Cristiana Catena

Cardiovascular outcomes in patients with primary aldosteronism after treatment.

BACKGROUND Experimental and human studies demonstrate that long-term exposure to elevated aldosterone levels results in cardiac and vascular damage. METHODS We investigated long-term cardiovascular outcomes in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with or without evidence of adrenal adenomas were prospectively followed up for a mean of 7.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with patients with essential hypertension and were treated to reach a blood pressure of less than 140/90 mm Hg. The main outcome measure was a combined cardiovascular end point comprising myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias. RESULTS At baseline, the prevalence of cardiovascular events was greater in primary aldosteronism (35%) than in essential hypertension (11%) (odds ratio, 4.61; 95% confidence interval, 2.38-8.95; P< .001), with odds ratios of 4.93, 4.36, and 2.80 for sustained arrhythmias, cerebrovascular events, and coronary heart disease, respectively. Blood pressure during follow-up was comparable in the primary aldosteronism and essential hypertension groups. Ten patients in the primary aldosteronism group and 19 in the essential hypertension group reached the primary end point (P= .85). Cox analysis indicated that older age and longer duration of hypertension were factors independently associated with the cardiovascular end point. Cardiovascular outcome was comparable in patients with aldosteronism treated with adrenalectomy vs aldosterone antagonists (P= .71). CONCLUSION Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.

Long-Term Cardiac Effects of Adrenalectomy or Mineralocorticoid Antagonists in Patients With Primary Aldosteronism

Exposure to excess aldosterone results in cardiac damage in hypertensive states. We evaluated the long-term cardiac structural and functional evolution in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with primary aldosteronism were enrolled in a prospective study and were followed for a mean of 6.4 years after treatment with adrenalectomy (n=24) or spironolactone (n=30). At baseline, echocardiographic measurements of patients with primary aldosteronism were compared with those of 274 patients with essential hypertension. Patients with primary aldosteronism had greater left ventricular mass, more prevalent left ventricular hypertrophy, lower early:late-wave diastolic filling velocities ratio, and longer deceleration time than patients with essential hypertension but no differences in relative wall thickness and systolic function. During follow-up, average blood pressure was 135/82 and 137/82 mm Hg in patients treated with adrenalectomy and spironolactone, respectively. In the initial 1-year period, left ventricular mass decreased significantly only in adrenalectomized patients. Subsequent changes in left ventricular mass were greater in patients treated with spironolactone, with an overall change from baseline to the end of follow-up that was comparable in the 2 groups. Prevalence of hypertrophy decreased in both treatment groups, whereas diastolic parameters had only mild and nonsignificant improvement. Changes in blood pressure and pretreatment plasma aldosterone were independent predictors of left ventricular mass decrease in both treatment groups. Thus, in the long-term, both adrenalectomy and spironolactone are effective in reducing left ventricular mass in patients with primary aldosteronism, with effects that are partially independent of blood pressure changes.

Intrarenal Hemodynamics in Primary Aldosteronism before and after Treatment

CONTEXT Elevated urinary albumin excretion has been reported in primary aldosteronism and might partially reflect reversible abnormalities initiated by glomerular hyperfiltration. OBJECTIVE The aim of the study was to examine the outcome of renal function and intrarenal Doppler velocimetric indices in primary aldosteronism. DESIGN We conducted a prospective study of patients with primary aldosteronism who were reevaluated 1 yr after either adrenalectomy or treatment with spironolactone. SETTING The study was conducted at a university referral center. PATIENTS Fifty-four patients with tumoral or idiopathic aldosteronism were followed after either surgical (n = 24) or medical (n = 30) treatment. Patients with primary aldosteronism were compared with 100 patients with primary hypertension and comparable severity and duration of disease. MAIN OUTCOME MEASURES Changes in renal function and intrarenal echo-Doppler indices were measured. RESULTS Patients with primary aldosteronism had greater creatinine clearance and urinary albumin excretion than patients with primary hypertension. Patients with primary aldosteronism and creatinine clearance above the median (105 ml/min per 1.73 m(2)) had significantly lower resistance and pulsatility index than patients with creatinine clearance below the median, independent of disease subtype. After 1 yr, creatinine clearance and albuminuria declined, and resistance and pulsatility index increased to the same extent in patients with primary aldosteronism treated with either adrenalectomy or spironolactone. Changes in glomerular filtration and albuminuria were inversely related with baseline values of the resistance index. In primary hypertension, echo-Doppler velocimetric indices did not change during follow-up. CONCLUSIONS In primary aldosteronism, sonographic evidence of decreased intrarenal vascular resistance is associated with glomerular hyperfiltration. Both adrenalectomy and spironolactone revert the intrarenal hemodynamic pattern and decrease urinary protein losses.

Relationships of Plasma Renin Levels with Renal Function in Patients with Primary Aldosteronism

BACKGROUND The renal damage that is present in primary aldosteronism might reflect functional and potentially reversible abnormalities that are initiated by glomerular hyperfiltration. The aim of this study was to investigate the relationships of plasma renin and aldosterone concentrations with renal outcomes after treatment of primary aldosteronism. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Fifty-six consecutive patients who had primary aldosteronism and were recruited in a university center were studied. Patients were prospectively followed after either surgical or medical treatment for a mean of 6.2 yr, during which they received antihypertensive drugs to reach a target BP of <140/90 mmHg. RESULTS At baseline, patients with primary aldosteronism had higher creatinine clearance and albuminuria than 323 patients with essential hypertension and 113 normotensive individuals. In patients with primary aldosteronism, plasma active renin levels that were higher than the lower limit of detection (2.5 pg/ml) were associated with higher BP, plasma potassium, and albuminuria and lower creatinine clearance. Plasma aldosterone concentrations that were higher than the median value (225 pg/ml) were associated with lower plasma potassium and higher creatinine clearance. Creatinine clearance was correlated directly with plasma aldosterone and inversely with renin. During follow-up, patients with higher baseline plasma renin required use of more antihypertensive drugs to obtain BP control and had a smaller early decline in albuminuria than did patients with suppressed renin. CONCLUSIONS Escape of renin from suppression by excess aldosterone is associated with evidence of more severe renal damage in patients with primary aldosteronism and predicts less favorable outcomes after treatment.

Renal antioxidant enzyme mRNA levels are increased in rats with experimental diabetes mellitus

Summary Exposure to high glucose concentrations increases the mRNA levels of oxygen radical scavenging enzymes in cultured endothelial cells, suggesting a compensatory response to increased free radical production. To test the hypothesis that this response also occurs in vivo, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase mRNA levels, were measured in the kidneys of Sprague-Dawley rats 17 days after intravenous injection of streptozotocin (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens (2, 3–8, 6–10 IU/day) in two different experiments that were designed to achieve varying degrees of metabolic control. Cu,Zn-SOD and catalase mRNA levels were measured by Northern blot hybridization and standardized by 28S ribosomal RNA determination. Renal Cu,Zn-SOD and catalase mRNA levels were significantly greater in untreated diabetic and in low-dose (2 IU/day) insulin-treated rats than in controls. Treatment with a moderate dose (3–8 IU/day) of insulin normalized catalase but not Cu,Zn-SOD mRNA levels. The highest insulin regimen (6–10 IU/day), in addition to achieving complete metabolic control as evidenced by normal growth and plasma glucose levels, normalized both catalase and Cu,Zn-SOD mRNA levels. Thus, in rats with streptozotocin-induced diabetes Cu,Zn-SOD and catalase renal mRNA levels are greater than in normal rats. This difference is prevented by sufficient insulin dosage to normalize plasma glucose and might be due to an increased production of free radicals. [Diabetologia (1997) 40: 23–29]

Cardiovascular and Renal Damage in Primary Aldosteronism: Outcomes After Treatment

Primary aldosteronism (PA) is one of the common forms of curable hypertension. Recent views have suggested that PA is far from being relatively benign, as it was previously thought, but it is associated with a variety of cardiovascular and renal sequelae that reflect the capability of inappropriately elevated aldosterone to induce tissue damage over that induced by hypertension itself. The evidence supporting these views has been obtained from experiments conducted in hypertensive animal models and studies involving patients with PA. Preclinical studies have also indicated that aldosterone causes cardiovascular and renal tissue damage only in the context of inappropriate salt status. It has been suggested that untoward effects of high-salt intake are dependent on activation of mineralocorticoid receptors (MRs) that might result from increased oxidative stress and changes in the intracellular redox potential. Unilateral adrenalectomy or treatment with MR antagonists are the current options for treating an aldosterone-producing adenoma (APA) or idiopathic adrenal hyperplasia (IHA). Treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent cardiovascular events and deterioration of renal function indicates that surgery and medical treatment are equally beneficial in the long term.

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension

BACKGROUND AND AIM Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. METHODS AND RESULTS The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P < 0.001), as defined by E/A ratio <1 and E-wave deceleration time >220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. CONCLUSIONS Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.

Elevated plasma levels of fibrinogen and activated coagulation pathways are risk factors of cardiovascular disease in the general population. In a cross-sectional study of a case series, we investigated the relationship between fibrinogen and hemostatic markers with target-organ damage (TOD) in patients with arterial hypertension. Prothrombin time, partial thromboplastin time, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), and antithrombin III were measured in 352 untreated patients with mild to moderate essential hypertension and 92 normotensive controls. Staging of TOD was assessed according to W.H.O. guidelines by clinical evaluation and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries. F1+2 concentrations were significantly greater in hypertensive patients than normotensive controls and were positively correlated with blood pressure. Age, blood pressure levels, duration of hypertension, smoking, HDL-cholesterol, triglycerides, and plasma fibrinogen, fibrin D-dimer, and F1+2 levels were significantly related to the presence and severity of TOD in univariate analysis. Plasma fibrinogen and D-dimer levels were related to organ damage independent of age, blood pressure, duration of hypertension, and smoking status. Separate analysis indicated significant association of fibrinogen and D-dimer levels with cardiac, cerebrovascular, peripheral vascular, and renal damage. In conclusion, elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence and severity of TOD in patients with essential hypertension and may contribute to the development of atherosclerotic disease in these patients.

Abnormalities of coagulation in hypertensive patients with reduced creatinine clearance

PURPOSE The prothrombotic state that occurs in uremic patients may increase their cardiovascular risk. We studied hypertensive patients with mild-to-moderate impairment of renal function to determine if they had evidence of abnormalities in the coagulation system. SUBJECTS AND METHODS Renal function was assessed in 382 patients with essential hypertension, in whom 24-hour creatinine clearance, urinary protein excretion, and microalbuminuria were measured. We evaluated the function of the coagulation system by measurement of platelet counts, prothrombin time, partial thromboplastin time, and plasma antithrombin III, fibrinogen, D-dimer, and prothrombin fragment 1 + 2 levels. RESULTS Impaired renal function, defined as a creatinine clearance of 30 to 89 mL per minute per 1.73 m(2) of body surface area, was found in 168 (44%) of the patients. Age, blood pressure, duration of hypertension, and plasma levels of fibrinogen, D-dimer, prothrombin fragment 1 + 2, and lipoprotein(a) were significantly greater in these patients than in those with normal renal function; these differences persisted after adjustment for potential confounders. Creatinine clearance was significantly and inversely correlated with levels of plasma fibrinogen (Spearmans rho = -0.26, P <0.001), D-dimer (rho = -0.33, P <0.001), and prothrombin fragment 1 + 2 (rho = -0.20, P <0.001). Levels of plasma fibrinogen (P = 0.009) and D-dimer (P = 0.003) were correlated with renal function independent of age, blood pressure, duration of hypertension, triglyceride level, urinary protein excretion, and erythrocyte sedimentation rate. Lipoprotein(a) levels were correlated with fibrinogen (rho = 0.16, P = 0.003) and D-dimer (rho = 0.26, P <0.001) levels. CONCLUSIONS Increased plasma levels of fibrinogen, D-dimer, and prothrombin fragment 1 + 2 are present in hypertensive patients with mildly decreased creatinine clearance, suggesting that the coagulation system is activated in these patients.

Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary 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.