GianLuca Colussi

Renal cysts and hypokalemia in primary aldosteronism: results of long-term follow-up after treatment

Background Cross-sectional studies have reported an elevated prevalence of renal cysts in patients with primary aldosteronism. The nature of this association could be related to hypokalemia and/or hypertension and has never been evaluated in prospective studies. Methods A consecutive sample of 54 patients with tumoral or idiopathic primary aldosteronism was followed after adrenalectomy or treatment with aldosterone antagonists. At baseline, renal cysts were evaluated by renal ultrasound and patients with primary aldosteronism were compared with 323 essential hypertension patients with the same severity and duration of disease, and 113 age- and sex-matched normotensive subjects. Results The adjusted prevalence and average number of renal cysts were significantly greater in patients with primary aldosteronism than in patients with essential hypertension and normotensive subjects. Multivariate analysis revealed that age and plasma potassium levels were independently associated with the presence of renal cysts in patients with primary aldosteronism. Treatment of primary aldosteronism decreased blood pressure (BP) and restored normal potassium concentrations. After a median follow-up of 6.2 years, no significant change from baseline of cyst number and cyst total volume was observed in patients with both tumoral and idiopathic aldosteronism and in a subset of 100 patients with essential hypertension. In patients with primary aldosteronism, stepwise logistic analysis showed that the presence of renal cysts was associated with worse BP outcome after treatment. Conclusion Renal cystic disease is highly frequent in patients with primary aldosteronism and either surgical or medical treatment halt its progression, supporting the contention that hypokalemia and its severity are the main contributors to cyst formation in these patients.

Predictive factors of left ventricular mass changes after treatment of primary aldosteronism.

A variety of abnormalities that occur in patients with primary aldosteronism indicate the capability of elevated aldosterone to induce cardiac damage over that induced by hypertension itself. This study investigates factors that can predict structural and functional changes of the heart after treatment of primary aldosteronism in a post-hoc analysis of 54 patients who were enrolled in a long-term follow-up study that was conducted after either adrenalectomy or treatment with spironolactone. Cardiac ultrasound assessment was performed before treatment and after with an average follow-up of 6.4 years. During follow-up, blood pressure decreased significantly and comparably in both treatment groups. In both treatment groups, left ventricular mass decreased significantly with a trend to improved diastolic filling profile and no changes in ventricular geometry. At univariate analysis, changes in left ventricular mass induced by treatment of primary aldosteronism were directly related with changes in systolic blood pressure and pretreatment plasma aldosterone levels measured both at baseline and after an intravenous saline load. This relationship was maintained when patients treated with adrenalectomy and spironolactone were analyzed separately. Multivariate regression analysis showed that changes in systolic blood pressure and pretreatment aldosterone levels were independent predictors of left ventricular mass changes after treatment. This study strongly supports a role of aldosterone in promoting left ventricular hypertrophy that is independent of the hypertension-related hemodynamic load and suggests a practical way to predict left ventricular mass changes following surgical and medical treatment of primary aldosteronism.

Involvement of endothelium-dependent and-independent mechanisms in midazolam-induced vasodilation

Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10u2009μmolu2009l−1 midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50u2009μmolu2009l−1 midazolam. Only the low concentration of midazolam (10u2009μmolu2009l−1) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50u2009μmolu2009l−1) reduced the CaCl2-induced vasoconstriction of aortic rings with EC50 (the concentration giving 50% of the maximal effect) values of 1 and 6u2009mmolu2009l−1 for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central γ-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation.

Mineralocorticoid Receptor Antagonists and Clinical Outcomes in Primary Aldosteronism: As Good as Surgery?

Primary aldosteronism (PA) is detected with increasing frequency in hypertensive patients and is associated with excess cardiovascular, renal, and metabolic complications. For these reasons, appropriate choices for treatment of this endocrine condition are mandatory. Adrenalectomy is safely performed in PA patients when adrenal venous sampling (AVS) demonstrates lateralized aldosterone secretion. AVS, however, is a complex procedure and even among worldwide referral centers there are substantial discrepancies for interpretation of results. Also, in the majority of PA patients with lateralized aldosterone secretion, hypertension may persist after adrenalectomy requiring use of additional antihypertensive agents. Treatment with mineralocorticoid receptor antagonists (MRAs) is currently recommended for PA patients with bilateral adrenal disease, but these agents effectively decrease blood pressure also in patients with unilateral disease, although concern remains for possible sex-related side effects. Prospective studies indicate that MRAs have therapeutic values comparable to surgery in the long-term, inasmuch as they effectively correct metabolic abnormalities and subclinical organ damage and reduce the risk of cardiovascular events and renal disease progression. This article overviews the clinical outcomes obtained in patients with PA with use of MRAs.

Salt, Aldosterone, and Parathyroid Hormone: What Is the Relevance for Organ Damage?

Structured interventions on lifestyle have been suggested as a cost-effective strategy for prevention of cardiovascular disease. Epidemiologic studies demonstrate that dietary salt restriction effectively decreases blood pressure, but its influence on cardiovascular morbidity and mortality is still under debate. Evidence gathered from studies conducted in patients with primary aldosteronism, essential hypertension, or heart failure demonstrates that long-term exposure to elevated aldosterone results in cardiac structural and functional changes that are independent of blood pressure. Animal experiments and initial clinical studies indicate that aldosterone damages the heart only in the context of an inappropriately elevated salt status. Recent evidence suggests that aldosterone might functionally interact with the parathyroid hormone and thereby affect calcium homeostasis with important sequelae for bone mineral density and strength. The interaction between aldosterone and parathyroid hormone might have implications also for the heart. Elevated dietary salt is associated on the one hand with increased urinary calcium excretion and, on the other hand, could facilitate the interaction between aldosterone and parathyroid hormone at the cellular level. This review summarizes the evidence supporting the contribution of salt and aldosterone to cardiovascular disease and the possible cardiac and skeletal consequences of the mutual interplay between aldosterone, parathyroid hormone, and salt.

THE ARTERIAL STIFFNESS IS INFLUENCED BY THE HEMOSTATIC SYSTEM IN NON-DIABETIC HYPERTENSIVE PATIENTS

Objective: In the general population an increased arterial stiffness is associated with a high risk of cardiovascular events. In essential hypertension high plasma fibrinogen and D-dimer levels are associated with cardiovascular damage. The aim of this study was to search for a relationship between indexes of activation of the coagulation system and parameters of arterial stiffness, such as the pulse wave velocity (PWV) and the augmentation index (AIx), in essential hypertensive patients without diabetes or renal failure. Design and method: In 76 hypertensive patients (age 52u200a±u200a14 y; 35 male; 30 never treated with antihypertensive drugs) we evaluated clinical and anthropometric variables, plasma level of glucose, lipids, fibrinogen and D-dimer, and creatinine clearance, PWV e AIx. Results: Patients were subdivided into tertiles of PWV. Patients with higher PWV were older, more frequently males, had a greater percentage of antihypertensive drugs, a greater alcohol consumption, and higher fibrinogen e D-dimer levels than in patients with lower PWV. At univariate analysis the PWV was significantly and directly related to age, BMI, systolic pressure, duration of hypertension, alcohol intake, plasma levels of glucose, fibrinogen (ru200a=u200a0.369, Pu200a=u200a0.001) and D-dimer (ru200a=u200a0.390, Pu200a<u200a0.001). The PWV was higher in males than females (Pu200a=u200a0.036) and in previously treated patients than in naive subjects (Pu200a=u200a0.003). At multivariate analysis including PWV as the dependent variable, PWV was independently associated with age (betau200a=u200a0.310, Pu200a=u200a0.015) and D-dimer levels (betau200a=u200a0.222, Pu200a=u200a0.049). At univariate analysis AIx was significantly and directly related to age, total and LDL-cholesterol, fibrinogen (ru200a=u200a0.349, Pu200a=u200a0.002), and inversely related to diastolic pressure, and it was higher in previous treated than in never treated patients. At multivariate analysis AIx was independently associated with age (betau200a=u200a0.235, Pu200a=u200a0.048) and LDL-cholesterol (betau200a=u200a0.328, Pu200a=u200a0.003). Conclusions: This study supports the hypothesis of an association of a prothrombotic state with the vascular damage of hypertension that might contribute to the cardiovascular risk in these patients.

PREECLAMPTIC WOMEN WITH FEATURES OF SUBCLINICAL SECONDARY HYPERPARATHYROIDISM HAVE ELEVATED BLOOD PRESSURE LEVELS AFTER DELIVERY

Objective: Calcium supplementation has shown beneficial effects on blood pressure and its metabolism is altered in pregnancy hypertensive-related disorders. In this study, we hypothesized that calcium metabolism can be associated with blood pressure levels in preeclampsia complicated pregnancy. Design and method: A group of 63 multiethnic preeclamptic women (age 35u200a±u200a6 y., 83% European, 14% African, and 3% Hispanic) was consecutively recruited at our Hypertension Unit at 1 month after delivery. We collected clinical and anthropometric variables, blood and urinary samples and performed 24-hours ambulatory blood pressure monitoring (ABPM). We measured plasma and 24-hours urinary calcium, plasma 25-hydroxycholecalciferol, parathyroid hormone (PTH), and creatinine levels, and 24-hours protein excretion. Renal function was estimated by the Modification of Diet in Renal Disease (MDRD) study equation. No women knew to be hypertensive before the current pregnancy or took calcium or vitamin D supplements. Results: At recruitment, 60% of women were taking antihypertensive agents, all of which alpha-methyldopa. For statistical purposes, we divided the group in tertiles according to PTH levels. Women in the third tertile showed biochemical characteristics of secondary hyperparathyroidism with elevated PTH and reduced vitamin D plasma levels (PTH 93u200a±u200a15u200apg/ml; 25-hydroxycholecalciferol 20u200a±u200a8u200ang/ml). In-office and ABPM blood pressure levels were higher in the third tertile then those in the first. At univariate analysis, PTH was directly associated with in-office systolic (Pearsons correlation coefficient ru200a=u200a0.417; Pu200a<u200a0.001) and diastolic (ru200a=u200a0.372; Pu200a=u200a0.003), 24-hours systolic (ru200a=u200a0.449; Pu200a<u200a0.001) and diastolic (ru200a=u200a0.401; Pu200a=u200a0.001), daytime systolic (ru200a=u200a0.421; Pu200a<u200a0.003) and diastolic (ru200a=u200a0.378; Pu200a=u200a0.002), and nighttime systolic (ru200a=u200a0.379; Pu200a=u200a0.002) and diastolic (ru200a=u200a0.442; Pu200a<u200a0.001) blood pressure. Multivariate analysis showed that PTH was associated with systolic and diastolic in-office and 24-hours blood pressure levels independently of age, body mass index, gestational week of delivery, plasma and urinary calcium, vitamin D, renal function, and urinary protein excretion. Conclusions: Plasma PTH is independently associated with blood pressure levels in the post-partum and higher blood pressure was observed in preeclamptic women with subclinical secondary hyperparathyroidism. Further evaluations on the effects of calcium and vitamin D supplementation on blood pressure control of women with a preeclamptic complication should be performed.

Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study

Carotid artery stenting (CAS) is a minimal invasive procedure used to resolve carotid occlusion that can be affected by peri-procedural complications. Statin use before CAS has shown to reduce peri-procedural risk and improve survival, though time-dependent cofactors that influence mortality has not been considered. The aim of this study was to evaluate long-term survival of patients who undergo CAS considering new occurred major adverse cardiovascular event (MACE) as time-dependent cofactor. In this study, 171 high cardiovascular risk patients (age 72 ± 8 years, 125 males) were enrolled after CAS procedure and were followed for a median of 8.4 years. Death occurred in 44% of patients with a mean time to death of 69 ± 39 months and MACE in 34% with a mean time of 35 ± 42 months. In patients who used or not statins at baseline, death occurred in 33% and 65%, respectively (p < 0.001). Survival analysis showed that statin use reduced risk of death (hazard ratio HR 0.36, 95% confidence interval CI 0.23–0.58, p < 0.0001). Including MACE as time-dependent variable did not change beneficial effects of statins. Additionally, statin use was associated with a protective effect on MACE (HR 0.48, 95% CI 0.27–0.85, p = 0.012); particularly, the prevalence of stroke was reduced by 59% (p = 0.018). In multivariate analysis, effects of statins were independent of demographic and anthropometric variables, prevalence of cardiovascular risk factors, renal function, antiplatelet use, and MACE occurrence. In conclusion, use of statins before CAS procedure is associated with increased long-term survival and reduced MACE occurrence. This evidence supports the hypothesis that statin use before CAS might be beneficial in high risk patients.

Atrial fibrillation and its complications in arterial hypertension: The potential preventive role of ω-3 polyunsaturated fatty acids

ABSTRACT Atrial fibrillation (AF) is the most common type of arrhythmia in the general population with a prevalence that reaches one third of patients with arterial hypertension. Several risk factors frequently associated with hypertension predispose the myocardium to AF by inducing atrial inflammation and fibrosis and altering atrial electrical and mechanical characteristics. AF influences the quality of life of hypertensive patients since it increases incidence of stroke and other thromboembolic events, and mortality. Polyunsaturated fatty acids of the ω-3 family (ω-3 PUFA) have been demonstrated to be beneficial in cardiovascular disease prevention by reducing plasma lipids and blood pressure levels and decreasing the risk of sudden death. These fatty acids can act as potent anti-inflammatory and anti-arrhythmic agents. Many studies have investigated a possible preventive effect of ω-3 PUFA on incident AF reporting contradictory results. This article overviews the evidence currently available on this important topic and provides some conclusive remarks on the possibility that these fatty acids could be beneficial in hypertensive patients.

Long-Term Renal and Cardiac Outcomes after Stenting in Patients with Resistant Hypertension and Atherosclerotic Renal Artery Stenosis

Background/Aims: Atherosclerotic renal artery stenosis (ARAS) is frequently detected in patients with resistant hypertension (RHTN), but the evidence supporting the utility of renal revascularization in these patients is limited. This prospective, observational study investigates the outcomes of renal stenting in patients with RHTN and hemodynamically significant ARAS. Methods: Fifty-four patients with RHTN were selected because of angiographic evidence of ARAS >70% and were followed for 4 years after renal stenting. Renal function and echocardiographic variables were assessed at baseline and during follow-up. Results: Blood pressure decreased rapidly after renal stenting and was normalized in 67% of patients at six months, with significant reduction in the number of antihypertensive drugs. Creatinine clearance increased in 39% of patients, decreased in 52%, and remained stable in the remaining 9%, with an average value that had a nonsignificant decrease during follow-up. Urinary albumin excretion did not change throughout the study. After 4 years, left ventricular (LV) wall thickness and concentric geometry decreased significantly and variables of LV diastolic function improved. Conclusion: In patients with RHTN, stenting of hemodynamically significant ARAS decreases blood pressure, preserves renal function in a substantial proportion of patients, and improves LV structure and function, suggesting the opportunity for timely identification of ARAS in these patients.