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

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

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

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

Microalbuminuria and plasma aldosterone levels in nondiabetic treatment-naïve patients with hypertension.

OBJECTIVES: Identification of factors that contribute to urinary albumin losses in hypertensive nephropathy is crucial for prevention of renal deterioration. The aim of this study was to investigate the relationship of low-grade albuminuria with plasma aldosterone levels in treatment-naïve hypertensive patients free of additional comorbidities that might affect renal function. METHODS: In 242 newly diagnosed patients with uncomplicated primary hypertension, we obtained duplicate 24-h urine collections for measurement of urinary albumin/creatinine ratio (UACR) and measured plasma aldosterone levels. Patients with diabetes, overt proteinuria (>300 mg/day), glomerular filtration rate less than 30 ml/min per 1.73 m, and previous renal diseases were excluded. RESULTS: Increasing UACR was associated with significantly and progressively higher blood pressure (BP), HDL-cholesterol, and plasma aldosterone levels, and with lower glomerular filtration. Microalbuminuria (30-300 mg/day) was detected in 41 (17%) of 242 hypertensive patients, and these patients had significantly higher BP and plasma aldosterone levels (178 ±â€Š113 vs. 128 ±â€Š84 pg/ml; P = 0.001), and lower glomerular filtration than patients without microalbuminuria. UACR was directly and independently correlated with BP and plasma aldosterone levels. In a logistic regression model, presence of microalbuminuria was associated with plasma aldosterone levels independently of glomerular filtration and demographic, anthropometric, and metabolic variables. CONCLUSION: In nondiabetic, treatment-naïve patients with hypertension, low-grade albuminuria is independently associated with elevated plasma aldosterone. These findings suggest a contribution of aldosterone to the early glomerular changes occurring in hypertensive nephropathy.

Intrarenal Vascular Resistance is Associated With a Prothrombotic State in Hypertensive Patients.

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.

Moderate Alcohol Consumption Is Associated With Left Ventricular Diastolic Dysfunction in Nonalcoholic Hypertensive Patients.

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 m2 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.

Dietary Salt Intake Is a Determinant of Cardiac Changes After Treatment of Primary Aldosteronism: A Prospective Study.

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 (ß=0.419; P=0.009) and urinary sodium excretion (ß=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.

Relationship of plasma renin with a prothrombotic state in hypertension: relevance for organ damage.

BACKGROUND: Components of the renin-angiotensin-aldosterone system (RAAS) and a prothrombotic state are predictors of cardiovascular events in hypertensive patients. A relationship between the RAAS and the coagulation/fibrinolytic systems has been demonstrated, but its clinical relevance in hypertension is unclear. We investigated the relationships of the RAAS and the hemostatic system with hypertensive organ damage. METHODS: Plasma components of the RAAS and parameters that directly assess the activation of coagulation and fibrinolysis were measured in 247 essential hypertensive patients in whom the extent of organ damage had been characterized at the cardiac, renal, and vascular level. RESULTS: Positive association with increasing plasma renin activity (PRA) was demonstrated for plasma fibrinogen, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) levels. PRA was directly correlated with plasma aldosterone, fibrinogen, d-dimer, and PAI-1. The relationship of PRA with fibrinogen and PAI-1 remained significant after correction for age, gender, duration of hypertension, and smoking status. Plasma aldosterone levels were directly correlated with fibrinogen, D-dimer, and PAI-1, whereas plasma angiotensin-converting enzyme was not related with any of the coagulation parameters. Elevated PRA, aldosterone, fibrinogen, D-dimer, prothrombin fragment 1+2, and PAI-1 levels were associated with clinical and/or instrumental evidence of hypertension-related cardiac and renal damage. Both fibrinogen and PAI-1 were independent predictors of the presence of organ damage and their inclusion in a multivariate model eliminated PRA and aldosterone as independent predictors. CONCLUSIONS: A strong and independent association exists between renin, aldosterone, and markers of a prothrombotic state in essential hypertension. This relationship might contribute to the development of hypertensive organ damage.

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

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

Insulin sensitivity in patients with primary aldosteronism: a follow-up study.

CONTEXT: The relationship between aldosterone and glucose metabolism is poorly understood, and there is substantial disparity among findings of studies that have examined glucose tolerance and insulin sensitivity in patients with primary aldosteronism. OBJECTIVE: The objective of the study was to determine the outcome of glucose tolerance and insulin sensitivity in patients with primary aldosteronism after treatment. DESIGN: This was a prospective study of patients who received a diagnosis of primary aldosteronism and were followed up for an average period of 5.7 yr (range, 3-9 yr). SETTING: The study was conducted at a university referral center. PATIENTS: A consecutive sample of 47 patients with tumoral or idiopathic aldosteronism was followed up after either surgical or medical treatment. Patients with primary aldosteronism were compared with 247 patients with essential hypertension with the same severity and duration of disease and 102 normotensive subjects. MAIN OUTCOME MEASURES: Short- and long-term changes in glucose tolerance and insulin sensitivity were measured. RESULTS: After adjustment for age, gender, and body mass index, patients with primary aldosteronism had greater homeostasis model assessment index (P < 0.05) and plasma insulin response to an oral glucose load (P < 0.05) and lower quantitative insulin sensitivity check index (P < 0.01) than normotensive controls. Changes in insulin sensitivity were significantly greater in essential hypertension than primary aldosteronism, and this difference was confirmed by assessment with the hyperinsulinemic-euglycemic clamp (P < 0.01). Treatment of primary aldosteronism decreased blood pressure significantly, and during the initial 6 months of follow-up, parameters of insulin sensitivity were restored to normal. Analysis of subsequent follow-up showed nonsignificant changes in glucose metabolism parameters in both adrenalectomized and spironolactone-treated patients. CONCLUSIONS: Insulin resistance is present in patients with tumoral and idiopathic aldosteronism, but the defect appears less severe than in patients with essential hypertension. Treatment with surgery or aldosterone antagonists restores rapidly and persistently normal sensitivity to insulin.

Long-term renal outcomes in patients with primary aldosteronism.

CONTEXT: Experimental animal studies indicate that exposure to increased aldosterone levels might result in renal damage, but the clinical evidence supporting this role of aldosterone is preliminary. OBJECTIVE: To determine the long-term outcome of renal function in patients with primary aldosteronism after surgical or medical treatment. DESIGN, SETTING, AND PARTICIPANTS: Prospective study conducted at an Italian university medical center among a consecutive sample of 50 patients who were diagnosed as having primary aldosteronism between January 1994 and December 2001 and who were followed up for a mean of 6.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with 100 patients with essential hypertension, matched for severity and duration of hypertension. All patients were treated with antihypertensive drugs to reach a target blood pressure of less than 140/90 mm Hg. MAIN OUTCOME MEASURES: Primary outcome measures were rates of change of glomerular filtration rate and albuminuria during follow-up. Detection of new-onset microalbuminuria and restoration of normal albumin excretion during follow-up were considered as secondary outcomes. RESULTS: At baseline, glomerular filtration rate and albuminuria were higher in patients with primary aldosteronism than those with essential hypertension. The mean blood pressure during the study was 136/81 mm Hg in the primary aldosteronism group and 137/81 mm Hg in the essential hypertension group. Glomerular filtration rate and albuminuria declined during the initial 6-month period in both groups, with a change that was significantly greater (P<.001 for both variables) in patients with primary aldosteronism. Subsequent rate of decline of glomerular filtration was comparable in the 2 groups, whereas albuminuria did not progress in the remainder of the follow-up. Restoration of normal albumin excretion from microalbuminuria was significantly more frequent in primary aldosteronism than in essential hypertension (P = .02). CONCLUSION: In the majority of patients in this study, primary aldosteronism was characterized by partially reversible renal dysfunction in which elevated albuminuria is a marker of a dynamic rather than structural renal defect.

New risk factors for atherosclerosis in hypertension: focus on the prothrombotic state and lipoprotein(a).

Although adequate control of blood pressure is of basic importance in cardiovascular prevention in hypertensive patients, correction of additional risk factors is an integral part of their management. In addition to classical risk factors, epidemiological research has identified a number of other conditions that might significantly contribute to cardiovascular risk in the general population and might achieve specific relevance in patients with high blood pressure. In fact, more than 20% of patients with premature cardiovascular events do not have any of the traditional risk factors and, although effective intervention on blood pressure and additional risk factors has significantly reduced cardiovascular morbidity and mortality, the contribution to stroke, coronary artery disease and renal failure is still unacceptably high. Evaluation of new risk factors may further expand our capacity to predict atherothrombotic events when these factors are included along with the traditional ones in the assessment of global cardiovascular risk in hypertensive patients. Because it could be anticipated that the role of these novel factors will become increasingly evident in the future, researchers with an interest in hypertension and physicians dealing with problems related to cardiovascular prevention should give them appropriate consideration. This review summarizes the basic biology and clinical evidence of two emerging risk factors that are reciprocally related and contribute to the development and progression of organ damage in hypertension: the prothrombotic state and lipoprotein(a).

Insulin receptors and renal sodium handling in hypertensive fructose-fed rats.

BACKGROUND: Insulin resistance and hypertension are present in Sprague-Dawley rats fed a fructose-enriched diet. In these rats, insulin might elevate blood pressure via an antinatriuretic action. METHODS: To investigate the sodium-insulin interaction in fructose-fed rats, we compared insulin sensitivity, insulin receptor binding, and insulin receptor mRNA levels in the kidney and skeletal muscle of rats that were fed standard rat chow or a fructose-enriched diet (66%) with either low (0.07%), normal (0.3%), or high (7.5%) NaCl concentrations for 3 weeks. RESULTS: Systolic blood pressure increased in the fructose-fed rats receiving the normal and high-salt diet, but not the low-salt diet. When the rats were fed the low-salt diet, the rate of glucose infusion required to maintain euglycemia during a hyperinsulinemic clamp and insulin receptor number and mRNA levels in skeletal muscle were lower in fructose-fed than control rats. High-salt diet decreased significantly the rate of glucose disposal during the clamp and muscular insulin receptor number and mRNA levels in control, but not fructose-fed rats. During the low-salt diet, renal insulin receptor number and mRNA levels were comparable in fructose-fed and control rats and hyperinsulinemia had comparable acute antinatriuretic effects in the two groups; when the rats were maintained on the high-salt diet, the expected decrease in renal insulin receptor number and mRNA levels occurred in control but not fructose-fed rats and, consistent with this finding, the antinatriuretic response to hyperinsulinemia was blunted only in controls. An inverse relationship between dietary NaCl content and renal insulin receptor mRNA levels was observed in control but not fructose-fed rats. CONCLUSION: Fructose-fed rats appear to have lost the feedback mechanism that limits insulin-induced sodium retention through a down-regulation of the renal insulin receptor when the dietary NaCl content is increased. This abnormality might possibly contribute to the elevation of blood pressure in these rats.

Cellular mechanisms of insulin resistance in rats with fructose-induced hypertension.

BACKGROUND: Feeding a high-fructose diet induces hypertension and insulin-resistance in Sprague-Dawley rats. METHODS: To investigate whether insulin receptors contribute to abnormal glucose metabolism and whether their regulation is differentially regulated in different tissues, we evaluated the glycemic and insulinemic response to an oral glucose load, insulin receptor binding, and insulin receptor messengerRNA (mRNA) levels in tissues of rats that were fed either standard rat chow or a diet containing 66% fructose for 2 weeks. RESULTS: Blood pressure and plasma triglycerides increased significantly in the fructose-fed rats, whereas body weight, fasting plasma glucose, and plasma insulin did not differ significantly from controls. Plasma glucose and insulin responses to oral glucose were significantly greater in fructose-fed than in control rats. Insulin receptor-binding characteristics were determined by an in situ autoradiographic technique associated with computerized microdensitometry. The insulin receptor number was significantly lower in both skeletal muscle and liver of fructose-fed rats as compared to controls, whereas no difference was observed in the kidney. No significant differences were found in binding affinity. Insulin receptor mRNA levels were determined by slot-blot hybridization with a cRNA probe encoding the 5' end of the rat insulin receptor cDNA. Consistent with binding data, mRNA levels were significantly lower in skeletal muscle and liver of fructose-fed rats as compared to controls, but not in the kidney. CONCLUSIONS: Decreased number of insulin receptors occurring at the level of gene expression is present in skeletal muscle and liver of fructose-fed rats and might contribute to insulin resistance in this model.

Serum lipoprotein(a) concentrations and alcohol consumption in hypertension: possible relevance for cardiovascular damage.

OBJECTIVES: To evaluate the relationships between alcohol intake and serum lipoprotein(a) [Lp(a)], a powerful predictor of organ damage, in patients with essential hypertension with a wide range of alcohol intake, and to investigate whether the association between alcohol intake and serum Lp(a) concentrations occurs over the entire spectrum of apo(a) phenotypes. DESIGN: Cross-sectional study of a case series. SETTING: University medical centre. PATIENTS: Four hundred and two patients with untreated essential hypertension recruited at a hypertension clinic. MAIN OUTCOME MEASURES: Serum Lp(a) concentrations, apo(a) isoforms, alcohol consumption, smoking habits and cardiovascular status. RESULTS: No difference in Lp(a) concentrations was observed between teetotalers and occasional drinkers. Light drinkers (1-20 g/day ethanol), moderate drinkers (21-50 g/day), and heavy drinkers (> 50 g/day) had, respectively, 21, 26 and 57% lower median Lp(a) concentrations than teetotalers and occasional drinkers. Similar findings were obtained when male and female patients were analysed separately. Log Lp(a) concentrations were inversely and independently correlated with alcohol consumption in both men and women with hypertension. The frequency distributions of apo(a) isoforms and liver function parameters were comparable across the different alcohol intake groups. Patients with evidence of cardiovascular damage had greater concentrations of serum Lp(a) and higher frequency of low-molecular weight apo(a) isoforms as compared with patients without such evidence. CONCLUSIONS: Serum Lp(a) is inversely and dose-dependently related with alcohol intake in patients with hypertension, and this relationship is independent of the size distribution of apo(a) isoforms. Reduction of Lp(a) concentrations by regular consumption of alcohol might favourably affect the atherosclerotic risk profile of patients with hypertension and thereby decrease cardiovascular morbidity.