli M, Mayer F, Letizia T, Wienhues-Thelen U, Mureddu GF, Davoli M, Boccanelli A, Latini R. The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk. J Intern Med 2015; 277: 318–330. Objectives. Fibroblast growth factor-23 (FGF-23) and vitamin D are hormones involved in phosphate homoeostasis. They also directly influence cardiomyocyte hypertrophy. We examined whether the relationships between levels of vitamin D or FGF23, cardiac phenotype and outcome were independent of established cardiac biomarkers in a large cohort of community-dwelling elderly subjects. Design and Setting. Plasma levels of FGF-23 and vitamin D were measured in 1851 men and women (65–84 years) resident in the Lazio region of Italy. Participants were referred to eight cardiology centres for clinical examination, electrocardiography, comprehensive Doppler echocardiography and blood sampling. All-cause mortality or hospitalizations were available after a median follow-up of 47 months with record linkage of administrative data. Results. Vitamin D deficiency (115 g m 2 in men [27]. Data sources Data were obtained from the health information system databases of the Lazio region (>5.7 million inhabitants). The Hospital Information System (HIS) provides information on patients’ demographic data (sex, age, place of birth, place of residence), dates of admission and discharge, discharge diagnoses (up to six) and medical procedures or surgical interventions (up to six) according to International Classification of Disease (9th revision), Clinical Modification (ICD-9-CM) status upon discharge (alive, dead, transferred to another hospital),ward(s) of stay, date(s) of in-hospital transfer) and a regional code corresponding to the admitting facility for patients discharged from all public and private hospitals in the Lazio region. The Out-of-Region Hospitalization System (ORS) collects information on all hospitalizations of residents in the Lazio region which occur in Italian regions other than Lazio. The Regional Registry of Causes of Death (ReNCaM) lists the causes of death coded according to the International Classification of Diseases (9th revision) for all deaths of residents of the region. Data from different sources can be linked through standardized methods based on a unique, anonymous, personal 15-digit identifier, as reported elsewhere [28, 29]. Outcomes and follow-up The PREDICTOR clinical database was linked to the HIS, ORS, and the Mortality Register 2007– 2012. Different outcomes were defined: (i) total mortality (ICD-9 codes 001-999), (ii) cardiovascular mortality (ICD-9 codes 390-459) identified through ReNCaM, and (iii) hospital admissions with a main diagnosis of cardiovascular diseases (ICD-9-CM codes 390-459) identified through the HIS. In the case of multiple admissions, the first admission was considered. Individual follow-up was based on the start date of the clinical examination. The observation period was considered terminated at the end of the study period (31 December 2012) or on the date of an outcome or emigration, whichever occurred first. Consequently, the potential observation period varied 320
ª 2014 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2015, 277; 318–330
FGF-23 and vitamin D in the elderly
between 4 days and 5.4 years with a mean followup of 3.8 years. Statistical analyses Categorical variables are presented as proportions. Continuous variables are expressed as mean ( SEM) or median (Q1–Q3) values. The relationship between circulating levels of biomarkers and demographic, clinical or echocardiographic variables were investigated with the chi-square test for categorical variables. Continuous variables were compared by the analysis of variance or by the nonparametric Kruskal–Wallis test for non-normally distributed data. Multiple linear or logistic regression models were used to identify the variables independently associated with higher levels of log-transformed FGF-23 or deficient vitamin D (
