Impact of simultaneous management of hypertension and hypercholesterolemia with ACE inhibitors and statins on cardiovascular outcomes in the Brisighella Heart Study: A 8-year follow-up.

BACKGROUND AND AIMS: To evaluate the long-term effect of simultaneous treatment of hypertension and hypercholesterolemia with angiotensin-converting enzyme (ACE) inhibitors and statins on the incidence of major cardiovascular events (MACE) and other clinical outcomes. METHODS AND RESULTS: We considered data from a subset of Brisighella Heart Study (BHS) participants who were consecutively evaluated in three epidemiological surveys between 2012 and 2020. We excluded normotensive subjects and individuals with a low calculated 10-year CVD risk, hypertensive patients treated with antihypertensive drugs different from ACE inhibitors and patients who changed antihypertensive medications during follow-up. The remaining participants were divided into four groups depending on whether they were treated with (I) perindopril ± amlodipine without statin treatment (N. 132), (II) perindopril ± amlodipine and atorvastatin (N. 132), (III) an ACE inhibitor other than perindopril ± a calcium-channel blocker without statin therapy (N. 133), (IV) an ACE inhibitor other than perindopril ± a calcium-channel blocker and statin therapy (N. 145). The long-term (8 years) effects of the different combined treatment were compared among the pre-defined groups. Over the follow-up period of 8 years, the proportion of subjects who developed MACE, type 2 diabetes mellitus and hyperuricemia, and the proportion of subjects needing for the intensification of antihypertensive treatment to improve blood pressure control were statistically different among the predefined groups (P < 0.05). CONCLUSION: Combined treatment with ACE inhibitors and statins (especially atorvastatin) in hypertensive patients seems to significantly reduce the risk of developing CVD in comparison with treatment with ACE inhibitors alone.

Role of calcium-sensing receptor in bone biology.

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Salt intake, hypertension, and osteoporosis.

A high salt intake has been correlated with several pathological conditions such as hypertension, cardiovascular disease, renal calcium stones, and osteoporosis. Some of these diseases present a high prevalence in the elderly and common pathogenetic mechanisms are proposed for some of them. A high salt intake has been associated with hypertension as well as osteoporosis and one of the proposed pathogenetic mechanisms is an increased calcium excretion in urine. Urinary calcium loss induces a negative calcium balance that may predispose hypertensive subjects to developing greater bone loss. The gene which encodes for the thiazide- sensitive sodium-chloride cotransporter (NCCT) represents a possible link between hypertension and osteoporosis. Subjects heterozygous for an inactivating mutation of NCCT present a positive effect on bone density as shown by the significantly higher Z-scores at the lumbar spine and total femur. Recent clinical studies also support the benefit of ACE inhibitors in reducing fracture risk or improving bone metabolism. These data suggest that the renin-angiotensin system may be one of the several factors involved in bone metabolism. Hypertension, together with stroke, has been demonstrated to be a risk factor for osteoporosis. Although the risk associated with hypertension was limited in terms of relative risk, it may have a significant impact on the general population owing to the high prevalence of hypertension. The treatment of hypertension may thus be very useful in also giving protection against fractures.

Long-term potassium citrate therapy and bone mineral density in idiopathic calcium stone formers.

Several authors have described an association between idiopathic calcium (Ca) stone disease and bone mass reduction. Hypocitraturia is a frequent feature of urolithiasis, and alkaline citrate has been recommended as one of the choice treatments in this disease. Some evidence exists as to the positive effect of potassium (K) citrate therapy on bone mass. The aim of this work was the longitudinal evaluation of bone mineral density (BMD) changes in a group of Ca oxalate stone formers treated with K citrate for two years. Enrolled patients were 120; 109 subjects completed the study (51 males and 58 females). A metabolic study and distal radius BMD measurements were conducted both at baseline (BAS) and at the end of the study (END). BMD (0.451 +/- 0.081 vs 0.490 +/- 0.080 g/cm2), T-score (-1.43 +/- 1.02 vs -0.90 +/- 1.04), net gastrointestinal alkali absorption (40.37 +/- 50.57 vs 61.26 +/- 42.26 mEq/day), urinary citrate (2.53 +/- 1.15 vs 3.10 +/- 1.44 mmol/day) and K (58.93 +/- 22.28 vs 65.45 +/- 23.97 mmol/day) excretion significantly increased from BAS to END. Urinary Ca excretion remained unchanged from BAS to END (5.16 +/- 2.74 vs 5.57 +/- 2.85 mmol/ day). Our results indicate that long-term treatment with K citrate increases forearm BMD in idiopathic Ca stone formers. It seems probable that the alkali load provided by this drug reduces bone resorption by a buffering of the endogenous acid production. K citrate appears to be a further therapeutic opportunity for the management of osteoporosis in Ca stone formers.

Comparative study of the influence of 3 types of mineral water in patients with idiopathic calcium lithiasis.

PURPOSE: While there is general agreement on the need to increase urinary volume in stone formers, contrasting opinions have been expressed about the hardness of water and stone incidence. We evaluate the influence of 3 types of mineral water on urinary analytes in 22 idiopathic calcium oxalate stone formers. MATERIALS AND METHODS: All patients underwent a nutritional and metabolic evaluation at baseline, and after a controlled diet including water with a high, medium or low calcium content. RESULTS: In patients who drank water with high and medium calcium contents calcium excretion increased, although the results did not reach statistical significance. In those who drank water with the highest calcium content oxalate excretion significantly decreased (p = 0.05), as did the oxalate-to-calcium ratio (p = 0.05). Moreover, these modifications did not induce relevant changes in urinary saturation. In patients who drank water with the greatest amount of bicarbonate citrate excretion increased (p = 0.03). CONCLUSIONS: Mineral water with a higher calcium content induced increased calcium excretion but significantly decreased oxalate excretion. These data are in accordance with those of others, who did not find definite evidence that hard water is more lithogenic than soft water. Furthermore, water components other than calcium can modify the tendency toward crystal formation, affecting inhibitory power and/or lithogenic salt excretion.

Renal stone formation in patients with inflammatory bowel disease.

Kidney stones are more common in patients with inflammatory bowel disease (IBD) than in the general population. The main lithogenetic risk factors were evaluated in patients affected by Crohn's disease and ulcerative colitis. Our results show the presence of several factors, besides hyperoxaluria, in patients with IBD although their behaviour appears different in Crohn's disease and ulcerative colitis at pre- and post-operative stages. Before surgery in patients with Crohn's disease we found a decreased citrate (p < 0.001) and magnesium (p < 0.005) excretion together with a low urinary volume (p < 0.001) and pH (p < 0.005). After surgery patients with Crohn's disease showed a further reduction of magnesium and citrate. Patients with ulcerative colitis before surgery showed a reduced citrate excretion (p < 0.05) and a more acidic pH (p < 0.05) than healthy subjects. Surgical treatment of proctocolectomy with ileal pouch-anal anastomosis seems to increase the risk of stone formation; in fact, after surgery we observed a relevant decrease of urinary volume (p < 0.001), pH (p < 0.0001) and urinary excretion of citrate (p < 0.0001) as well as magnesium (p < 0.005). Patients with IBD seem to be at greater risk of stone formation than patients with idiopathic calcium lithiasis; in fact, they show a lower excretion of citrate (p < 0.001) and magnesium (p < 0.001) together with a low urinary pH (p < 0.001) and volume (p < 0.001). Urinary volume reduction is probably one of the major risk factors together with the decrease of small molecular weight inhibitors that is a constant finding in all patients with IBD.

Relationships between some lithogenetic factors and vitamin B6-status in idiopathic calcium lithiasis.

Several researchers have shown that a reduced intake of vitamin B6 can induce increased oxalate urinary excretion leading to a higher incidence of calcium oxalate stones. Furthermore, the treatment with pyridoxine in patients with urinary stones and high oxalate excretion has led to contradictory results as the excretion of oxalate was either decreased, unchanged or increased. To verify if these divergent results were linked to a different B6 status of the patients undergoing the treatment, we studied the vitamin B6 and the main lithogenetic factor levels in patients with idiopathic calcium lithiasis as compared to normal subjects. The results showed that a high oxalate excretion is not necessarily coupled with a low vitamin B6 status and viceversa. However, some stone formers present a non homogeneous vitamin pattern that could be the consequence of an abnormal vitamin B6 metabolism.

Idiopathic calcium urolithiasis: genetic aspects.

Seventy-nine stone-formers underwent a metabolic investigation and ABO blood group determination. Incidence of blood groups in patients was similar to ABO phenotypes distribution in general population. The 37.7 p. 100 showed family history for stones. Idiopathic hypercalciuria was present in 40.3 p. 100 of cases; stone-formers with positive family history had a higher incidence of hypercalciuria (46.8 p. 100) than subjects without affected relatives (31.5 p. 100). Patients with blood group A displayed hypercalciuria in the 54.5 p. 100 of cases while subjects with blood group O only in the 30.7 p. 100 (p less than 0.05). Glycosaminoglycans (GAGs) were reduced in the 36.9 p. 100 of the whole group and particularly in patients of blood group A. Patients with blood group A, with positive family history, showed higher mean values of calcium excretion and lower ones of GAGs. Our results seem to suggest that not only familiar factors play a significant role in stone disease pathogenesis but also some metabolic alteration may be linked to ABO phenotypes.

Preliminary results of glycosminoglycans excretion in normal and stone forming subjects: relationship with uric acid excretion.

In calcium lithiasis, pathogenesis inhibitors have a significant role to play which permits raising of the upper metastability limit in the urine, thus reducing the crystallization processes. The aim of this work is to evaluate glycosaminoglycans excretion and concentration in a group of patients with idiopathic calcium lithiasis, and in a control group for detecting possible differences between the 2 groups. Analysis of our results shows that no significant differences exist between the 24-hour average excretion of glycosaminoglycans in normal and stone forming subjects, but there was a significant difference in the mean concentration values between the 2 groups, either as whole or when separately considered with respect to normal or increased uric acid excretion. Particularly interesting was the correlation study between glycosaminoglycans and uric acid which shows a linear relationship with a positive slope in all groups but in stone formers with hyperuricosuria.