C. Catena

Mineralocorticoid antagonists treatment versus surgery in primary aldosteronism.

Recent evidence indicates a greater frequency of primary aldosteronism (PA) among patients with hypertension than the previously accepted prevalence. PA was once considered a relatively benign form of hypertension associated with low incidence of organ complications. Recent views, however, suggest that long-term exposure to increased aldosterone levels might result in cardiovascular, renal, and metabolic sequelae that occur independently of the blood pressure level. Cross-sectional comparisons with patients with essential hypertension have demonstrated that patients with PA are at higher risk of cardiovascular events, have more frequent left ventricular hypertrophy and diastolic dysfunction, have greater urinary albumin losses as a marker of a hemodynamic intrarenal adaptation, and are insulin resistant. Some of these findings have been corroborated by the results of short-term, follow-up studies where it was shown that unilateral adrenalectomy or treatment with mineralocorticoid receptor (MR) antagonists are effective in correcting hypertension and hypokalemia. Normalization of blood pressure and correction of hypokalemia, however, are not the only goals in managing PA and effective prevention of organ complications is mandatory in these patients. The relative efficacy of adrenalectomy and MR antagonists, in the long-term, on the cardiovascular, renal, and metabolic outcomes still needs evaluation, being the aldosterone-induced tissue damage the main factor that could justify the cost of increasing efforts in screening of disease and differentiation of subtypes. In this narrative review, we summarize the results obtained with either surgical or medical treatment of PA and outline the findings of long-term, prospective studies on the effects of treatment on cardiovascular and renal outcomes and on insulin sensitivity.

Subclinical carotid artery disease and plasma homocysteine levels in patients with hypertension

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.

Association of Post-Saline Load Plasma Aldosterone Levels With Left Ventricular Hypertrophy in Primary Hypertension

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.

The vascular response to vasodilators is related to the membrane content of polyunsaturated fatty acids in hypertensive patients.

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.

Plasma Parathyroid Hormone Is Independently Related to Nocturnal Blood Pressure in Hypertensive Patients: The Styrian Hypertension Study.

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.

Carotid artery stiffness is related to hyperinsulinemia and insulin-resistance in middle-aged, non-diabetic hypertensive patients

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.

Omega-3 Polyunsaturated Fatty Acids in Blood Pressure Control and Essential Hypertension

Hypertension is a worldwide problem that affects up to 22% of adults and contributes to the global burden of disability due to cardiovascular disease. Several factors influence blood pressure and participate to the development of hypertension. Among these factors, polyunsaturated fatty acids of the omega-3 family (omega-3 PUFA) are effective hypotensive agents. Through their anti-inflammatory and antioxidant properties, omega-3 PUFA can improve cardiac hemodynamics and vascular function and potentially reduce arterial stiffness and atherosclerotic damage. However, despite this promising evidence many meta-analyses on the cardiovascular effect of omega-3 PUFA were inconclusive. The choice of the omega-3 PUFA sources, baseline tissue content of these fatty acids, and individual compliance to their intake can be reasons for such a discrepancy between studies. Basic and clinical research on these fatty acids docu‐ ments interesting mechanisms through which these molecules could be useful in the treatment of hypertension and its related organ damage. The role of the maternal dietary habit during pregnancy and the quality of prenatal growth on the effect of omega-3 PUFA in cardiovascular system need further investigations. This chapter summarizes the literature of the past 30 years on the antihypertensive effects of this family of essential fatty acids.

1C.12: DIETARY SALT INTAKE AND ALDOSTERONE-RELATED ORGAN DAMAGE IN HYPERTENSION.

Objective: Chronic exposure to elevated aldosterone levels results in cardiac and renal tissue injury with mechanisms that are independent of blood pressure levels. Although the interaction between dietary salt intake and circulating aldosterone in causing organ damage has received support in animal experiments, the evidence of this interaction in the clinical setting is much weaker. In this study we have investigated the relevance of dietary salt on aldosterone related cardiac and renal damage in primary hypertension. Design and method: In 315 untreated, grade1–2, hypertensive patients (age 47 ± 13 yr.; 173 males) we measured anthropometric variables, general biochemistries, plasma active renin and aldosterone levels, glomerular filtration rate, and 24-hour urinary sodium (UNaE) and albumin excretion (UAE), and assessed cardiac morphology and function by B-mode echocardiography. Secondary forms of hypertension were excluded by exhaustive examination in all patients. For statistical reasons, patients were subdivided into tertiles or quartiles according to their UNaE that was used as a measure of salt intake. Results: UAE increased progressively across tertiles of UNaE and patients with plasma aldosterone levels above the median of the distribution (125 pg/ml) had significantly higher UAE than patients with lower levels in all tertiles of UNaE. Search for statistical interaction between plasma aldosterone and UNaE in the association with UAE, however, did not reveal interaction. Left ventricular mass index (LVMI) was significantly greater in patients with plasma aldosterone levels above the median than patients with lower levels, but no change of LVMI was observed across quartiles of UNaE. LV geometry and ejection fraction did not differ across quartiles of UNaE and were comparable in patients with high or low plasma aldosterone levels. Both UAE and LVMI were significantly and independently related with age, body mass index, systolic blood pressure, and plasma aldosterone. UNaE was significantly related with UAE, but this relationship was lost after correction for confounders. Conclusions: In summary, circulating aldosterone contributes to subclinical renal and cardiac damage in primary hypertension, but its contribution is independent of dietary salt intake.

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 52 ± 14 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 (r = 0.369, P = 0.001) and D-dimer (r = 0.390, P < 0.001). The PWV was higher in males than females (P = 0.036) and in previously treated patients than in naive subjects (P = 0.003). At multivariate analysis including PWV as the dependent variable, PWV was independently associated with age (beta = 0.310, P = 0.015) and D-dimer levels (beta = 0.222, P = 0.049). At univariate analysis AIx was significantly and directly related to age, total and LDL-cholesterol, fibrinogen (r = 0.349, P = 0.002), 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 (beta = 0.235, P = 0.048) and LDL-cholesterol (beta = 0.328, P = 0.003). 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 35 ± 6 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 93 ± 15 pg/ml; 25-hydroxycholecalciferol 20 ± 8 ng/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 r = 0.417; P < 0.001) and diastolic (r = 0.372; P = 0.003), 24-hours systolic (r = 0.449; P < 0.001) and diastolic (r = 0.401; P = 0.001), daytime systolic (r = 0.421; P < 0.003) and diastolic (r = 0.378; P = 0.002), and nighttime systolic (r = 0.379; P = 0.002) and diastolic (r = 0.442; P < 0.001) 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.