Achille C. Pessina

Endothelial function and dysfunction. Part Ii: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension*

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

Renal Damage in Primary Aldosteronism: Results of the PAPY Study

Primary aldosteronism (PA) has been associated with cardiovascular hypertrophy and fibrosis, in part independent of the blood pressure level, but deleterious effects on the kidneys are less clear. Likewise, it remains unknown if the kidney can be diversely involved in PA caused by aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hence, in the Primary Aldosteronism Prevalence in Italy (PAPY) Study, a prospective survey of newly diagnosed consecutive patients referred to hypertension centers nationwide, we sought signs of renal damage in patients with PA and in comparable patients with primary hypertension (PH). Patients (n=1180) underwent a predefined screening protocol followed by tests for confirming PA and identifying the underlying adrenocortical pathology. Renal damage was assessed by 24-hour urine albumin excretion (UAE) rate and glomerular filtration rate (GFR). UAE rate was measured in 490 patients; all had a normal GFR. Of them, 31 (6.4%) had APA, 33 (6.7%) had IHA, and the rest (86.9%) had PH. UAE rate was predicted (P<0.001) by body mass index, age, urinary Na+ excretion, serum K+, and mean blood pressure. Covariate-adjusted UAE rate was significantly higher in APA and IHA than in PH patients; there were more patients with microalbuminuria in the APA and IHA than in the PH group (P=0.007). Among the hypertensive patients with a preserved GFR, those with APA or IHA have a higher UAE rate than comparable PH patients. Thus, hypertension because of excess autonomous aldosterone secretion features an early and more prominent renal damage than PH.

Creatine Kinase System in Failing and Nonfailing Human Myocardium

BACKGROUND The creatine kinase (CK) reaction is important for rapid resynthesis of ATP when the heart increases its work. Studies defining the CK system in human failing and nonfailing myocardium are limited and in conflict. To resolve this conflict, we measured the activities of CK and its isoenzymes and the contents of creatine and CK-B in homogenates of human myocardium. METHODS AND RESULTS Myocardium was sampled from 23 subjects who underwent heart transplant, 36 subjects maintained in an intensive care unit before heart harvesting, 13 accident victims, and 2 patients undergoing heart surgery. Since the characteristics of myocardium of potential organ donors differed from those of myocardium of accident victims, data are presented for three groups: failing, donor, and control. CK activity was 7.7 +/- 1.9 and 6.0 +/- 1.4 IU/mg protein in left (LV) and right (RV) ventricles of failing, 9.4 +/- 2.5 and 10.7 +/- 2 IU/mg protein in LV and RV of donor, and 11.6 +/- 2.4 IU/mg protein in LV of control hearts. CK-MM and the mitochondrial isoenzyme activities were lower in failing and donor LV, and CK-MB activity and CK-B content were higher in failing and donor hearts. Creatine contents were 64 +/- 25 and 56 +/- 18.6 nmol/mg protein in LV and RV of failing, 96 +/- 30 and 110 +/- 24 nmol/mg protein in LV and RV of donor, and 131 +/- 28 nmol/mg protein in LV of control hearts. CONCLUSIONS In failing and nonfailing donor human myocardium, there is a combined decrease of CK activity and creatine that may impair the ability to deliver ATP to energy-consuming systems.

The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness.

Background It is unclear whether the carotid intima–media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents, such as calcium antagonists, may have a greater effect on this parameter than others, such as diuretics. The present paper reports the principal results of the ultrasound substudy of the randomized, prospective, controlled, Verapamil in Hypertension and Atherosclerosis Study (VHAS). Design and methods In 498 hypertensive patients in eight Italian centres, randomized to either verapamil (240 mg once a day) or chlorthalidone (25 mg once a day), a B-mode ultrasound scan was performed according to a standardized procedure at baseline and after 3, 12, 24, 36 and 48 months of treatment. The maximum intima–media thicknesses of the far walls of common, bifurcation and internal carotid arteries were measured bilaterally, and the following indices calculated: the mean thickness at the six measured sites, the mean thickness at the common and bifurcation sites and the single maximum thickness. The primary endpoint for treatment efficacy was the slope of the change over 4 years (rate of change, mm/year), corrected by using the initial mean over the six sites (baseline + 3 months) as a covariate (mm/year per mm). The patients were also classified into three strata according to their baseline single maximum thickness: those with normal carotid arteries (single maximum (1 mm), those with thickened carotid arteries (single maximum >1 and ≤ 1.5 mm and those with carotid plaques (single maximum >1.5 mm). Results Among the 456 patients with satisfactory baseline ultrasound readings, 33% were classified with normal carotid arteries, 27% with thickened carotid arteries and 40% with plaques. In the intention-to-treat population (377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years), the rate of change in the mean thickness at the six sites measured was rather small (0.015 mm/year), but significantly (P < 0.05) smaller in patients with plaques (0.003 mm/year) than in patients with thickened or with normal carotids (0.023 and 0.025 mm/year, respectively). When related to initial values, the rate of change in the mean thickness at the six sites had a negative slope (−0.059 mm/year per mm, P < 0.01). Although rates of change in the carotid intima–media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone, when changes in the mean thickness of six sites were related to the initial value, the slope of this relationship was significantly different in the two treatment groups (verapamil −0.082 versus chlorthalidone −0.037 mm/year per mm, P < 0.02). The blood pressure-lowering effect of the two randomized treatments was similar. Taking fatal and nonfatal, major and minor cardiovascular events together, there were 19 events in the verapamil group and 35 in the chlorthalidone group, with a significantly (P < 0.01) greater incidence in patients with plaques, and among patients with plaques in those who were randomized to chlorthalidone (P < 0.05). Conclusions In accord with evidence from animal models of atherosclerosis, the calcium antagonist verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions. Changes in the carotid intima–media thickness were small in both groups, and the differences between the changes under the two treatments were consequently small, but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events (better intima–media thickness regression with verapamil paralleled by a lower cardiovascular event rate) suggests that even small effects on carotid plaques may have clinical and prognostic relevance.

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.

Excess Aldosterone Is Associated With Alterations of Myocardial Texture in Primary Aldosteronism

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+, ECG PQ interval duration, plasma renin activity, and aldosterone levels (all P ≤0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7±1.8 versus 45.5±2.0 g/m2.7;P =0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVIs; −12.02±5.84% versus 6.06±3.08%;P =0.012) and posterior wall (−11.13±6.42% versus 8.63±9.62%;P =0.012). A regression analysis showed that CVIs was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for ≈36% of CVIs 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.

Role of echocardiography and carotid ultrasonography in stratifying risk in patients with essential hypertension: the Assessment of Prognostic Risk Observational Survey

Background Echocardiography and carotid ultrasonography, by providing a more accurate assessment of cardiac and vascular damage related to hypertension, may lead to a more precise stratification of the global cardiovascular risk. However, current guidelines do not recommend systematic use of ultrasound examination of heart and large arteries in evaluating the cardiovascular risk in patients with hypertension. Objective To assess the impact of echocardiography and carotid ultrasonography on global risk stratification in hypertensive patients classified as being at low or medium risk according to routine clinical work-up as suggested by current hypertension guidelines. Methods Among 8502 consecutive patients screened at 44 outpatient hypertension hospital clinics in different parts of Italy, 1074 untreated individuals with low-to-medium risk essential hypertension were identified on the basis of the diagnostic routine procedures suggested by 1999 World Health Organization/International Society of Hypertension guidelines: medical history, physical examination and clinic blood pressure measurement; routine blood chemistry and urine analysis; electrocardiogram. The extent of risk for the 1074 individuals was reassessed by adding the results of ultrasound examinations of heart and carotid arteries: left ventricular hypertrophy (defined as left ventricular mass index > 120 g/m2 in men and > 100 g/m2 in women), carotid intima–media thickening (defined as diffuse thickening if ⩾ 0.8 mm), and presence of plaque (defined as focal thickening > 1.3 mm). Results According to routine classification, 18.7% (n = 201) of the 1074 patients were considered at low risk and 81.3% (n = 873) at medium risk. A marked change in risk stratification was obtained when ultrasound markers of target-organ damage were taken into consideration: the proportion of low-risk patients decreased to 11.1%, and that of medium risk patients to 35.7%, whereas more than 50% of the patients previously classified at low-medium risk were found to be at high absolute risk. According to a multivariate analysis, age, grade of hypertension, male sex, and serum cholesterol concentration were the variables with the greatest impact on risk class change. Conclusions Ultrasound assessment of the heart and carotid wall helps to obtain a more valid assessment of global cardiovascular risk in hypertensive patients without evidence of target-organ damage after routine examination.

Target-Organ Damage in Stage I Hypertensive Subjects With White Coat and Sustained Hypertension: Results From the HARVEST Study

Controversy remains on whether white coat hypertension is a benign clinical condition or carries an increased risk of target-organ damage. Nine hundred forty-two stage I hypertensive subjects enrolled in the HARVEST trial underwent 24-hour ambulatory blood pressure monitoring and urine collection for albumin measurement. Reliable echocardiographic data were obtained in 722 subjects. White coat hypertensive subjects were defined on the basis of three different partition values: mean daytime blood pressure <130/90 mm Hg, <135/85 mm Hg, or <140/90 mm Hg. Ninety-five normotensive subjects with similar age and sex distribution were studied as controls. With all threshold levels, left ventricular mass index and wall thicknesses were greater in the sustained hypertensive subjects than in the white coat hypertensive subjects, also when these differences were adjusted for blood pressure readings taken in the office. Relative wall thickness was similar in the two hypertensive groups. All echocardiographic dimensional data were greater in the white coat hypertensive subjects than in the normotensive subjects. Urinary albumin and the prevalence of microalbuminuria were also greater in the sustained hypertensive subjects than in the white coat hypertensive subjects. No significant differences in urinary albumin were found between the white coat hypertensive and the normotensive subjects. These results show that within a population of subjects with stage I hypertension, subjects with white coat hypertension have a smaller degree of hypertensive complications than those with sustained hypertension, irrespective of their blood pressure levels taken in the office. However, in comparison with normotensive subjects, white coat hypertensive subjects seem to be at greater risk. Cardiac involvement seems to precede glomerular damage in the early stage of hypertension.