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Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the "Eplerenone in Primary Hyperparathyroidism" (EPATH) Trial. Multivariate linear regression analyses with LV ejection fraction (LVEF, systolic function) or peak early transmitral filling velocity (e', diastolic function) as dependent variables and N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin (OC), bone-specific alkaline phosphatase (BALP), or beta-crosslaps (CTX) as the respective independent variable were performed. Analyses were additionally adjusted for plasma parathyroid hormone, plasma calcium, age, sex, HbA1c, body mass index, mean 24-hours systolic blood pressure, smoking status, estimated glomerular filtration rate, antihypertensive treatment, osteoporosis treatment, 25-hydroxy vitamin D and N-terminal pro-brain B-type natriuretic peptide. Independent relationships were observed between P1NP and LVEF (adjusted β-coefficient = 0.201, P = 0.035) and e' (β = 0.188, P = 0.042), respectively. OC (β = 0.192, P = 0.039) and BALP (β = 0.198, P = 0.030) were each independently related with e'. CTX showed no correlations with LVEF or e'. In conclusion, high bone formation markers were independently and paradoxically related with better LV diastolic and, partly, better systolic function, in the setting of pHPT. Potentially cardio-protective properties of stimulated bone formation in the context of hyperparathyroidism should be explored in future studies.

Aims: To overview the effects of omega-3 polyunsaturated fatty acids (PUFA) on blood vessels and blood pressure (BP) and their relevance for cardiovascular prevention., Data Synthesis: The importance of omega-3 PUFA for the cardiovascular system has come under the spotlight during the last decades. These fatty acids are present in variable amounts in cell membranes of mammal species, and their content affects a variety of cellular functions. Evidence obtained in animal and human studies suggests that omega-3 PUFA affect many steps of the atherosclerotic process. In blood vessels, omega-3 PUFA improve endothelial function; promote vasodilatation through relaxation of smooth muscle cells; exert antioxidant, anti-inflammatory, and antithrombotic actions; delay development of plaques and increase their stability; and decrease wall stiffening. Omega-3 PUFA might affect BP, and studies conducted with ambulatory monitoring suggest that supplementation with these fatty acids decreases the average 24-h BP levels. This effect on BP is related to the pretreatment membrane content of omega-3 PUFA, and this might explain some inconsistencies among intervention trials. Meta-analyses indicate that omega-3 PUFA have a mild but significant BP lowering effect. While encouraging results were initially obtained with the use of omega-3 PUFA supplements in secondary prevention trials, meta-analyses have not confirmed the ability of these fatty acids to decrease the risk of coronary heart and cerebrovascular disease., Conclusions: Omega-3 PUFA are associated with significant improvement in vascular function and lowering of BP. However, the evidence currently supporting the role of these fatty acids in cardiovascular prevention is weak and needs further investigation., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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.

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., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Ethanol consumption is associated with left ventricular dysfunction in heavy ethanol drinkers. The effect of moderate ethanol intake on left ventricular function in hypertension, however, is unknown. We investigated the relationship between ethanol consumption and cardiac changes in nonalcoholic hypertensive patients. In 335 patients with primary hypertension, we assessed daily ethanol consumption by questionnaires that combined evaluation of recent and lifetime ethanol exposure and examined cardiac structure and function by echocardiography. Patients with abnormal liver tests, previous cardiovascular events, left ventricular ejection fraction <50%, and creatinine clearance <30 mL/min 1.72 m 2 were excluded. Left ventricular hypertrophy was found in 21% of hypertensive patients and diastolic dysfunction was detected in 50% by tissue-Doppler imaging. Ethanol consumption was comparable in hypertensive patients with and without left ventricular hypertrophy, whereas patients with left ventricular diastolic dysfunction had significantly greater consumption than patients with normal ventricular filling. Left atrial diameter, e' wave velocity, e'/a' ratio, and E/e' ratio changed progressively with increasing levels of ethanol consumption, and prevalence of left ventricular diastolic dysfunction increased with a change that became statistically significant in patients consuming 20 g/d of ethanol or more. The e' wave velocity was inversely correlated with ethanol consumption, and multivariate logistic regression indicated that ethanol consumption predicted diastolic dysfunction independently of age, body mass index, blood pressure, insulin sensitivity, and left ventricular mass index. In conclusion, ethanol consumption is independently associated with left ventricular diastolic dysfunction in nonalcoholic hypertensive patients and might contribute to development of diastolic heart failure., (© 2016 American Heart Association, Inc.)

Objectives: The high prevalence of arterial hypertension in primary hyperparathyroidism (pHPT) is largely unexplained. Apart from parathyroid hormone (PTH), the mineral hormones fibroblast growth factor (FGF)-23 and aldosterone-to-renin ratio (ARR) are upregulated in pHPT. We aimed to determine whether nocturnal blood pressure (BP) is related with PTH, FGF-23 or ARR in a relatively large sample of pHPT patients., Methods: Cross-sectional data of the single-center "Eplerenone in Primary Hyperparathyroidism" trial were used. All patients with a biochemical diagnosis of pHPT who had both available 24-h ambulatory BP monitoring and valid laboratory data were included., Results: Full data were available in 136 patients (mean age 67 ± 10 years, 78% women). Median PTH was 99 (interquartile range: 82-124) pg/ml and mean calcium was 2.63 ± 0.15 mmol/l. ARR, but not PTH or FGF-23, was significantly and directly related with nocturnal SBP (Pearson's r = 0.241, P < 0.01) and DBP (r = 0.328, P < 0.01). In multivariate regression analyses, with adjustment for age, sex, PTH, FGF-23, traditional cardiovascular risk factors, antihypertensive medication and parameters of calcium metabolism ARR remained significantly and directly related with nocturnal BP (SBP: adjusted β-coefficient = 0.289, P < 0.01; DBP: β = 0.399, P < 0.01). The relationship between ARR and nocturnal SBP was exclusively present in patients with PTH levels above the median of 99 pg/ml., Conclusion: ARR, but not FGF-23 or PTH, was independently and directly related with nocturnal BP parameters in patients with pHPT, and this relationship was dependent on pHPT disease severity. Inappropriately, elevated aldosterone may partially explain the high prevalence of arterial hypertension in pHPT.

Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and "trim and fill" tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: -15.72 ng/ml, 95 % confidence interval [CI]: -25.01, -6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: -21.32 ng/ml, 95 % CI: -32.73, -9.91, I²=99 %) and particularly atorvastatin (WMD: -20.88 ng/mL, 95 % CI: -28.79, -12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.

Primary aldosteronism is associated with increased left ventricular (LV) mass independently of blood pressure. Previous studies suggest that elevated aldosterone causes cardiac damage only in the presence of an inappropriate salt status. We examined the relevance of dietary salt intake on cardiac changes in patients with primary aldosteronism before and after treatment. Sixty-five patients with tumoral or idiopathic primary aldosteronism were recruited at a University medical center and followed after either surgical (n=30) or medical (n=35) treatment. At baseline and 1 year after treatment, cardiac morphology and functional variables were measured by echocardiography together with duplicate 24-hour urinary sodium collections. At baseline, LV mass index was associated with urinary sodium excretion and plasma aldosterone levels. During follow-up, blood pressure (from 167/102-135/83 mm Hg; P<0.001) and LV mass index (from 50.5±13.0-44.4±8.9 g/m(2.7); P<0.001) decreased significantly with nonsignificant changes in LV geometry and functional properties. At the end of follow-up, percentage decrease in LV mass index was significantly greater in patients who had >10% reduction in urinary sodium excretion (15.0±12.5%) than in the remaining patients (5.5±9.3%; P<0.001). Changes in LV mass index induced by both surgical and medical treatment were directly and independently correlated with changes in blood pressure (β=0.419; P=0.009) and urinary sodium excretion (β=0.334; P=0.012) observed at follow-up. These findings strongly support the hypothesis that dietary salt intake has a crucial role in aldosterone-related LV changes and could contribute to cardiac damage in patients with primary aldosteronism., (© 2016 American Heart Association, Inc.)

High parathyroid hormone (PTH) has been linked with high blood pressure (BP), but the relationship with 24-hour ambulatory blood pressure monitoring is largely unknown. The authors therefore analyzed cross-sectional data of 292 hypertensive patients participating in the Styrian Hypertension Study (mean age, 61±11 years; 53% women). Median plasma PTH (interquartile range) determined after an overnight fast was 49 pg/mL (39-61), mean daytime BP was 131/80±12/9 mm Hg, and mean nocturnal BP was 115/67±14/9 mm Hg. In multivariate regression analyses adjusted for BP and PTH-modifying parameters, PTH was significantly related to nocturnal systolic and diastolic BP (adjusted β-coefficient 0.140 [P=.03] and 0.175 [P<.01], respectively). PTH was not correlated with daytime BP readings. These data suggest a direct interrelationship between PTH and nocturnal BP regulation. Whether lowering high PTH concentrations reduces the burden of high nocturnal BP remains to be shown in future studies., (©2015 Wiley Periodicals, Inc.)

Background: Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity in hypertension. Current evidence suggests a contribution to LVH of plasma aldosterone levels that are inappropriately elevated for the salt status. The aim of this study was to investigate whether inappropriate modulation of aldosterone production by a saline load is associated with left ventricular (LV) mass in hypertensive patients., Methods: In 90 hypertensive patients free of clinically relevant cardiovascular complications in whom secondary forms of hypertension were ruled out, we performed a standard intravenous saline load (0.9% NaCl, 2 l in 4 hours) with measurement of plasma aldosterone and active renin at baseline and end of infusion. Bi-dimensional echocardiography was performed for the assessment of cardiac morphology and function., Results: LVH was present in 19% of patients who had significantly worse renal function and higher body mass, blood pressure, and plasma aldosterone levels measured both at baseline and after the saline load than patients without LVH. LV mass was directly related to age, body mass, systolic blood pressure, duration of hypertension, baseline, and post-saline load plasma aldosterone levels and inversely to glomerular filtration. Multivariate regression analysis showed independent correlation of LV mass with body mass, systolic blood pressure, and plasma aldosterone levels measured after intravenous saline load, but not at baseline., Conclusions: In patients with hypertension, aldosterone levels measured after intravenous saline load are related to LV mass independent of age, body mass, and blood pressure, suggesting that limited ability of salt to modulate aldosterone production could contribute to LVH., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aldosterone is considered to exert direct effects on the myocardium and the sympathetic nervous system. Both QT time and heart rate (HR) variability (HRV) are considered to be markers of arrhythmic risk and autonomous dysregulation. In this study, we investigated the associations between aldosterone, QT time, and HRV in patients with arterial hypertension.We recruited 477 hypertensive patients (age: 60.2 ± 10.2 years; 52.3% females) with a mean systolic/diastolic 24-hour ambulatory blood pressure monitoring (ABPM) value of 128 ± 12.8/77.1 ± 9.2 mmHg and with a median of 2 (IQR: 1-3) antihypertensive agents. Patients were recruited from the outpatient clinic at the Department of Internal Medicine of the Medical University of Graz, Austria. Blood samples, 24-hour HRV derived from 24-hour blood pressure monitoring (ABPM) and ECG's were obtained. Plasma aldosterone and plasma renin concentrations were measured by means of a radioimmunoassay. Twenty-four-hour urine specimens were collected in parallel with ABPM.Mean QTc was 423.3 ± 42.0 milliseconds for males and 434.7 ± 38.3 milliseconds for females. Mean 24H-HR and 24H-HRV was 71.9 ± 9.8 and 10.0 ± 3.6 bpm, respectively. In linear regression analyses adjusted for age, sex, body mass index, ABPM, and current medication, aldosterone to active renin ratio (AARR) was significantly associated with the QTc interval, a marker for cardiac repolarization abnormalities (mean = 426 ± 42.4 milliseconds; β-coefficient = 0.121; P = 0.03) as well as with the 24-hour heart rate variability a surrogate for autonomic dysfunction (median = 9.67 [IQR = 7.38-12.22 bpm]; β-coefficient = -0.133; P = 0.01).In hypertensive patients, AARR is significantly related to QTc prolongation as well as HRV. Further studies investigating the effects of mineralocorticoid receptor blocker and aldosterone synthase inhibitors on QTc and HRV are warranted.

Background/aims: Hypertensive nephroangiosclerosis is associated with progressive increase of intrarenal vascular resistance. In addition to blood pressure, other factors can contribute to hypertensive renal damage including a prothrombotic state. We investigated the relationship between hemostatic markers and intrarenal vascular resistance in hypertension., Methods: In 115 untreated, nondiabetic, hypertensive subjects free of cardiovascular complications and advanced renal function impairment, we measured 24-hour creatinine clearance (GFR) and urinary albumin excretion (UAE), fasting plasma glucose, HOMA-index, and plasma levels of fibrinogen, D-dimer, prothrombin fragment 1+2, plasminogen activator inhibitor-1, homocysteine, and lipoprotein(a). In all patients, measurement of intrarenal resistance was obtained by renal Doppler ultrasound with calculation of the renal resistance index (RI)., Results: Patients in the highest tertile of RI were older and had greater body mass index, pulse pressure, fibrinogen, and D-dimer levels and lower GFR than patients in the lowest RI tertile. RI was directly correlated with age, pulse pressure, HOMA-index, UAE, D-dimer, and inversely with GFR. On multivariate analysis, RRI was independently associated with age, GFR, and plasma D-dimer., Conclusions: A prothrombotic state is associated with increased intrarenal vascular resistance in nondiabetic hypertensive patients and might contribute to the early stages of hypertensive renal disease., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Experimental and clinical evidence obtained in the last 2 decades clearly indicates that protracted exposure to inappropriately elevated aldosterone levels causes significant changes in left ventricular structure and function. Animal studies have demonstrated that aldosterone induces myocardial inflammatory changes and fibrosis in the presence of a high salt diet. Moreover, the effects of aldosterone on the heart have been investigated in different clinical conditions. These conditions include systolic and diastolic heart failure, essential hypertension, and primary aldosteronism that offers a unique clinical model to study the cardiac effects of excess aldosterone because these effects are isolated from those of the renin-angiotensin axis. A relatively clear picture is emerging from these studies with regard to aldosterone-related changes in left ventricular mass and geometry. Conversely, no direct effect of aldosterone on left ventricular diastolic function can be demonstrated and improvement of diastolic function obtained in some studies that have employed mineralocorticoid receptor blockers could result from left ventricular mass reduction. Animal experiments demonstrate that effects of aldosterone on the left ventricle require high salt intake to occur, but the evidence of this contribution of salt to aldosterone-induced cardiac changes in humans remains weaker and needs further research. The article reviews the results of clinical studies addressing the role of aldosterone in regulation of LV remodeling and diastolic function, and focuses on the possible relevance of salt intake., (© Georg Thieme Verlag KG Stuttgart · New York.)

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., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Polyunsaturated fatty acids (PUFA) have been reported to be beneficial on some components of the metabolic syndrome (MetS). We tested the hypothesis that in hypertensive patients, presence of MetS and its related components is associated with cell membrane content of PUFA, a measure that reflects the dietary intake of these fatty acids., Methods: In 55 consecutive patients with primary hypertension referred to our university center, we measured anthropometric variables, 24-hour ambulatory blood pressure, general biochemistries including plasma lipids, and the fatty acid composition of red blood cell (RBC) membrane by gas chromatography., Results: The prevalence of the MetS was 36.4% and in hypertensive patients with MetS, the RBC membrane content of total PUFA, PUFA of the n-6 family (n-6 PUFA), PUFA of the n-3 family (n-3 PUFA), polyunsaturated to saturated fatty acid ratio (PUFA/SFA), and omega-3 index was significantly lower than in patients without MetS. RBC membrane total PUFA, n-6 PUFA, n-3 PUFA, PUFA/SFA ratio, and omega-3 index were significantly and directly correlated with high-desity lipoprotein (HDL) cholesterol levels, a correlation that did not differ across tertiles of plasma apolipoprotein-A1. In multivariate linear regression analysis, HDL-cholesterol resulted to be directly and independently related to RBC membrane n-6 PUFA, PUFA/SFA ratio, and omega-3 index. Conversely, total cholesterol to HDL-cholesterol ratio had inverse and independent relationship with n-6 PUFA, PUFA/SFA ratio, and omega-3 index., Conclusions: In patients with hypertension the MetS is associated with lower cell membrane content of PUFA that is explained by a direct and independent relationship of membrane PUFA with HDL-cholesterol. This observation suggests reduced dietary intake of PUFA in these patients that might contribute to their cardiovascular risk.

Background and Aims: Glycometabolic abnormalities are frequently found in hypertension and could affect the mechanical properties of carotid arteries. The aim of the study was to investigate the relationship of glucose tolerance, plasma insulin, and insulin sensitivity with carotid distensibility in middle-aged, non-diabetic hypertensive patients free of cardiac and vascular complications., Method and Results: In 93 patients with grade 1-2, uncomplicated, primary hypertension and 68 matched normotensive controls we measured plasma glucose and insulin at fast and after an oral glucose load (OGTT), calculated the HOMA-index as a marker of insulin sensitivity, and assessed distensibility of common carotid arteries by B-mode ultrasonography. Hypertensive patients were hyperinsulinemic and insulin-resistant as compared to normotensive controls. Hypertensive patients with impaired fasting glucose and/or impaired glucose tolerance had comparable distensibility of carotid arteries. Patients with decreased carotid distensibility were older and had higher body mass, fasting and post-OGTT plasma insulin, HOMA-index, and carotid IMT than the remaining patients, but no differences in glycated hemoglobin, and fasting or post-OGTT plasma glucose. Carotid coefficient of distensibility was inversely related and β-stiffness directly related with fasting and post-OGTT plasma insulin, and HOMA-index. Multivariate logistic regression showed that age and post-OGTT plasma insulin levels predicted carotid artery stiffening independent of body mass index, sex, blood pressure, and plasma glucose levels., Conclusions: The study demonstrates that decreased insulin sensitivity and the related hyperinsulinemia but not hyperglycemia could contribute to carotid artery stiffening in middle-aged, non-diabetic hypertensive patients free of cardiovascular complications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Patients with renal failure are at increased risk of cardiovascular events even at the earliest stages of disease. In addition to many classic cardiovascular risk factors, many conditions that are commonly identified as emerging risk factors might contribute to occurrence of cardiovascular disease. Changes in circulating levels of many of these emerging risk factors have been demonstrated in patients with early stages of renal failure caused by different types of renal disease and have been associated with detection of cardiovascular complications. However, for most of these factors evidence of benefits of correction on cardiovascular outcome is missing. In this article, we comment on the role of lipoprotein(a) and prothrombotic factors as potential contributors to cardiovascular events in patients with early renal failure.

Background: Hyperhomocysteinemia and the metabolic syndrome are established cardiovascular risk factors and are frequently associated with hypertension. The relationship of plasma homocysteine (Hcy) with the metabolic syndrome and insulin resistance, however, is debated and studies in hypertensive patients are limited. In this study, we have investigated the association of Hcy with the metabolic syndrome and cerebro- cardiovascular events in hypertension., Methods: In 562 essential hypertensive patients who underwent accurate assessment of fasting and postload glucose metabolism, insulin sensitivity, and renal function, we measured plasma levels of Hcy, vitamin B12, folate, and fibrinogen and assessed the prevalence of the metabolic syndrome and of coronary heart and cerebrovascular disease (CVD)., Results: Patients with the metabolic syndrome had significantly higher plasma Hcy levels. After correction for covariates, increasing Hcy levels were associated with an increasing prevalence of the metabolic syndrome, coronary heart disease, and CVD. Plasma Hcy was directly correlated with age, waist circumference, fasting glucose, triglyceride, uric acid, and fibrinogen levels, and homeostatic model assessment index and inversely with creatinine clearance and high-density lipoprotein cholesterol, vitamin B12, and folate levels. Logistic regression analysis showed an independent association of Hcy levels with age, male gender, vitamin B12 and folate levels, and the metabolic syndrome. Logistic regression indicated also an independent association of Hcy with cerebro-cardiovascular disease that was independent of the metabolic syndrome., Conclusions: Elevated plasma Hcy is associated with the metabolic syndrome in hypertensive patients. Prevalence of events increases with increasing plasma Hcy levels suggesting a contribution of Hcy to cerebro-cardiovascular diseases in these patients., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aldosterone has hypertrophic and profibrotic effects on the heart. The relationship between plasma aldosterone levels and left ventricular diastolic function in hypertension, however, is unclear. The aim of this study was to examine this relationship in treatment-naïve hypertensive patients free of comorbidities that could affect left ventricular diastolic filling properties. In 115 patients with primary hypertension who were eating a standard diet and 100 matched normotensive controls, we measured plasma aldosterone and active renin levels and performed both conventional echocardiography and tissue-Doppler imaging for assessment of left ventricular diastolic function. Left ventricular hypertrophy was found in 21% of hypertensive patients, and diastolic dysfunction was detected in 20% by conventional echocardiography and in 58% by tissue-Doppler imaging. Patients with left ventricular diastolic dysfunction at tissue-Doppler imaging were older and more frequently men, had greater body mass index, blood pressure, alcohol intake, left ventricular mass index, relative wall thickness, and lower plasma aldosterone levels than patients with preserved diastolic function. Plasma aldosterone correlated directly with left ventricular mass index in addition to age, body mass index, and systolic blood pressure. Plasma aldosterone was also directly related to e' velocity at tissue-Doppler imaging, but this relationship was lost after multivariate adjustment. In conclusion, plasma aldosterone levels are associated with left ventricular hypertrophy but have no independent relationship with left ventricular diastolic properties in hypertensive patients., (© 2015 American Heart Association, Inc.)

Introduction: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature., Aim: To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage)., Methods: HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona)., Results and Conclusion: The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.

Objective: Abnormal vascular reactivity contributes to the pathophysiology of hypertension and hypertension-related organ damage. As the dietary content of fatty acids may affect the vascular responses, we investigated the relationship of endothelium-independent and endothelium-dependent vasodilation with the fatty acid composition of red blood cell (RBC) membranes in hypertension., Methods: In 45 uncomplicated hypertensive patients, we measured the content of fatty acids in RBC membrane as a marker of dietary intake of fatty acids, and the vasodilatory response of the brachial artery to both nitrate-donor compound (nitrate-mediated vasodilation, NMD) and postischemic reactive hyperemia (flow-mediated vasodilation, FMD)., Results: Baseline diameter of the brachial artery was significantly lower and vasodilatory response to NMD was significantly greater in patients with RBC membrane polyunsaturated-to-saturated fatty acid (PUFA/SFA) ratio above the median of the distribution than in patients with PUFA/SFA ratio below the median, whereas no difference was observed in FMD. n-3 PUFA and n-6 PUFA content, and the PUFA/SFA ratio of RBC membranes were related inversely with brachial artery diameter and directly with maximal NMD, whereas no relationship of fatty acid components of RBC membrane with FMD was observed. Multivariate analysis that included demographic, anthropometric, clinical, and biochemical variables indicated that the RBC membrane PUFA/SFA ratio was an independent determinant of brachial artery diameter and NMD response., Conclusion: The endothelium-independent brachial artery vasodilation is independently related to the PUFA content of RBC membranes in patients with hypertension. This suggests the possible benefits of PUFA-enriched diets on the regulation of vascular tone and blood pressure in these patients.

Information on the association between homocysteine (Hcy) levels and subclinical carotid artery disease is limited. We investigated the relationship of plasma Hcy concentration with carotid artery plaques and intima-media thickness (IMT) in patients with hypertension. In 486 essential hypertensive patients who underwent ultrasound examination of the carotid arteries, we measured plasma levels of Hcy, vitamin B12, folate, and C-reactive protein. Plaques were detected in 34% of the study patients. Plasma Hcy levels were significantly greater in hypertensive patients with evidence of carotid plaques than patients without carotid plaques. Carotid IMT progressively increased across quartiles of plasma Hcy levels. Multivariate regression showed that carotid IMT was independently related with age, blood pressure, C-reactive protein, and Hcy levels. In a logistic regression, age, blood pressure, triglyceride, and Hcy independently predicted the presence of carotid plaques. Thus, elevated plasma Hcy levels are associated with asymptomatic carotid disease in hypertensive patients suggesting a role of Hcy in the development and progression of carotid atherosclerosis in these patients., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Primary aldosteronism (PA) is associated with an increase in left ventricular (LV) mass beyond the amount needed to compensate the hypertension-related workload. Available evidence suggests effectiveness of surgical treatment of PA in decreasing LV mass, whereas data on medical treatment are controversial. We have conducted a meta-analysis of long-term follow-up studies on surgical and medical treatment of PA to compare the effects of treatments on LV mass., Methods: Medline and Cochrane searches were performed including the following words: hyperaldosteronism, left ventricular mass, mineralocorticoid receptor antagonists, surgery, adrenalectomy, and follow-up studies. Studies published within 2013 focusing on cardiac effects of treatment and follow-up longer than 6 months were selected. Data extraction was performed independently by 2 authors., Results: Of 61 retrieved articles, 4 were included in the analysis. These studies enrolled 355 patients with PA who had an average follow-up of 4.0 years after unilateral adrenalectomy (n = 178) or treatment with mineralocorticoid receptor antagonists (n = 177). Despite greater effect of surgery over medical treatment in reducing blood pressure, meta-analysis of the selected studies demonstrated no significant difference in LV mass change between patients with PA who were treated with mineralocorticoid receptor antagonists or adrenalectomy (standard mean difference = 0.130; 95% confidence interval = -0.085 to 0.345; P = 0.24; I2 = 0%)., Conclusions: Available evidence indicates that reduction of LV mass is not different in PA patients treated with adrenalectomy or mineralocorticoid receptor antagonists., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/aims: The contribution of emergent cardiovascular risk factors to atherosclerotic renal artery stenosis (ARAS) is debated. We investigated the relationship of lipoprotein(a) and prothrombotic factors with ARAS in hypertension., Methods: In 50 hypertensive patients with angiographic evidence of ARAS and 58 hypertensive patients who had comparable cardiovascular risk factor burden but no evidence of renovascular disease, we measured renal function, lipoprotein(a), homocysteine, and hemostatic-fibrinolytic markers., Results: Patients with ARAS were more frequently smokers and had longer duration of hypertension, heavier antihypertensive treatment, and worse renal function than controls. Lipoprotein(a) was higher in patients with ARAS than controls, whereas no differences were found in homocysteine and all hemostatic variables. Multivariate analysis showed that lipoprotein(a) was associated with ARAS independent of other confounders including renal function and history of coronary heart, cerebrovascular, and peripheral artery disease., Conclusion: Lipoprotein(a) might contribute to the development of ARAS and detection of elevated levels of this lipoprotein could raise the suspicion of renovascular disease in patients with high blood pressure., (© 2015 S. Karger AG, Basel.)

Primary aldosteronism is a frequent form of secondary hypertension that had long been considered relatively benign. Experimental and clinical evidence collected in the last two decades, however, has clearly demonstrated that this endocrine disorder is associated with excess cardiovascular and renal complications as compared to essential hypertension. These complications reflect the ability of inappropriate elevation of plasma aldosterone to cause tissue damage beyond that induced by high blood pressure itself, thereby setting the stage for major cardiovascular and renal disease. Because of the impact of elevated aldosterone on organ damage, goals of treatment in patients with primary aldosteronism should not be limited to normalization of blood pressure, and prevention or correction of organ complications is mandatory. Treatment with mineralocorticoid receptor antagonists or unilateral adrenalectomy is the respective options for treatment of idiopathic adrenal hyperplasia or aldosterone-producing adenoma. Last years have witnessed a rapid growth in knowledge concerning the effects of these treatments on cardiovascular and renal protection. This paper is an overview of the cardiovascular and renal complications that occur in patients with primary aldosteronism and a summary of the results that have been obtained in the long term on cardiovascular and renal outcomes with either medical or surgical treatment.

Background: Lipoprotein(a) [Lp(a)] is an emergent cardiovascular risk factor that is related to the presence and severity of cardiovascular damage in hypertensive patients. In these patients, insulin resistance is frequently detected but its relationship with plasma Lp(a) is not clear. The aim of this study was to examine the relationships between Lp(a) and variables of glucose metabolism in hypertension., Methods: In 527 consecutive, non-diabetic, middle-aged hypertensive patients we measured anthropometric indexes, 24-hour creatinine clearance, lipid profile including Lp(a) levels, fasting glucose, insulin and C-peptide, and calculated the Homeostatic Model Assessment (HOMA) index., Results: Lp(a) levels were significantly and progressively lower with increasing HOMA-index values. Lp(a) was inversely related to fasting glucose, insulin, and C-peptide, HOMA-index, and creatinine clearance and directly related to LDL-cholesterol. Multiple regression analysis adjusted for age, sex, body mass index, blood pressure, smoking habit, alcohol intake, renal function, lipid profile, history of cardiovascular events, and drug use showed that HOMA-index and creatinine clearance were inversely and independently associated to Lp(a) levels., Conclusions: Insulin resistance and higher fasting insulin levels are associated with lower plasma Lp(a) in hypertensive patients. This association might be relevant in the assessment of cardiovascular risk in these patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Receptors for mineralocorticoid hormones are expressed in myocardial cells and evidence obtained in animal studies suggests that activation of these receptors causes cardiac damage independent from blood pressure levels. In the last years, many of the issues related to the effects of aldosterone on the heart have received convincing answers and clinical investigation has focused on a variety of conditions including systolic and diastolic heart failure, arrhythmia, primary hypertension, and primary aldosteronism. Some issues, however, await clarification in order to obtain better understanding of what could be the role of aldosterone blockade in prevention and treatment of cardiovascular diseases. In this article, we overview the most recent findings of animal studies that have examined the contribution of aldosterone to cardiac function and clinical studies that have investigated the influence of aldosterone on left ventricular structure and function in the setting of primary hypertension and primary aldosteronism.

Background: Both hyperuricaemia and left ventricular (LV) hypertrophy are associated with the metabolic syndrome and increased cardiovascular risk. The relationship between uric acid levels and left ventricular mass in hypertension, however, is unclear. In this study, we have investigated this relationship in hypertensive patients without the metabolic syndrome., Materials and Methods: In a cross-sectional study, 367 nondiabetic, essential hypertensive patients (age 52 ± 14; 194 males and 173 females) free of clinically relevant cardiovascular complications and without the metabolic syndrome were consecutively recruited at a university hypertension clinic. In these patients, we measured plasma levels of uric acid, lipids, glucose and insulin at fast and after an oral glucose load (OGTT), renal function and performed both conventional and tissue Doppler echocardiography., Results: Hypertensive patients with LV hypertrophy had higher uric acid levels and greater prevalence of hyperuricemia than patients with normal left ventricular mass. Uric acid levels were directly related with fasting and post-OGTT plasma insulin and with the HOMA index and inversely with 24-h creatinine clearance. Uric acid was also significantly and directly related with the left ventricular mass and multivariate regression analysis showed that this relationship was independent from components of the metabolic syndrome and renal function in women, but not in men., Conclusions: Elevated uric acid levels are independently related to the left ventricular mass in hypertensive women without the metabolic syndrome. In these patients with a low cardiovascular risk profile, uric acid might contribute to the development of subclinical cardiac damage., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression., Methodology/principal Findings: Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities., Conclusions/significance: These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Studies on fish oil effects on ambulatory blood pressure (ABP) are inconclusive. We evaluated fish effects on fatty acid composition of red blood cell (RBC) membrane and ABP values and tested the hypothesis that the starting membrane fatty acid composition affects the ability to incorporate additional polyunsaturated fatty acids (PUFA) and decrease blood pressure., Methods: In 55 hypertensive patients, we measured RBC membrane fatty acid by gas chromatography and performed ABP monitoring. Patients received nutritional counseling and 3 weekly meals of trout rich in PUFA. In 42 patients, RBC membrane fatty acid and ABP were reassessed after 6 months., Results: At baseline, the PUFA/saturated fatty acid (SFA) ratio of RBC membrane (PUFA/SFA) was inversely related to 24-hour, daytime, and nighttime systolic and pulse pressure, a relationship that was independent of covariables. At follow-up, the PUFA/SFA ratio increased in 20 (48%) of 42 patients. Patients with increased PUFA/SFA ratio at follow-up had lower baseline PUFA/SFA ratio than patients without such increase. Fish meal supplementation decreased 24-hour systolic and diastolic pressure only in patients who had increased PUFA/SFA ratio, a change that was more prominent during the nighttime. The change in PUFA/SFA was inversely and independently related to the change in 24-hour systolic and pulse pressure, and a logistic regression analysis indicated low baseline PUFA/SFA ratio as the only independent predictor of PUFA/SFA increase and blood pressure decrease., Conclusions: The ability of fish meals to increase membrane PUFA content and decrease blood pressure in hypertensive patients depends upon the starting membrane fatty acid composition.

Aim: The composition of dietary fat affects various modifiable cardiovascular risk factors and cardiovascular outcomes in the general population. We investigated the effects of the regular consumption of fish meals on the fatty acid composition of red blood cell (RBC) membranes and the relationship of this parameter with the carotid intima-media thickness (IMT), an early marker of atherosclerosis., Methods: In 56 hypertensive patients, we measured the carotid IMT using ultrasound imaging and the RBC membrane fatty acid composition using gas-chromatography and calculated the polyunsaturated to saturated fatty acid (PUFA/SFA) ratio. The patients received intensive nutritional counseling and three weekly meals of fish containing elevated amounts of PUFA, in order to increase the membrane PUFA content. The RBC membrane fatty acid composition and IMT were reassessed after one year., Results: At baseline, the membrane PUFA/SFA ratio was inversely related to the carotid IMT, and the relationship was independent of all major cardiovascular risk factors. At follow-up, the PUFA/SFA ratio increased in the RBC membranes of 25 (45%) of 56 patients. The regular consumption of fish meals resulted in a decreased carotid IMT only in the patients with an increased membrane PUFA/SFA ratio. Changes in the PUFA/SFA ratio induced by the dietary intervention were inversely related to the changes in the IMT, independent of variations in body mass, blood pressure and plasma lipids., Conclusions: In hypertensive patients, a low RBC membrane PUFA/SFA ratio is associated with more prominent vascular damage, and the regular consumption of fish reduces the carotid IMT in patients in whom dietary intervention affects the membrane fatty acid composition.

Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid of the ω-3 family of polyunsaturated fatty acids (PUFA) are abundant in fatty fish and other marine sources. Their consistent consumption has been related to an improved cardiovascular risk especially in high risk patients and populations. In this review, we presented major findings about potential mechanisms of action and clinical evidence regarding ω-3 PUFA effect on the control and prevention of cardiovascular disease. This review is an update of our previous review (Colussi et al. Recent Pat Cardiovasc Drug Discov 2007;2:13-31) in which we additionally summarize and comment new literature of the past few years. Despite clinical studies have been significantly increased in the last years, the evidence in support of a beneficial role of ω-3 PUFA in cardiovascular prevention is still relatively weak. The growing improvement of medical interventions for cardiovascular prevention might explain why these molecules appear to have limited impact on the cardiovascular risk.

Long-term exposure to elevated aldosterone levels or activation of the mineralocorticoid receptors results in cardiac, vascular and renal tissue injury with mechanisms that are independent of blood pressure levels. This evidence has been obtained in experiments carried out in hypertensive animal models, and clinical studies involving patients with heart failure, essential hypertension and primary aldosteronism. Animal studies have shown that aldosterone causes cardiovascular and renal tissue damage only in the context of an inappropriate salt status. It has also been suggested that some of the untoward effects of high-salt intake might depend on activation of mineralocorticoid receptors resulting from increased generation of reactive oxygen species and changes in the intracellular redox potential. Although the interaction between dietary salt intake and circulating aldosterone in causing organ damage has received robust support from the results of animal experiments, the evidence of such interaction in the clinical setting is only preliminary and will require further investigation in appropriately designed studies., (© 2013 Wiley Publishing Asia Pty Ltd.)

Background: Changes in left ventricular (LV) diastolic filling anticipate diastolic heart failure and are frequently detected in patients with hypertension or diabetes. We tested the hypothesis that increased fasting and postload glucose levels are associated with diastolic dysfunction as assessed by tissue Doppler imaging (TDI) in hypertensive patients., Methods: In 104 untreated, nondiabetic, hypertensive patients free of cardiovascular complications, we measured glucose and insulin at fast and after an oral glucose load, calculated the Homeostatic Model Assessment (HOMA) index, and performed electrocardiogram (ECG), conventional echocardiography, and TDI., Results: Thirty-one patients who had impaired fasting glucose/impaired glucose tolerance had more frequent LV strain at ECG and worse TDI markers of diastolic function than patients with normal plasma glucose but no differences in variables LV mass, LV geometry, systolic function, and early-/late-wave transmitral diastolic velocity. TDI detected diastolic dysfunction in 46 patients who were older and had greater body mass index, blood pressure, fasting and postload glucose, insulin, HOMA index, LV mass, and left atrial diameter than patients with preserved diastolic function. Variables of diastolic function measured at TDI were significantly related with age, body mass index, LV mass, and fasting and postload plasma glucose. Stepwise regression analysis showed that the relationship of markers of diastolic dysfunction with both fasting and postload glucose levels was independent of possible confounders., Conclusions: Initially abnormal fasting and postload glucose levels are associated with more prominent diastolic impairment in uncomplicated hypertensive patients, suggesting that hyperglycemia might increase the risk of diastolic heart failure even in the absence of diabetes., (© American Journal of Hypertension, Ltd 2013. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: In hypertensive patients the propensity to develop organ damage is under the influence of several factors, including the existence of a prothrombotic state. We tested the hypothesis that an activated hemostatic system is associated with left-ventricular diastolic dysfunction as assessed by tissue-Doppler imaging (TDI)., Methods: In 198 patients with untreated essential hypertension free of clinically relevant cardiovascular complications, we measured plasma levels of fibrinogen, prothrombin fragment 1 + 2, D-dimer, plasminogen activator inhibitor-1, and tissue plasminogen activator, and performed conventional echocardiography and TDI., Results: Left-ventricular diastolic dysfunction was detected in 61 patients (31%) by conventional echocardiography and in 105 patients (53%) by TDI, 39% of whom had left-ventricular hypertrophy. Left-ventricular hypertrophy was associated with increased plasma fibrinogen and prothrombin fragment 1 + 2 levels. Patients with diastolic dysfunction at TDI were older and had greater BMI, SBP, left-ventricular mass index, and plasma fibrinogen and D-dimer levels than patients with normal diastolic function. Variables of diastolic function measured both at conventional echocardiography and TDI were significantly related with age, BMI, left-ventricular mass index, and plasma fibrinogen, D-dimer, and prothrombin fragment 1 + 2. Multivariate regression analysis showed that diastolic variables obtained at TDI were related to plasma fibrinogen levels independent of covariates., Conclusion: Elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence of left-ventricular diastolic dysfunction in hypertensive patients with no evidence of ischemic heart disease and might increase the risk of diastolic heart failure.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) has been found to be strongly related to an increased arterial stiffness in patients with essential hypertension, suggesting a pathophysiologic link between major cardiovascular and metabolic abnormalities associated with liver steatosis and the functional and structural alterations of the arterial wall. The aim of our study was to investigate, in a group of essential hypertensive patients without additional cardiovascular risk factors, the relationship between NAFLD and arterial stiffness., Methods and Results: Sixty-eight consecutive patients with essential hypertension underwent 24-h ambulatory blood pressure monitoring (ABPM) and were separated according to the presence (n = 40) or absence (n = 28) of NAFLD at liver ultrasonography. The Ambulatory Arterial Stiffness Index (AASI) and Symmetric AASI (Sym-AASI) were derived from ABPM tracings. Patients with diabetes, obesity, hyperlipidaemia or other risk factors for cardiovascular or liver disease were excluded. Hypertensive patients were compared with a normotensive control group.The two hypertensive groups had comparable age, sex distribution and clinic/ABPM blood pressure levels. In hypertensive patients with NAFLD, body mass index, fasting glucose, insulin, homeostasis model of assessment of insulin resistance index and triglyceride levels were higher, whereas plasma adiponectin was lower than in patients without NAFLD. In hypertensive patients, AASI and Sym-AASI were higher (P < 0.001) than in normotensive subjects, but both indices of vascular stiffness were comparable in patients with and without NAFLD., Conclusions: In essential hypertensive patients without additional cardiovascular risk factors, NAFLD is associated with insulin resistance but not with increased arterial stiffness., (Copyright © 2012 Elsevier B.V. All rights reserved.)

An independent association between non-alcoholic fatty liver disease (NAFLD), a condition characterized by insulin-resistance, and low serum 25-hydroxyvitamin D [25(OH)D] levels has been reported. 25(OH)D concentrations are directly related with insulin sensitivity, whereas low [25(OH)D] predicts development of hypertension independent of glucose homeostasis alterations. We hypothesized that hypertensive patients with NAFLD have lower 25(OH)D than those without. Forty-four essential hypertensive (EH) patients with (n = 23) or without (n = 21) NAFLD were studied. No patient had diabetes mellitus, obesity, hyperlipidemia. The two hypertensive groups were compared with 24 healthy normotensive sex-, age-, body mass index (BMI)-matched subject, as controls. The two hypertensive groups had comparable age, sex, and blood pressure. BMI, glucose, insulin, homeostasis model assessment (HOMA) index and alanine aminotransferase were higher (P < 0.001 to <0.05) and plasma adiponectin was lower (P < 0.05) in EH patients with NAFLD than in those without NAFLD. Vitamin D deficiency, as defined by 25(OH)D levels <50 nmol/L, was similarly frequent in EH patients and controls (47.7 % vs. 45.8%, P NS). Prevalence of hypovitaminosis D was not different in EH patients with and without NAFLD (37.5% vs. 38.8%, P NS). In patients with EH and no additional cardiometabolic risk factors NAFLD is not associated with vitamin D deficiency.

Background: Plasma aldosterone concentration is an independent determinant of left ventricular (LV) mass in hypertensive patients, and is related to some hemostatic variables along with it may contribute to a prothrombotic state. We conducted a study to investigate the relationship between hemostatic variables, plasma aldosterone, and cardiac morphology and function in essential hypertension., Methods: In 205 patients with untreated essential hypertension, we measured components of the renin-angiotensin-aldosterone system, plasma levels of fibrinogen, D-dimer, prothrombin fragment 1 + 2 (F1 + 2), and plasminogen activator inhibitor-1 (PAI-1), and assessed cardiac characteristics with standard echocardiography. For statistical purpose, patients were divided into two groups according to whether their median value of plasma aldosterone was > 125 pg/ml or < 125 pg/ml., Results: Left ventricular mass index (LVMI) was significantly greater in patients with a high (> 51 ± 13 g/m(2.7)) than with a low plasma aldosterone level (< 41 ± 11 g/m(2.7); P < 0.01) only in patients with fibrinogen levels in the highest tertile. Significant interaction was observed between plasma fibrinogen and aldosterone in the association with LVMI (P = 0.04). Left ventricular mass index was significantly and directly related to age, systolic blood pressure (BP), body mass index (BMI), plasma aldosterone, fibrinogen, and D-dimer levels, whereas no relationships were observed between echocardiographic parameters and other hemostatic variables. Fibrinogen was directly related to age, systolic BP, plasma aldosterone, LVMI, relative wall thickness, and left atrial diameter. Multivariate analysis indicated that LVMI was related to plasma fibrinogen and aldosterone (both P < 0.01) independently of age, BP, and BMI., Conclusions: Plasma fibrinogen levels interact with plasma aldosterone in its association with left ventricular mass in patients with hypertension.

Mineralocorticoid receptor antagonists (MRAs) are commonly used to reduce blood pressure, left-ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. Effects of MRAs on hypertensive organ damage seem to occur beyond what is expected from the mere reduction of blood pressure. This suggests that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. However, broad use of classic MRAs such as spironolactone has been limited by significant incidence of gynecomastia and other sex-related adverse effects. To overcome these problems, new aldosterone blockers have been developed with different strategies that include use of nonsteroidal MRAs and inhibition of aldosterone synthesis. Both strategies have been designed to avoid the steroid receptor cross-reactivity of classic MRAs that accounts for most adverse effects. Moreover, inhibition of aldosterone synthesis could have an additional benefit due to blockade of the mineralocorticoid receptor-independent pathways that might account for some of the untoward effects of aldosterone. The new aldosterone blockers are currently having extensive preclinical evaluation, and one of these compounds has passed phase 2 trials showing promising results in patients with primary hypertension and primary aldosteronism. This narrative review summarizes the knowledge on the use of classic MRAs in hypertension and covers the evidence currently available on new aldosterone blockers.

Primary aldosteronism (PA) is one of the commonest forms of curable hypertension, and use of the plasma aldosterone-to-renin ratio as a screening test has led to a more efficient identification of this condition. Both animal and human studies have indicated that PA is associated with a variety of cardiovascular and renal complications that reflect the capability of elevated aldosterone to induce tissue damage exceeding that induced by hypertension itself. Involvement of the kidney in PA is highly relevant because structural renal damage is associated with less favorable outcome, both in terms of blood pressure response to treatment and possibility to develop progressive renal failure. However, early involvement of the kidney in PA is characterized by functional changes that are largely reversible with treatment. Unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adenoma or idiopathic adrenal hyperplasia. Both treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that both surgery and medical treatment are of considerable value.

Background and Aim: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH)., Methods and Results: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18-65 years, with grade 1-2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P = 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r = -0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r = 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P = 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P = 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found., Conclusions: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (© Georg Thieme Verlag KG Stuttgart · New York.)

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: A prothrombotic state is associated with organ damage in hypertensive patients. Carotid intima-media thickness (IMT) is an early marker of vascular damage that anticipates the development of atherosclerotic plaques. The aim of the present study was to investigate the relationships between subclinical carotid damage and markers of the prothrombotic state in hypertension., Methods: In 258 essential hypertensive patients who were consecutively recruited at a hypertension clinic an ultrasound carotid scan was performed with assessment of the IMT and plasma levels of C-reactive protein, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2, homocysteine, and lipoprotein(a) were measured., Results: Patients with an IMT above the median of the distribution (800 µm) were older and had greater BMI, pulse pressure, duration of hypertension, and prevalence of coronary heart disease than patients with an IMT below the median. Patients with higher IMT had also greater levels of C-reactive protein, fibrinogen, fibrin D-dimer, and homocysteine. Regression analysis showed a direct relationship of IMT with age, waist circumference, pulse pressure, fibrinogen, fibrin D-dimer, and number of cigarettes smoked per day, and an inverse relationship with creatinine clearance. On multivariate analysis, age, pulse pressure, and fibrin D-dimer were independently related with IMT., Conclusion: In hypertensive patients, subclinical carotid damage is related with evidence of activated coagulation system suggesting a prothrombotic state. This might contribute to the development of hypertensive arterial damage even in the earliest stages.

Experimental and clinical studies indicate that exposure to high aldosterone concentrations causes cardiac damage independent of the blood pressure level. In recent years, it has become clear that the effects of aldosterone on the heart are mediated by actions on a variety of cell types and intracellular mechanisms that contribute to regulation of specific tissue responses, leading to hypertrophy and fibrosis. Most cardiac effects of aldosterone are mediated by activation of mineralocorticoid receptors that are detected in cardiac myocytes and fibroblasts. Clinical evidence of the unfavorable cardiac effects of aldosterone has been established in landmark studies that have tested the benefits of aldosterone antagonists in patients with heart failure and decreased ejection fraction. However, evidence of benefits of aldosterone antagonists occurring independent of the renal effects of these agents is not limited to patients with systolic heart failure. In this article, we briefly summarize the current knowledge on the effects of aldosterone antagonists on cardiac protection and highlight the most recent findings that have been obtained in different cardiac conditions with use of these drugs.

Background: Nonalcoholic fatty liver disease (NAFLD) is strongly associated to oxidative stress, metabolic syndrome, and cardiovascular risk. Hepatocytes overloaded with fatty acids (FA) could generate substances that interfere with endothelial function, providing a potential explanation for this association. We have investigated the response of cultured human hepatoblastoma cells (Hep-G2) that were exposed to FA by measuring markers of oxidative stress and thrombosis and expression of the insulin receptor., Methods: Hep-G2 cells were conditioned with a mixture of FA with or without N-acetyl-L-cysteine (NAC), glutathione (GSH), or adiponectin (ADN). After 7 days, we measured intracellular GSH (iGSH), nitric oxide (NO), malondialdehyde (MDA), and tissue plasminogen inhibitor-1 (PAI-1). Real-time polymerase chain reaction (PCR) was used to determine gene expression of inducible nitric oxide synthase (iNOS) and insulin receptor (INS-R)., Results: Exposure to FA decreased iGSH and NO levels in Hep-G2 cells and increased MDA and PAI-1 production. Gene expression of iNOS and INS-R in Hep-G2 cells was decreased by exposure to FA. Co-incubation with NAC and GSH prevented the change of iNOS mRNA levels, but not of INS-R; co-incubation with ADN restored the gene expression of INS-R, but not of i-NOS. ADN prevented also the FA-induced increase in MDA in cultured human endothelial cells., Conclusion: Exposure to FA activates oxidative stress and production of prothrombotic markers and decreases expression of insulin receptors in cultured human hepatocytes. These effects of FA are partially prevented by ADN and might contribute to the increased cardiovascular risk in patients with NAFLD and metabolic syndrome.