We investigated the effects on the heart of hypertension due to the excess of aldosterone and suppression of the renin-angiotensin system caused by primary aldosteronism with M-mode echocardiography and transmitral Doppler flow velocity measurements. We studied 34 consecutive patients with primary aldosteronism and 34 with essential hypertension individually matched for age, gender, race, body mass index, blood pressure values, and duration of hypertension. The groups were similar in age, body mass index, blood pressure, and duration of hypertension. However, lower serum potassium levels (3.5 +/- 0.6 versus 4.1 +/- 0.2 mmol/L, P < .0001) and plasma renin activity (0.53 +/- 0.45 versus 1.82 +/- 1.59 ng Ang I x mL-1 x h-1, P < .0001) and higher plasma aldosterone levels (1107 +/- 774 versus 206 +/- 99 pmol/L, P < .0001), left ventricular wall thickness, and left ventricular mass index (112 +/- 4.7 versus 98 +/- 3.7 g/m2, P = .029) were found in patients with primary aldosteronism compared with those with essential hypertension. Similarly, the PQ interval was longer (173 +/- 20 versus 141 +/- 14 milliseconds, P < .001) in primary aldosteronism than in essential hypertension patients. Significantly more primary aldosteronism than essential hypertension patients had left ventricular hypertrophy or left ventricular concentric remodeling (50% versus 15%, chi 2 = 11.97, P = .007). Both the E wave flow velocity integral (1063 +/- 65 versus 1323 +/- 78, P = .013) and the E/A integral ratio (0.91 +/- 0.05 versus 1.25 +/- 0.08, P < .001) were lower, and atrial contribution to left ventricular filling was higher (53.3 +/- 1.5% versus 45.5 +/- 1.3% P < .001) in patients with primary aldosteronism compared with essential hypertension patients. After 1 year of follow-up, highly significant decreases of left ventricular wall thickness and mass were observed in patients treated with surgical excision of an aldosterone-producing tumor, but not in those with medical therapy. Thus, in patients with primary aldosteronism, the excess aldosterone with suppression of the renin-angiotensin system is associated with both increased left ventricular mass and significant changes of left ventricular diastolic filling. The former changes appear to be reversible on removal of the cause of excessive aldosterone production.

Abstract-Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remains unclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primary aldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wall thickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PA and 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, and known duration of hypertension. The groups differed in serum K ϩ , ECG PQ interval duration, plasma renin activity, and aldosterone levels (all PՅ0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7Ϯ1.8 versus 45.5Ϯ2.0 g/m 2.7 ; Pϭ0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVI s ; Ϫ12.02Ϯ5.84% versus 6.06Ϯ3.08%; Pϭ0.012) and posterior wall (Ϫ11.13Ϯ6.42% versus 8.63Ϯ9.62%; Pϭ0.012). A regression analysis showed that CVI s was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for Ϸ36% of CVI s variance. PA is associated with alterations of myocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolic filling from presystole and the prolongation of the PQ interval. Key Words: hypertension, endocrine Ⅲ aldosterone Ⅲ myocardial Ⅲ hypertrophy Ⅲ fibrosis Ⅲ echocardiography L eft ventricular hypertrophy (LVH) is commonly associated with arterial hypertension and represents an important independent predictor of cardiovascular events, 1 including congestive heart failure. Extracellular matrix and collagen deposition are invariable findings of LVH and lead to cardiac fibrosis (CF), which occurs particularly in the perivascular areas and correlates directly with the severity of LVH. 2 CF is a major cause of cardiac dysfunction because an excessive deposition of collagen may be responsible for abnormal tissue stiffness and diastolic dysfunction. The latter is an early marker of heart involvement in hypertension (for review, see Agabiti-Rosei and Muiesan 3 ) and is associated with CF more closely than with LVH. 4,5 Fibroblasts constitute the vast majority (Ͼ90%) of nonmyocyte cells in the heart; they can increase the production of extracellular matrix on exposure to a variety of injuries, including pressure overload. The latter seems to be only one of the determinants of CF, because it was experimentally shown, both in vitro and in vivo, that CF in both ventricles was linked to activation of the renin-angiotensin-aldosterone system 6 and that it could be prevented by nonantihypertensive dosages of spironolactone. 7 Thus, angiotensin II and aldosterone play important roles in the heart (for review, see Swynghedauw 8 ). Angiotensin II induces cardi...

The objectives of this study were to investigate the usefulness of adrenal vein sampling in identifying the etiology of primary aldosteronism (PA) in patients with equivocal CT and MR findings. Between 1990 and 1999, 104 referred hypertensive patients (45 women and 59 men, aged 49.6 +/- 11.6 yr) were diagnosed to have PA with inconclusive computed tomography scan and magnetic resonance results, based on established criteria. Adrenal vein sampling (AVS) for measurement of plasma aldosterone (A) and cortisol (C) levels was performed in all. Selectivity of AVS was assessed by the ratio between C levels in each adrenal vein and in the infrarenal inferior vena cava plasma (C(side)/C(IVC)). A receiver operator characteristics analysis was carried out to establish 1) the best AVS-derived index, 2) the degree of selectivity that could provide an accurate diagnosis, and 3) whether a correct diagnosis could be made from a unilaterally selective AVS. An aldosterone-producing adenoma (average diameter, 12.2 +/- 0.08 mm) was eventually diagnosed in 41 patients (39.4%) and was excluded in the rest. Adrenal vein rupture leading to partial adrenal loss occurred in 1 patient (0.9% complication rate). By assuming a cut-off value of C(side)/C(IVC) > or = 1.1, AVS was selective in 85.7% and 94.1% of cases on the right and left sides, respectively, and bilaterally in 80.6% of cases. Of all AVS-derived indexes, the A/C of one over the A/C contralateral side [(A/C)(side)/(A/C)(contralateral side)] furnished the best diagnostic accuracy. With a bilaterally selective AVS, a value of (A/C)(side)/(A/C)(contralateral side) > or = 2 provided a conclusive etiological diagnosis of PA in 79.7% of cases. At variance, no accurate diagnosis could be made from unilaterally selective AVS. AVS was feasible and safe in most PA patients with inconclusive computed tomography and magnetic resonance scans. When bilaterally selective (i.e. C(side)/C(IVC) > or = 1.1) a ratio of (A/C)(side)/(A/C)(control) > or = 2 provided the best compromise of sensitivity and false positive rate for lateralization of the etiology of PA.

In APA patients, the excess aldosterone is associated with both increased LV wall thickness and mass and decreased early diastolic LV filling indexes compared with demographically similar EH with superimposable blood pressure values, profile, and variability.

The renin-angiotensin-aldosterone (RAA) system and the endothelin (ET) system entail the most potent vasopressor mechanisms identified to date. Although they were studied in depth in relation to arterial hypertension and cardiovascular diseases, limited information on their interrelationships in causing hypertension and related target organ damage exists. The identification of consensus sequences for jun in the regulatory region of the preproendothelin-1 (ppET-1) gene raised the possibility of its transcriptional regulation by angiotensin II (Ang II). This was confirmed by the finding that stimulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to contribute to the hypertrophic response of cardiomyocytes to Ang II and thereby to cardiac hypertrophy. Furthermore, ET-1 exerts multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldosterone secretion. The finding of abundant specific ET-1 receptors in the adrenocortical zona glomerulosa (ZG) suggested a direct secretagogue effect of ET-1. In rats, ETB receptors mediate such an effect, whilst in humans, both ETA and ETB receptor subtypes intervene in regulating the transcription of the aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis and proliferation of ZG cells via ETA receptors and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adrenal tumours. Studies on the in vivo interactions between ETs and the RAA system have given conflicting results, insofar as some suggested a participation of ET-1 in the pressor and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the two-kidney, one clip.

Abstract-We investigated the role of angiotensin II (Ang II) and endothelin-1 (ET-1) in transgenic (mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension and cardiovascular disease. Four-week-old heterozygous male transgenic (mREN2)27 rats (nϭ24) were matched according to body weight (BW) and blood pressure (BP) and randomly allocated to receive a placebo (group P), the mixed endothelin type A and B receptor antagonist bosentan (100 mg/kg BW PO, group B), the Ang II type 1-specific receptor antagonist irbesartan (50 mg/kg BW PO, group I), or the endothelin type A-selective antagonist BMS-182874 (52 mg/kg BW PO, group BMS). After 4 weeks of treatment, during which BW and BP were measured weekly, animals were euthanized, and the heart, left ventricle, right ventricle, adrenal gland, brain, and kidney were weighed. The plasma levels of adrenocortical steroids were measured by high-performance liquid chromatography. The tension responses of ET-free segments of the thoracic aorta to 5ϫ10 Ϫ6 mmol/L phenylephrine, 60 mmol/L KCl, and cumulative doses of ET-1 were assessed. The density of ET-1 receptor subtypes in the aorta and vascular structural changes in the mesenteric arterioles (100 to 200 m ID) were also measured with autoradiography and myography, respectively. Compared with all other groups, group I rats showed significantly (PϽ0.001) lower systolic BP (group I, 161Ϯ8 mm Hg; group P, 269Ϯ23 mm Hg; group B, 275Ϯ17 mm Hg; and group BMS, 254Ϯ21 mm Hg), left ventricular weight (2.28Ϯ0.15 versus 3.71Ϯ0.26, 3.38Ϯ0.27, and 3.96Ϯ0.51 mg/g BW, respectively), tension responses to vasoconstrictors, and normalized media thickness of the mesenteric arterioles (22.3Ϯ0.6 versus 25.3Ϯ0.5, 25.5Ϯ0.7, and 24.1Ϯ1.5 m, respectively). Compared with levels in group P (78Ϯ25 pmol/mL), plasma aldosterone levels were significantly decreased in group B (51Ϯ11 pmol/mL) and group I (40Ϯ16 pmol/mL). Thus, endogenous ET-1 and Ang II contribute to the regulation of aldosterone, but only Ang II is crucial for the development of hypertension and related target organ damage via the Ang II type 1 receptor. Endogenous Ang II does not appear to enhance cardiovascular production of ET-1 in this model of hypertension within the time span of our experiment. 8 by acting on Ang II type 1 (AT 1 ) receptors linked to activation of transcription via activator protein-1/ protein kinase C-mediated mechanisms. 7-11 ET-1 might be involved in mediating renin-dependent hypertension and also cardiovascular damage (CVD), because it was found to contribute to the hypertrophic response to Ang II. 10 -14 However, data concerning the interactions between Ang II and ET-1 in hypertension are conflicting (see Reference 4 for a review). Studies in rats with Ang II infusion and administration of bosentan suggested that ET-1 could importantly contribute to renal and systemic vasoconstriction and thus to arterial hypertension. 15,16 Bosentan was also reported to prevent the increase in heart weight, albuminuria, and carotid medial thickness (MT)...

These results, besides confirming an association of both IMT and CAL with primary hypertension and ageing, demonstrate that CAL and IMT have different correlates. However, they do not support the contention that a high renin-sodium profile carries an excess risk of CAL in primary hypertensives with no clinical evidence of cerebro-vascular disease.

These findings confirm that PA patients exhibit: (1) a modest increase of CI; (2) an LV diastolic filling mainly occurring with the atrial kick. However, they do not lend support to the contention that the excess of plasma aldosterone seen in PA is associated with enhanced LV inotropism under resting conditions.