Left ventricular structural and functional characteristics in patients with renovascular hypertension,primary aldosteronism and essential hypertension

To investigate the effect of different etiologies of hypertension on left ventricular structure and function, we compared echocardiographic findings in 10 patients with renovascular hypertension (35 ± 9 years), 10 patients with primary aldosteronism (42 ± 9 years), and 14 patients with essential hypertension (41 ± 6 years). There were no significant differences among the three groups in age, sex, body surface area, blood pressure, interventricular septal thickness, posterior wall thickness, left ventricular end-diastolic dimension or end-systolic dimension, relative wall thickness, left ventricular mass index, or spectrum of left ventricular adaptation (concentric remodeling, concentric hypertrophy, or eccentric hypertrophy). There were no differences in systolic function or diastolic function, which was assessed in terms of the peak rate of increase in dimension normalized for left ventricular end-diastolic dimension (dD/dt/D), the relaxation time, and the relaxation time to peak velocity of lengthening among groups. Multiple regression analysis showed that the systolic blood pressure was the most important determinant of left ventricular mass index (r = 0.56, P < .01), and that left ventricular mass index was the most important determinant of relaxation time and the relaxation time to peak velocity of lengthening (r = 0.48, P < .01 and r = 0.59, P < .01, respectively). The dD/dt/D was correlated only with left ventricular end-systolic dimension (r = 0.59, P < .01). Our results suggest that blood pressure may be a strong determinant of left ventricular hypertrophy, irrespective of the etiology of hypertension, and that the degree of hypertrophy may be related to left ventricular diastolic dysfunction in hypertensive patients with normal systolic function.     

Left ventricular structural characteristics in unilateral renovascular hypertension and primary aldosteronism

To assess the importance of the renin-angiotensin system and plasma volume as determinants of hypertensive left ventricular hypertrophy and its anatomy, patients with unilateral renovascular hypertension and primary aldosteronism were studied by echocardiography. Blood pressure, age and sex were matched as closely as possible. The 19 patients with unilateral renovascular hypertension and the 19 patients with primary aldosteronism were similar in age, sex and blood pressure (168 +/- 19/97 +/- 11 and 163 +/- 17/99 +/- 10 mm Hg, respectively), but plasma volume was increased in the patients with primary aldosteronism. Interventricular septal thickness, left ventricular posterior wall thickness, left ventricular mass index and relative wall thickness did not differ between the 2 groups of patients. There was a significant correlation between the level of systolic blood pressure and either left ventricular mass index (r = 0.34, p less than 0.05) or relative wall thickness (r = 0.58, p less than 0.001) in both groups of patients. Left ventricular end-diastolic dimension index was increased in the patients with primary aldosteronism compared with those with unilateral renovascular hypertension (3.2 +/- 0.4 vs 2.9 +/- 0.3 cm/m2, p less than 0.02). When confined to the patients with systolic pressure greater than or equal to 150 mm Hg, relative wall thickness was significantly increased in the patients with unilateral renovascular hypertension. Patients with primary aldosteronism and unilateral renovascular hypertension of similar blood pressure levels, age and sex have almost identical degrees of left ventricular hypertrophy and anatomy. In contrast, the patients with primary oldosteronism had increased left ventricular dimension index.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protein phosphorylation and intracellular free calcium in platelets of patients with essential hypertension.

Platelet intracellular free calcium concentration [Ca2+]i from patients with essential hypertension has been found to be elevated, but the intracellular effects of this increase are still unclear. As protein phosphorylation is an important regulatory step in cell activation and increased protein phosphorylation has been demonstrated in platelets from hypertensive animals, we investigated protein phosphorylation and [Ca2+]i in platelets from patients with essential hypertension and age-matched normotensives. We measured the 32P incorporation into a 20 kDa protein and a 47 kDa protein in 17 hypertensive patients and 20 normotensive, age-matched subjects. The [Ca2+]i was measured with the fluorescent dye fura-2. Protein phosphorylation and [Ca2+]i were assessed in unstimulated platelets and after exposure of the cells to 0.1 and 0.25 U/mL thrombin at 20, 60, and 300 sec. In addition we assessed the activity of protein kinase C by incubating the platelets with phorbol-ester TPA at 20, 60, and 300 sec. Basal phosphorylation of the two proteins was not different between the two groups. After exposure of the platelets to thrombin 32P, incorporation into the 20 kDa protein and the 47 kDa protein was significantly increased in platelets from hypertensive patients at all times. Furthermore, the specific stimulation of protein kinase C with TPA resulted in a significantly higher phosphorylation of the 47 kDa protein, whereas the 20 kDa protein was not phosphorylated after incubation with TPA for 1 min. Basal [Ca2+]i was higher in platelets from hypertensive patients (124 +/- 7 nmol/L v 104 +/- 5 nmol/L, P less than .05), although there was a wide overlap between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytosolic calcium and insulin resistance in elderly patients with essential hypertension.

We evaluated insulin sensitivity in normotensive (blood pressure, BP, less than 135/85 mm Hg) and hypertensive (BP greater than 160/90 mm Hg) elderly subjects over 65 years old who were stratified as normal weight (body mass index, BMI, less than 27) and obese (BMI greater than 27). Obese hypertensive individuals demonstrated marked hyperinsulinemia (P less than .01) and significantly reduced (P less than .05) submaximally stimulated adipocyte 2-deoxyglucose (2-DOG) uptake (abdominal wall fat biopsy). Normal weight hypertensive subjects also demonstrated higher levels of insulinemia and lower insulin-stimulated 2-DOG uptake than nonobese controls. Adipocyte [Ca2+]i levels were elevated in all elderly subjects compared to young individuals (P less than .01). Basal and maximally stimulated 2-DOG uptake were similar in all groups. One month of therapy with a calcium channel blocker, 10 mg nitrendipine twice daily, reduced blood pressure in the hypertensive subjects, reduced plasma insulin to control values during an oral glucose tolerance test in obese hypertensive individuals (P less than .01), and restored adipocyte 2-DOG uptake at submaximally effective insulin concentration to control values in normal weight and obese hypertensive subjects. In summary, older hypertensive, and particularly older obese hypertensive, patients manifest significant insulin resistance accompanied by elevated levels of [Ca2+]i in their adipocytes.     

Cytosolic free calcium in platelets: relationships to blood pressure and indices of systemic calcium metabolism

Relationships between cytosolic free calcium ([Ca2+]i) in platelets, indices of systemic calcium metabolism and blood pressure were examined in 86 subjects; 29 patients with untreated and 29 patients with treated essential hypertension, six patients with borderline hypertension and 22 healthy reference subjects. In order to analyse interactions between the variables, multivariate statistical analyses were employed. The patients with untreated hypertension had higher [Ca2+]i values in non-activated platelets (P = 0.04) and lower levels of plasma ionized calcium (P = 0.02) than the reference subjects. In multivariate models analysing platelet [Ca2+]i mean blood pressure (MBP), plasma ionized calcium, serum parathyroid hormone (PTH) and body mass index (BMI), the relationship between platelet [Ca2+]i and blood pressure was attenuated (P = 0.13), whereas the inverse relationships between plasma ionized calcium and MBP (P = 0.01) and between platelet [Ca2+]i and serum PTH (P = 0.06) seen in univariate analyses persisted. According to the multivariate models the [Ca2+]i value explained only 5% of the MBP variability. Thus, the data from this investigation do not support a close relationship between basal platelet [Ca2+]i and blood pressure. The inverse relationship between plasma ionized calcium and blood pressure, independent of platelet [Ca2+]i and serum PTH, suggests a direct interaction between plasma ionized calcium and blood pressure regulation.     

QT interval in patients with primary aldosteronism and low-renin essential hypertension

INTRODUCTION: QT interval prolongation increases the risk of sudden death in several medical conditions. Patients with primary aldosteronism and salt-sensitive hypertension experience more cardiovascular events than those with normal-renin essential hypertension. QT interval prolongation might represent one of the risk factors for cardiovascular events in these patients. The aim of the present study was to evaluate the QT interval in patients with primary aldosteronism and low-renin essential hypertension (LREH). METHODS: Twenty-seven patients with primary aldosteronism, 17 patients with LREH, 117 patients with essential hypertension and 25 healthy individuals were studied. Plasma aldosterone, plasma renin activity, and aldosterone to plasma renin activity ratio (ARR) were determined. Corrected QT intervals (QTcs) were measured from a 12-lead electrocardiogram. RESULTS: The QTc was longer in primary aldosteronism (434 +/- 23 ms) and LREH (430 +/- 18 ms) compared with essential hypertension (419 +/- 22 ms) and healthy controls (412 +/- 19 ms) (P = 0.0004). The prevalence of QTc longer than 440 ms was higher in primary aldosteronism (48%) and LREH (23%) compared with essential hypertension (11%) and healthy controls (4%) (P < 0.0001). QTc correlated with plasma aldosterone (P = 0.01), ARR (P = 0.02), and diastolic blood pressure (P = 0.01). ARR (P = 0.01) and systolic blood pressure (P = 0.01) were identified as independent predictors of QTc. CONCLUSIONS: We postulate that the elevated aldosterone secretion contributes to the prolongation of the QT interval in patients with primary aldosteronism and LREH through both a depletion of intracellular potassium concentration and higher blood pressure values. QTc measurement might represent one simple, non-invasive and reproducible index to characterize the cardiovascular risk in patients with primary aldosteronism and LREH.     

Discriminating factors for recurrent hypertension in patients with primary aldosteronism after adrenalectomy.

Patients with primary aldosteronism show relatively high rates of hypertension after adrenalectomy, but the risk factors for postoperative hypertension remain unclear. Forty-six patients with primary aldosteronism (PA) who had undergone adrenalectomy between 1976 and 1998 were enrolled in this study. Follow-up information including blood pressure (BP) and cardiovascular complications was collected by means of correspondence or telephone contact. At discharge BP was normalized in 34 patients (72%); hypertension persisted in the remaining 12 patients, but BP control was significantly improved. The patients who remained hypertensive at discharge had longer durations of hypertension than did those with normalized BP. After an average follow-up period of 12.2 years, 16 of 34 BP-normalized patients (47%) had recurrent hypertension. Age at adrenalectomy, preoperative serum creatinine level and systolic blood pressure at discharge were significantly higher in patients with recurrent hypertension than in those without it. A multivariate logistic regression analysis revealed that only the level of serum creatinine was independently associated with the incidence of recurrent hypertension. Patients with serum creatinine of 0.9 mg/dl or greater had significantly higher rates of recurrent hypertension than those with lower values of serum creatinine. Cardiovascular complications occurred in 5 patients prior to the surgery and in 2 patients during the follow-up period. Although the severity of renal involvement is subclinical, renal damage may play an important role in the development of hypertension during a long period after adrenalectomy in patients with PA.     

原发性醛固酮增多症与原发性高血压代谢异常的比较

目的 探讨原发性醛固酮增多症的代谢异常.方法 入选已确诊的原发性醛固酮增多症(原醛)患者220例(男117例,女103例)与性别、年龄及高血压病程相匹配的同期住院原发性高血压(EH)患者200例(男104例,女96例).记录入选者一般临床资料和生化指标,在两组间行代谢综合征患病率及两组代谢异常特点比较.结果 (1)原醛组代谢综合征患病率显著高于同期住院EH组(47.3％对31.5％,P=0.009).(2)原醛患者整体血压水平显著高于EH患者[24 h平均收缩压(150.67±15.45)mm Hg对(145.69±17.13)mm Hg,P=0.042;24 h平均舒张压(93.03±10.51)mm Hg对(85.83±14.44)mm Hg,P=0.037],且原醛组以2、3级高血压为主.(3)原醛患者腹型肥胖和胰岛素抵抗发生率显著高于EH患者[86.8％(191/220)对78.5％(157/200),P=0.024;胰岛素抵抗指数42.42±16.11对49.58±22.43,P=0.008].结论 原醛以腹型肥胖、中重度高血压及严重的胰岛素抵抗为主要特征,直接导致其代谢综合征患病率显著高于EH患者.     

Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism.

The ratio of serum aldosterone to plasma renin activity (PRA) has been proposed as sensitive screening method in the diagnosis of primary aldosteronism under random conditions. However, the method for determination of renin activity is hampered by the necessity of ice cooling during storage and transport. The present study was therefore conducted to examine the ratio of serum aldosterone to plasma renin concentration (ARR) and its usefulness in diagnosis of primary aldosteronism under ambulatory conditions and given antihypertensive medication. 146 patients with arterial hypertension who consecutively attended the outpatient clinic were studied prospectively. Patients with secondary hypertension besides primary aldosteronism were not included in the series. 37 normotensive patients served as control. Also, 17 patients with known primary aldosteronism were retrospectively examined. Among the hypertensive group 2 patients with Conn's syndrome were newly detected (1.4%). ARR was 7.92 +/- 6.04 [pg/ml]/[pg/ml] in normotensive controls (range from 2.03 to 26.98), 14.61 +/- 18.50 [pg/ml]/[pg/ml] in patients with essential hypertension (n = 144, range from 0.41 to 115.45) and 155.92 +/- 127.84 [pg/ml]/[pg/ml] in patients with primary aldosteronism (n = 19, range from 6.75 to 515). 17 of the 19 patients with Conn's syndrome had an ARR of more than 50. Under ongoing drug treatment this represents a sensitivity of 89% and a specificity of 96%. Sensitivity decreased to 84% and specificity increased to 100% when a second criteria (aldosterone > or = 200 pg/ml) was included. In summary, ARR using renin concentration is a useful screening parameter for primary aldosteronism.     

血钾正常伴高血压的原发性醛固酮增多症患者224例的临床分析

目的探讨血钾正常伴高血压的原发性醛固酮增多症(原醛)患者的临床特点。方法选择2006-01-2010-03在新疆维吾尔自治区人民医院高血压中心住院,经过醛固酮肾素活性比值(ARR)初筛、卡托普利试验或盐水负荷试验确诊的224例血钾正常伴高血压的原醛患者,回顾性分析临床和生化资料。结果血钾正常伴高血压的原醛患者224例中1、2、3级高血压分别占4.5%、18.3%、77.2%;主要症状依次是头痛(52.1%)、头晕(49.7%)、乏力(4.1%)、心悸(3.0%)、肢体麻木(1.8%);心血管并发症中脑梗死的发生率为24.1%,冠状动脉粥样硬化性心脏病的发生率为11.6%;血钠平均为(140.8±2.8)mmol/L,高钠血症患者仅占2.7%;低肾素活性者占97.3%。以ARR≥20(ng/dL)/[μg/(L·h)]且肾素活性减低为标准诊断血钾正常伴高血压的原醛的阳性率明显高于肾素活性降低且醛固酮浓度升高、ARR≥20(ng/dL)/[μg/(L·h)]且醛固酮浓度升高、ARR≥30(ng/dL)/[μg/(L·h)]为标准的阳性率。结论血钾正常伴高血压的原醛患者主要表现为中重度高血压,血浆肾素活性降低,血管并发症中脑梗死比冠状动脉粥样硬化性心脏病更多见,以ARR≥20(ng/dL)/[μg/(L·h)]且肾素活性减低为标准筛查血钾正常伴高血压的原醛可能有助于减少漏诊率。     

Intralymphocytic sodium and free calcium concentration in relation to salt sensitivity in patients with essential hypertension

In order to clarify the relation between salt sensitivity and changes in intracellular sodium ([Na]i) and free calcium concentration ([Ca2+]i) after salt loading, [Na]i and [Ca2+]i were determined in lymphocytes of twenty patients with essential hypertension under a low salt diet (3 g/day) and a high salt diet (20 g/day) for seven days, respectively. They were classified as "salt-sensitive" (n = 10) or "nonsalt-sensitive" (n = 10) on the basis of the changes in blood pressure after salt loading. Both lymphocytic [Na]i and [Ca2+]i were significantly increased with salt loading in salt-sensitive patients (p less than 0.05 for both), while they were not affected by salt loading in nonsalt-sensitive patients. Lymphocytic [Ca2+]i showed a positive correlation with lymphocytic [Na]i under both low salt diet (r = 0.62, p less than 0.01) and high salt diet (r = 0.70, p less than 0.01) in all patients in both groups. In addition, a close and positive correlation was observed between the changes in lymphocytic [Na]i and those in lymphocytic [Ca2+]i after salt loading in all patients in both groups (r = 0.80, p less than 0.001). These results suggest that the increase in [Ca2+]i, possibly linked with the increase in [Na]i, may be involved in elevation of blood pressure in the salt-sensitive patients after salt loading.     

Plasma aldosterone concentration in patients with primary aldosteronism in the last decade

We analyzed the chronological variation of plasma aldosterone concentration (PAC) in 27 surgically confirmed patients with primary aldosteronism (PA) during the period from 1975 to 1984. PAC values in PA-patients were significantly higher than those in 82 age-matched patients with essential hypertension (EHT). However, although average PAC in the PA-patients declined consistently in recent years, no chronological trend of PAC was observed in the EHT-patients. Therefore, the distributions of PAC in the two groups of patients overlapped in the last few years. Such chronological variations of PAC in the PA-patients were not related to serum potassium concentration, blood pressure level on admission, duration of hypertension, or diameter of the adrenal adenomas. In some recently observed cases of PA, not only was the basal PAC relatively low, PAC also responded to either salt depletion or salt loading. These findings could not be explained simply by the change of methodology for PAC determination but rather by the technological advance of diagnostic radiology. As a result, PA might be diagnosed in the early stages or before becoming fullblown. Further study should be necessary to clarify the exact mechanism.     

Genetic alterations in patients with primary aldosteronism.

The syndrome of primary aldosteronism is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. The most common clinical subtypes of primary aldosteronism are aldosterone-producing adrenocortical adenoma (APA) and bilateral adrenal cortical hyperplasia (idiopathic hyperaldosteronism, or IHA). It has been reported that renin suppression and aldosterone levels are lower and hypokalemia milder in patients with IHA than in patients with APA. In the present study, we investigated the genetic analysis of aldosterone synthase gene, CYP11B2 in patients with primary aldosteronism and review the recent studies. The chimeric CYP11B1/CYP11B2 gene, which is a candidate gene for glucocorticoid-remediable hyperaldosteronism, was not found in either the DNA from aldosteronoma or in the genomic DNA from patients with APA or IHA. Mutations in the CYP21 or CYP11B1 gene were not present in patients with APA. No mutations in the coding region of the CYP11B2 gene were found in patients with IHA or APA. The level of CYP11B2 messenger RNA (mRNA) was much higher in the aldosteronoma portion than in nonadenomatous portion. The overexpression of CYP11B2 mRNA seen in the mononuclear leukocytes of patients with IHA suggests that unidentified aldosterone-stimulating factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA. The variants of the CYP11B2 gene may also contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.     

Plasma aldosterone response to ACTH in primary aldosteronism and in patients with low renin hypertension.

ACTH alpha 1-24 was infused at incremental rates of 12.5-200 mIU/30 min in dexamethasone-suppressed hypertensive patients on a regular sodium diet. The plasma aldosterone response to this stimulus in 8 patients with hyperaldosteronism due to an adrenal aldenoma and 11 with adrenal hyperplasia was significantly greater at all infusion rates (P less than 0.05) when compared with the response in 6 normal subjects on a similar diet. This responsiveness to ACTH in the patients with primary hyperaldosteronism was similar to that of the normal subjects on a low sodium diet. Twelve patients with low renin and 6 patients with normal renin essential hypertension were similarly studied. There was no significant difference in the median aldosterone response between these 2 groups and the normal subjects on a normal diet, but the response was significantly lower compared with that in patients with primary hyperaldosteronism. These data show that patients with hyperaldosteronism from an adrenal adenoma or hyperplasia have a consistent and exaggerated response to ACTH. The hyper-responsiveness is not apparently shared by the majority of patients with low renin essential hypertension and does not support the concept that this group is an intermediate form of primary aldosteronism. Individual patients within this group, however, may have such a response and might be identified by this type of testing.     

Cytosolic calcium in platelets of spontaneously hypertensive rats

To test the hypothesis that an abnormality of the intracellular concentration of ionized calcium, [Ca2+]i, is associated with high blood pressure, we measured [Ca2+]i in the platelets of spontaneously hypertensive (SHR) and Wistar-Kyoto control (WKY) rats using the Quin 2 technique after separation of the platelets in calcium-free medium, during calcium repletion, and upon exposure to agonists which increase platelet [Ca2+]i (thrombin, adenosine diphosphate, serotonin and ionomycin). Despite clear-cut changes in [Ca2+]i during these manipulations, there were no differences between the SHR and WKY rats in baseline levels of [Ca2+]i or in the kinetics of changes in [Ca2+]i. These results do not support the hypothesis that high levels of [Ca2+]i at rest or abnormal kinetics of changes in [Ca2+]i play a pathophysiological role in the hypertension of SHR.     

Increased platelet cytosolic free calcium concentration in essential hypertension

Cytosolic free calcium concentration [Ca2+] was studied in platelets of hypertensive patients with the use of the fluorescent indicator Quin 2/AM. Cytosolic free Ca2+ was significantly higher in platelets of hypertensive patients than in those of normotensive subjects (241 +/- 9 versus 192 +/- 7 nmol/l, n = 58 and 57, respectively P less than 0.001). When all 115 subjects were included, there was a significant correlation between cytosolic free Ca2+ and systolic or diastolic blood pressure (r = 0.262, P less than 0.0025 and r = 0.251, P less than 0.0025, respectively). Intracellular Quin 2 concentration was measured to evaluate the formaldehyde production (a product of Quin 2/AM hydrolysis which has been described as reducing the adenosine triphosphate (ATP) production). The Quin 2 concentrations in platelets of the two groups of subjects were observed to be similar (0.41 +/- 0.03 versus 0.38 +/- 0.03 mmol/l, n = 8 and 7 for hypertensives and normotensives, respectively). The effects of prostaglandin E1 (PGE1), an adenylate cyclase stimulator, on cytosolic free Ca2+ were studied. The presence of 10(-7) mol/l PGE1 lowered the Ca2+ in platelets of hypertensive patients only, suppressing the difference between the two groups.     

Urinary albumin excretion in patients with renovascular hypertension.

Twenty-four hour urinary excretion of albumin (UEalb), IgG and beta-2 microglobulin was investigated at a 3 hour-interval in a control group (C) of healthy subjects, in 30 patients with renovascular hypertension (RVH), and in 16 patients with essential hypertension (EH). Mean UEalb in RVH was significantly higher than in C. A significant direct correlation was demonstrated between diastolic blood pressure and UEalb (p < 0.01). Microalbuminuria (MA) > or = 30 micrograms.min-1 was found in about 18% of RVH patients; it was higher than 16.7 micrograms.min-1 in approx. 31%. These results did not substantially differ from those obtained in patients with EH. The cause for increased UEalb in hypertensive patients may be functional, haemodynamic changes, or structural ones. In either case, MA indicates renal injury, and these patients should be given increased attention when monitoring their blood pressure and when selecting antihypertensive drugs.     

Management of hypertension in primary aldosteronism

Hypertension causes significant morbidity and mortal-ity worldwide, owing to its deleterious effects on the cardiovascular and renal systems. Primary hyperaldo-steronism(PA) is the most common cause of revers-ible hypertension, affecting 5%-18% of adults with hypertension. PA is estimated to result from bilateral adrenal hyperplasia in two-thirds of patients, and from unilateral aldosterone-secreting adenoma in approxi-mately one-third. Suspected cases are initially screened by measurement of the plasma aldosterone-renin-ratio, and may be confirmed by additional noninvasive tests. Localization of aldostosterone hypersecretion is then determined by computed tomography imaging, and in selective cases with adrenal vein sampling. Solitary adenomas are managed by laparoscopic or robotic re-section, while bilateral hyperplasia is treated with min-eralocorticoid antagonists. Biochemical cure following adrenalectomy occurs in 99% of patients, and hemo-dynamic improvement is seen in over 90%, prompting a reduction in quantity of anti-hypertensive medica-tions in most patients. End-organ damage secondary to hypertension and excess aldosterone is significantly improved by both surgical and medical treatment, asmanifested by decreased left ventricular hypertrophy, arterial stiffness, and proteinuria, highlighting the im-portance of proper diagnosis and treatment of primary hyperaldosteronism. Although numerous independent predictors of resolution of hypertension after adrenalec-tomy for unilateral adenomas have been described, the Aldosteronoma Resolution Score is a validated multifac-torial model convenient for use in daily clinical practice.