Alfredo Sacchetto

Changes in Left Ventricular Anatomy and Function in Hypertension and Primary Aldosteronism

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.

Remodeling of the Left Ventricle in Primary Aldosteronism Due to Conn’s Adenoma

BACKGROUND Since hyperaldosteronism has been experimentally related to myocardial interstitial fibrosis, we investigated the effects of hypertension and excess aldosterone due to aldosterone-producing adenomas (APAs) on the heart. METHODS AND RESULTS In 52 hypertensive individuals, we performed Doppler echocardiography for estimation of left ventricular (LV) wall thickness and dimensions, transmitral LV filling flow velocity indexes, and 24-hour ambulatory blood pressure monitoring. Consecutive patients with APAs (n = 26) and essential hypertension (EH, n = 26) were individually matched for age, sex, race, body mass index, casual blood pressure, and known duration of hypertension. The matched groups were similar for demography, casual and 24-hour blood pressure values and variability, and duration of hypertension but differed for serum potassium, plasma renin activity, and aldosterone levels (all P < .001). A thicker interventricular septum (P = .015) and posterior wall (P = .009) and a higher LV mass index (118 +/- 5 versus 100 +/- 4 g/m2, P = .009) were observed in APA compared with EH patients. Both septum and posterior wall thicknesses had a significant direct relationship with age, plasma aldosterone, and mean blood pressure. The integral of the early diastolic filling wave (Ei) (P = .011) and the ratio Ei/Ai (A wave integral) (P = .038) were lower and the atrial contribution to LV filling was higher (52 +/- 2% versus 46 +/- 2%, P = .038) in APA than in EH patients. The ratio Ei/Ai was significantly (P = .008) inversely related only to age and plasma aldosterone. CONCLUSIONS 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.

Interactions between endothelin-1 and the renin–angiotensin–aldosterone system

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.

Hypertensive Cerebrovascular Disease and the Renin-Angiotensin System

BACKGROUND Arterial hypertension is the leading cause of cardiovascular disease and is associated with an increased risk of stroke and heart attack. These complications have been largely attributed to the remodeling of the arterial wall, including accelerated atherosclerosis occurring in hypertensive patients. Although the risk of haemorrhagic stroke seems to be directly related to the level of blood pressure elevation, no such tight relationship has been found between blood pressure levels and atherosclerosis. This observation has led to the concept that a number of genetic, humoral, and cellular factors may be involved in atherogenesis in hypertensive patients. SUMMARY OF REVIEW The experimental and clinical evidence concerning the role of the renin-angiotensin system in cardiovascular remodeling and atherogenesis of the cerebrovascular bed as well as the data supporting an association between angiotensin II and thrombotic stroke are examined. CONCLUSIONS The contribution of the renin-angiotensin system to the pathogenesis of accelerated carotid artery atherosclerosis and particularly of cerebrovascular disease remains to be definitively proven. However, the bulk of experimental and clinical data are consistent with the hypothesis that the renin-angiotensin system may play a detrimental role.

Left ventricular systolic function in primary aldosteronism and hypertension.

Objective This study was designed to investigate whether the excess aldosterone found in primary aldosteronism (PA) influences left-ventricular systolic function (LVSF), through a positive inotropic effect. Methods M-mode and two-dimensional echocardiography and transmitral Doppler flow velocity measurements were performed in 82 patients: 44 with confirmed PA (23 male; 21 female; aged 51.8 ± 13 years) and 38 essential hypertension patients (16 male; 22 female; aged 48.5 ± 12 years) matched for demography and blood pressure (BP) values. We measured left- ventricular (LV) midwall fractional shortening (MwFSho) and LV circumferential end-systolic stress (cESS, calculated according to Reicheks equation) and analysed the relationship between MwFSho and cESS. Results These are given as the mean ± standard deviation. PA patients had significantly higher cardiac index (CI) (3.55 ± 0.94 l/m2 vs 2.98 ± 0.58, P < 0.005) and lower E wave/A wave time-velocity integral ratio (0.93 ± 0.27 vs 1.26 ± 0.41, P < 0.001) than EH, whereas mean BP (126 ± 12 mmHg vs 128 ± 12), MwFSho (17.1 ± 2.4 % vs 16.3 ± 1.9), cESS (118 ± 19 Kdynes/cm2vs 121 ± 18) and the relationship between LV MwFSho and LV cESS did not differ between groups. Conclusion 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.

Endothelin-1: A scientist's curiosity, or a real player in ischemic heart disease?

Endothelin-1, the most potent endothelium-derived vasoconstrictor peptide identified so far, exerts multiple biologic effects that are potentially relevant for the pathogenesis of coronary atherosclerosis and ischemic heart disease. Since the discovery of the peptide, a good deal of experimental and clinical data have been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous endothelin-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary atherosclerosis, acute myocardial infarction, and angina. Given its growth-promoting and mitogenic action, endothelin-1 has also been suspected to participate in the mechanism of restenosis after PTCA. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of endothelin-1 in ischemic heart disease and the results of more recent studies on the effects of endothelin-1 blockade on experimental myocardial necrosis and restenosis after PTCA.

Comparative effects of the dual ACE–NEP inhibitor MDL-100,240 and ramipril on hypertension and cardiovascular disease in endogenous angiotensin II-dependent hypertension

We investigated the effects of MDL-100,240 in a transgenic rat model (TGRen2) of hypertension with severe cardiovascular damage (CVD) due to enhanced tissue synthesis of angiotensin II (Ang II). Male heterozygous TGRen2 rats (5 weeks old) were allocated to receive MDL-100,240, ramipril (RAM) or placebo (PLAC) for 4 weeks, during which blood pressure (BP) was measured. We then evaluated: 1) left ventricle (LV) and right ventricle (RV), brain, kidney and adrenals weight; 2) structural changes in the aorta and the mesenteric arterioles wall; 3) tension responses of segments of the aorta to phenylephrine, KCl, and endothelin-1; and 4) creatinine, aldosterone, atrial natriuretic peptide (ANP), and cyclic GMP (cGMP) plasma levels. Compared to PLAC, both MDL-100,240 and RAM significantly (P < .001) lowered BP (after 4 weeks: 255 +/- 15 mm Hg PLAC, v 174 +/- 6 MDL-100,240, v 166 +/- 5 RAM). They hindered LV hypertrophy (3.73 +/- 0.25 mg/g body weight (PLAC) v 2.71 +/- 0.22 (MDL-100,240) P < .001; v 2.36 +/- 0.2 (RAM), P < .001). MDL-100,240 also prevented aortic dilatation and hypertrophy of the mesenteric arterioles (media thickness, 25.3 +/- 0.5 microm PLAC, v 21.1 +/- 0.9 MDL-100,240, P < .007; v 20.2 +/- 1.5 RAM, P = .033) and lowered the tension responses to phenylephrine (P < .01), KCl (P < .01), and endothelin-1 (P < .001). Plasma aldosterone (710 +/- 153 pmol/L PLAC, v 237 +/- 61 MDL-100,240, v 180 +/- 22 RAM) and creatinine levels (0.69 +/- 0.33 mg/dL PLAC, v 0.41 +/- 0.02 MDL-100,240, v 0.41 +/- 0.04 RAM) were also decreased (P < or = .001). Compared to PLAC, plasma ANP levels were 11% and 2.4% higher in MDL-100,240 and RAM, respectively (both P = not significant); cGMP levels were unaffected. Thus, severe hypertension and related CVD were regressed by MDL-100,240, which resulted to be as effective as a full dosage of ramipril in TGRen2.

Interactions between endothelin-1 and the renin-angiotensin-aldosterone system (RAAS)

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.