Polymorphisms of the farnesyl diphosphate synthase gene modulate bone changes in response to atorvastatin.

Although their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins.

Vitamin d levels and lipid response to atorvastatin.

Adequate vitamin D levels are necessary for good vascular health. 1,25-dihydroxycholecalciferol activates CYP3A4, an enzyme of the cytochrome P450 system, which metabolizes atorvastatin to its main metabolites. The objective of this study was to evaluate the response of cholesterol and triglycerides to atorvastatin according to vitamin D levels. Sixty-three patients with acute myocardial infarction treated with low and high doses of atorvastatin were included. Levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured at baseline and at 12 months of follow-up. Baseline levels of 25-hydroxyvitamin D (25-OHD) were classified as deficient (<30 nmol/L), insufficient (30-50 nmol/L), and normal (>50 nmol/L). In patients with 25-OHD <30 nmol/L, there were no significant changes in levels of total cholesterol (173 +/- 47 mg/dL versus 164 +/- 51 mg/dL), triglycerides (151 +/- 49 mg/dL versus 177 +/- 94 mg/dL), and LDL cholesterol (111 +/- 48 mg/dL versus 92 45 +/- mg/dL); whereas patients with insufficient (30-50 nmol/L) and normal vitamin D (>50 nmol/L) had a good response to atorvastatin. We suggest that vitamin D concentrations >30 nmol/L may be required for atorvastatin to reduce lipid levels in patients with acute myocardial infarction.

Levels of DKK1 in patients with acute myocardial infarction and response to atorvastatin.

The Wnt-LPR5 signalling pathway plays an important role in skeletal homeostasis, especially in regulating osteoblastic activity. Activation of this pathway is regulated by various inhibitors, including DKK1. The objective of this study was to evaluate DKK1 levels in patients with ischemic heart disease, the response to atorvastatin and the relationship with bone mass. Twenty-one patients with acute myocardial infarction and twenty-three controls with a mean age of 61 ± 9 years with acute coronary syndrome were included. Patients were allocated to low (10-20mg) and high doses (40-80 mg) of atorvastatin according to baseline levels of cholesterol and triglycerides and the index of vascular risk. Patients were studied at hospital admission (baseline) and at 12 months of follow up. DKK1 was determined in all patients at baseline and at 12 months of follow up. Densitometric studies were conducted in the lumbar spine (L2-L4) and the femoral neck and trochanter using an X-ray densitometer. Patients had higher levels of DKK1 than controls, (111 ± 41 nmol/l versus 84 ± 27 nmol/l, p=0.014). Osteoporotic patients had higher levels of DKK1 (137.5 ± 33 nmol/l versus 95.4 ± 36 nmol/l, p=0.021). Analysis of the response to atorvastatin showed reduced DKK1 levels. In conclusion, in patients with acute coronary syndrome, atorvastatin decreases DKK1 levels. This may be a previously unreported mechanism of action of atorvastatin on bone, stimulating the Wnt signalling pathway and increasing bone mass.

Atorvastatin and BMD in coronary syndrome. Role of Lys656Asn polymorphism of leptin receptor gene.

OBJECTIVES: To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome according to the Lys656Asn leptin receptor gene polymorphism. METHODS: Sixty-two patients with acute coronary syndrome were included. Patients were allocated to low and high doses of atorvastatin according to baseline levels of cholesterol and triglycerides and the index of vascular risk and were studied at hospital admission and at 12 months. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow up. Densitometric studies were conducted in the lumbar spine and hip. Patients with a T-score<-2.5 were considered osteoporotic. The Lys656Asn leptin receptor gene polymorphism was determined by PCR. RESULTS: Forty-two patients were Lys/Lys homozygotic and 20 Lys/Asn heterozygotic. The prevalence of osteoporosis was 31% for the Lys/Lys genotype and 27% for the Lys/Asn genotype with no significant differences between groups. There was a significant increase in bone mineral density in the lumbar spine (1.117 +/- 0.24 versus 1.135 +/- 0.24, P = 0.008) in patients with the Lys/Lys genotype. CONCLUSION: Atorvastatin increases lumbar spine bone mineral density only in patients with the Lys/Lys genotype of the Lys656Asn polymorphism.

Effect of the TNFalpha-308 G/A polymorphism on the changes produced by atorvastatin in bone mineral density in patients with acute coronary syndrome.

AIMS: To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome depending on the tumor necrosis factor-alpha (TNFalpha)-308 G/A polymorphism. METHODS: Sixty-two patients with acute coronary syndrome (35 males and 27 females), average age 60 +/- 10 years, were included. Patients were given low (10-20 mg) and high doses (40-80 mg) atorvastatin according to their baseline levels of cholesterol and triglycerides and their index of vascular risk. Patients were studied during hospital admission (baseline) and at 12 months of follow-up. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow-up. Densitometric studies were conducted in the lumbar spine (L(2)-L(4)), femoral neck and trochanter using an X-ray densitometer. The TNFalpha-308 G/A polymorphism was determined by the polymerase chain reaction. RESULTS: Forty-five patients were homozygous for G/G (72.5%) and 17 were heterozygous for G/A (27.5%). The prevalence of osteoporosis (T score < or = 2.5 in the lumbar spine and/or hip) was 33% for the G/G genotype and 35% for the G/A genotype, with no statistically significant differences between groups. There was a statistically significant increase in bone mineral density (BMD) in the lumbar spine (1.107 +/- 0.32 vs. 1.129 +/- 0.23; p = 0.0001) in patients with the G/G genotype. No changes were observed in patients with the G/A genotype. CONCLUSION: In patients with acute coronary syndrome, atorvastatin increases lumbar spine BMD solely in patients with the G/G genotype of the TNFalpha-308 G/A polymorphism.

Bone mineral density, bone remodeling and osteoprotegerin in patients with acute coronary syndrome.

The objective of this study was to evaluate the relationship between coronary disease and osteoporosis and determine the effect of osteoprotegerin (OPG) on bone remodeling and bone mineral density (BMD) in a group of patients with acute coronary syndrome. Eighty-three patients (52 males and 31 women) with acute coronary syndrome (75 patients with acute myocardial infarction and 8 with unstable angina) with an average age of 61+/-10 years were studied. Levels of osteocalcin, urinarydeoxypyridinoline, OPG and the receptor activator of nuclear factor-kappaB ligand (RANKL) were determined during the hospital stay. Femoral neck, trochanter and lumbar spine densitometry was carried out using a DXA densitometer. Thirty percent of patients presented osteoporosis (39% of females and 26% of males). Osteoporotic patients were older and had a lower weight and height and elevated serum levels of osteocalcin (3.6+/-2.25 2.63 versus +/-1.55, p=0.05). Levels of OPG and RANKL were similar in both groups and showed no relationship with BMD. In conclusion, no relationship was observed between the OPG/RANKL system and BMD in these patients.

Ghrelin and bone mass in postmenopausal hypertensive women.

BACKGROUND: Ghrelin, a recently discovered peptide mainly secreted by the stomach, has an orexigenic effect which stimulates secretion of the growth hormone. It also has vasodilator effects which reduce blood pressure and stimulate in vitro, bone formation. OBJECTIVES: To evaluate the effect of ghrelin on bone mass and bone remodeling markers in postmenopausal hypertensive women. MATERIAL AND METHODS: 25 postmenopausal hypertensive women, light to moderate based on the JNC-VII criteria, were studied. They had a mean age of 58 +/- 8 years, a body mass index of 28 +/- 6 and a hypertension development time of 65 +/- 84 months. Osteocalcin, PTHi, 25-vitamin D, ghrelin in serum and deoxypiridinoline in urine were determined in all patients. A lumbar spine densitometer was made (DXP Lunar, Madison, Wisc., USA). RESULTS: Diminished levels of ghrelin were observed in the osteoporotic group (40 +/- 19 vs. 78 +/- 40, p = 0.027). When the patients were separated according to ghrelin tertiles, a greater bone mass was observed in the upper tertiles, which was associated with a decrease in the urinary deoxypiridinoline. When the total population was analyzed, no relation between the ghrelin and bone mass was found, nor with any of the parameters of calcium metabolism. Only a statistically significant relation between ghrelin and deoxypiridinoline was observed (r = -0.428, p = 0.026). CONCLUSIONS: In postmenopausal hypertensive women, ghrelin may produce a protecting effect over bone mass through an anticatabolic mechanism manifested by a decrease of bone resorption.

Effects of Atorvastatin on vitamin D levels in patients with acute ischemic heart disease.

Vitamin D deficiency is a risk factor for osteoporosis and other chronic diseases, including type 1 diabetes, hypertension, metabolic syndrome, and ischemic heart disease. Cholesterol and vitamin D share the 7-dehydrocholesterol metabolic pathway. This study evaluated the possible effect of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Eighty-three patients (52 men and 31 women) with an acute coronary syndrome (75 with acute myocardial infarction and 8 with unstable angina) were included. After diagnosis, patients received atorvastatin as secondary prevention. Serum vitamin D was measured by high-performance liquid chromatography at baseline and at 12 months. Atorvastatin treatment produced a statistically significant decrease in cholesterol and triglyceride levels and an increase in vitamin D levels (41+/-19 vs 47+/-19 nmol/L, p=0.003). Vitamin D deficiency was decreased by 75% to 57% at 12 months. In conclusion, atorvastatin increases vitamin D levels. This increase could explain some of the beneficial effects of atorvastatin at the cardiovascular level that are unrelated to cholesterol levels.

Effect of beta-blockers on bone mass and biomechanical parameters of the femoral neck in males with acute myocardial infarction.

OBJECTIVES: Evaluate the effect of cardioselective beta-blockers on bone mass and biomechanical properties of the femoral neck in males with acute myocardial infarction. METHODS: Forty males with acute myocardial infarction were studied during one year. Seventy-five percent of the patients (30 patients) were treated with cardioselective beta-blockers and 10 were not similarly treated. A hip densitometry was performed upon release and one year later. The BMD was measured in the femoral neck and in biomechanical elements obtained by DXA. RESULTS: Both groups had similar clinical conditions at the beginning of the study and after a one-year follow-up. No differences in the BMD (0.934+/-0.12 vs. 0.921+/-0.14) were observed in the group without beta-blockers or in the group with beta-blockers (0.980+/-0.12 vs. 0.977+/-0.12). No differences were observed in the measured structural parameters. CONCLUSION: The cardioselective beta-blockers do not modify bone mass or the structural bone parameters in males with acute myocardial infarction.

[Myocardial infarction. Population case-fatality in seven Spanish autonomous communities: the IBERICA Study]. / Mortalidad poblacional por infarto agudo de miocardio. Estudio IBERICA.

BACKGROUND AND OBJECTIVE: The magnitude of the problem of myocardial infarction (MI) is better understood by assessing the population case-fatality than by analyzing only the number of patients attending hospitals. PATIENTS AND METHOD: Our data come from the IBERICA Study (Investigation, Specific Search and Registry of Acute Myocardial Ischemic Syndrome). Twenty eight-day MI population case-fatality is described in the population aged 25 to 74 years during 1997 and 1998 in the following Spanish autonomous communities: Castilla-La Mancha (Toledo and Albacete), Catalonia (Girona), Valencia Community (Valencia), Balearic Islands (Majorca), Murcia, Navarra and Basque Country. The relationship between case-fatality and other variables such as sex, age and geographic area is also analyzed. RESULTS: A total of 10,660 MI cases were registered, 4,106 of whom died within the period of 28 days following the onset of symptoms (38.5%; CI 95%, 37.6-39.4%). The overall case-fatality was 37.0% (CI 95%, 35.9-38.0%) in men and 44.3% (CI 95%, 42.3-46.4%) in women. Death occurred out of hospitals in 2,869 (69.9%) cases. An increased case-fatality in women was associated with a higher in-hospital case-fatality (45% higher than men). The proportion of patients who died before reaching a hospital was similar in both genders. Classical symptoms of MI were more common among men than women (82.7% vs. 77.6%, p < 0,001). The interval between symptoms' onset and hospitalization was 30 minute longer among hospitalized women as compared with men (p < 0,001). CONCLUSIONS: Population MI case-fatality is high in the seven Spanish autonomous communities studied. Approximately 2 out of 3 deaths occur without patients being able to reach a hospital. These results emphasize the importance of primary and secondary prevention measures and the necessity to design ready-access systems to defibrillation and resuscitation manoeuvres for patients with cardiopulmonary arrest.

Mortalidad poblacional por infarto agudo de miocardio. Estudio IBERICA / Myocardial infarction. Population case-fatality in seven Spanish autonomous communities: the IBERICA Study

FUNDAMENTO Y OBJETIVO: El estudio de la mortalidad poblacional del infarto agudo de miocardio (IAM), que incluye las muertes ocurridas antes de llegar al hospital, ofrece una visión más completa sobre la magnitud del problema que la obtenida estudiando únicamente la mortalidad de los casos que reciben atención hospitalaria. PACIENTES Y MÉTODO: Los datos provienen del estudio IBERICA (Investigación, Búsqueda Específica y Registro de Isquemia Coronaria Aguda). Se describe la mortalidad en los primeros 28 días desde el inicio de los síntomas de los episodios de IAM registrados, durante 1997 y 1998, en la población de 25 a 74 años residente en 7 comunidades autónomas españolas: Castilla-La Mancha (Toledo y Albacete), Cataluña (Girona), Comunidad Valenciana (Valencia), Islas Baleares (Mallorca), Murcia, Navarra y País Vasco. Además, se estudia la relación entre mortalidad y otras variables como el sexo, la edad y el área geográfica. RESULTADOS: Se registraron 10.654 casos de IAM de los que 4.105 fallecieron durante los 28 primeros días (38,5 por ciento; intervalo de confianza [IC] del 95 por ciento, 37,6-39,4 por ciento). La mortalidad fue del 37,0 por ciento (IC del 95 por ciento, 35,9-38,0 por ciento) en los varones y del 44,3 por ciento (IC del 95 por ciento, 42,3-46,4 por ciento) en las mujeres. La muerte se produjo fuera del hospital en 2.869 (69,9 por ciento) casos. La mayor mortalidad en mujeres estuvo relacionada fundamentalmente con una mayor mortalidad hospitalaria (45 por ciento superior a la registrada en los varones), siendo menor la diferencia en la proporción de casos que fallecieron fuera del hospital. La sintomatología típica de presentación del episodio fue más frecuente en varones (el 82,7 frente al 77,6 por ciento) (p < 0,001). Entre los pacientes que llegaron vivos al hospital, el tiempo transcurrido entre el comienzo de los síntomas y el inicio del tratamiento fue, en promedio, 30 min menor en los varones (p < 0,001). CONCLUSIONES: La mortalidad poblacional por IAM en estas 7 áreas españolas es muy elevada aunque inferior a la de otros países industrializados. Aproximadamente dos de cada tres muertes ocurren antes de llegar al hospital. Estos datos refuerzan el papel prioritario de la prevención primaria y secundaria, ya que los cuidados hospitalarios tienen un impacto limitado en el control de la mortalidad poblacional por IAM. También indican que una forma de reducir la mortalidad debería incluir el acceso rápido a la desfibrilación y a las maniobras de resucitación de los pacientes que presenten una muerte súbita (AU)