R Pedrinelli

Microalbuminuria, an integrated marker of cardiovascular risk in essential hypertension

This paper reviews the existing epidemiological and clinical evidence about the relationships of non-diabetic microalbuminuria with cardiovascular risk factors such as elevated blood pressure (BP), systolic particularly, cardiac hypertrophy, adverse metabolic status, smoking habits, elevated angiotensin II levels, endothelial dysfunction, acute and perhaps subclinical inflammation. Because of that unique property of reflecting the influence of so many clinically relevant parameters, microalbuminuria may legitimately be defined as an integrated marker of cardiovascular risk, an unique profile among the several prognostic predictors available to stratify risk in hypertensive patients. Recent cohort studies also showed associations with cardiovascular morbidity and mortality independently from conventional atherogenic factors. This behaviour, whose understanding still needs further elucidation, suggests to measure albuminuria and to screen patients at a higher absolute risk in whom preventive treatment is expected to be more beneficial than in those with a lower absolute risk.

Incremental Value of Ultrasonic Tissue Characterization (Backscatter) in the Evaluation of Left Ventricular Myocardial Structure and Mechanics in Essential Arterial Hypertension

Background—Ultrasonic backscatter parameters were analyzed in hypertensive patients and divided into groups according to both severity of left ventricular hypertrophy (LVH) (group A: no LVH [n=52]; B: mild to moderate LVH [n=55]; and C: severe LVH [n=10]) and left ventricular geometry (normal geometry [n=44]; concentric remodeling [n=8]; concentric hypertrophy [n=25]; and eccentric hypertrophy [n=40]). Methods and Results—We studied 117 male, essential hypertensive patients and 19 normotensive, age-matched (40±5 years), healthy subjects who served as controls. Ambulatory and office blood pressure measurements were taken and 2-dimensional Doppler echocardiography and ultrasonic myocardial integrated backscatter (IBS) were performed. A group from the hypertensive study population (n=16) was observed after a period of pharmacological antihypertensive treatment to determine the behavior of backscatter parameters in relation to eventual regression of left ventricular mass (LVM). The cyclic variation index (CVIs) of the backscatter signal at the septum level was grouped according to each LVM level and was 29.4±9.3 (controls), 15±11 (group A), 9.5±10 (group B), and −1.5±8.6 (group C) (P <0.001). CVI septum values grouped according to left ventricular geometry were 15±11 (normal geometry), 12±7 (concentric remodeling), 7±11 (concentric hypertrophy), and 7.8±11 (eccentric hypertrophy) (P <0.01). Follow-up data demonstrate a significant reduction of LVM after therapy, as well as a significant increase in CVIs toward normal values. Conclusions—Hypertensive patients with higher LVM had the worst prognosis; in fact, those patients had the most significant CVI alterations. Regression of LVM subsequent to chronic pharmacological therapy induces a normalization of ultrasonic backscatter parameters. Ultrasonic tissue characterization (backscatter) analysis could allow early identification of patients at risk of developing complications of hypertensive cardiopathy.

Lack of association between endothelial nitric oxide synthase gene polymorphisms, microalbuminuria and endothelial dysfunction in hypertensive men

Background The Glu298Asp, T786C and 4a/4b genetic polymorphisms within the endothelial nitric oxide synthase (e-NOS) gene may predispose to hypertension, ischaemic heart disease and renal damage, possibly by reducing the generation of nitric oxide (NO), a fundamental substance in renal and cardiovascular biology. That same mechanism may contribute to raise albuminuria, a correlate of endothelial dysfunction and a marker of early kidney damage and poor cardiovascular prognosis in patients with hypertension. To assess that hypothesis, we evaluated the association of albuminuria with eNOS genotypes and their interacting potential with the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism. We also tested their impact on systemic NO availability, as reflected by endothelial-mediated forearm vasodilatation. Methods Albuminuria (three overnight collections), blood pressure, body mass index, renal function, glucose, lipids and prevalence of the metabolic syndrome were measured in 235 genetically unrelated, never-treated, uncomplicated white men with essential hypertension. Endothelial function was assessed in a patient subgroup (n = 94) by measuring plethysmographic forearm blood flow vasodilatation in response to intra-arterial acetylcholine with sodium nitroprusside as a control. Polymerase chain reaction or a 5′ nuclease assay were used to characterize the eNOS and ACE I/D variants. Results Albuminuria or microalbuminuria (albuminuria ≥ 15 μg/min) showed no association with eNOS polymorphisms either per se or after accounting for the co-existing ACE I/D genetic configuration. Forearm responses to acetylcholine did not differ by eNOS polymorphisms. Cardiovascular, renal, metabolic parameters were homogeneously distributed across different genetic backgrounds. Conclusion eNOS polymorphisms apparently play no role in promoting hypertensive renal damage, and do not influence endothelial-mediated vasodilatation in never-treated men with essential hypertension.

Myocardial and forearm blood flow reserve in mild-moderate essential hypertensive patients

Background Structural readaptation of systemic resistance-sized arterioles in response to an elevated blood pressure reduces the forearm vasodilator reserve in patients with essential hypertension. The development of a similar process at the coronary microvascular level has frequently been hypothesized, but little information about coronary remodeling during the uncomplicated stage of hypertension has been obtained, and the relationship with concomitant changes in forearm blood flow reserve is not known. Objective To assess the minimal myocardial resistance and its relationship with the minimal forearm resistance in a group of male patients with mild-to-moderate uncomplicated hypertension and carefully matched controls. Material and methods The minimal myocardial resistance (Rminmyocardial, the mean arterial pressure: hyperemic myocardial flow ratio after administration of 0.84 mg/kg dipyridamole, measured by using positron emission tomography and [13N]-ammonia), minimal forearm vascular resistance (Rminforearm, a hemodynamic index of arteriolar structure derived from the mean blood pressure and maximal postischemic forearm blood flow by venous plethysmography), echocardiographic cardiac mass and wall thickness were measured in 25 male patients with mild-to-moderate uncomplicated essential hypertension, most of whom had previously been treated, and in seven sex- and age-matched normotensive controls. Results Rminmyocardial (and hyperemia: baseline myocardial flow ratios) did not differ significantly between the two groups, whereas Rminforearm was significantly higher in hypertensives. There was no significant intraindividual correlation between the two parameters. The left ventricular mass index was greater in patients and was related positively to Rminforearm but not to Rminmyocardial for the overall sample. In a subgroup analysis, Rminforearm values were 2SD above control values in nine patients and within the normal range in the remaining 16. The myocardial reserve was very similar in the two subgroups. Conclusions The myocardial vasodilator reserve appeared to be preserved in these mild-to-moderate uncomplicated hypertensive patients, whereas the forearm vasodilator capacity was reduced, suggesting that the hypertensive readaptation process was not distributed homogeneously over the two vascular beds.

Microalbuminuria, pulse pressure, left ventricular hypertrophy, and myocardial ultrasonic tissue characterization in essential hypertension

Microalbuminuria (UAE) may be considered a marker of systemic vascular dysfunction, while pulse pressure (PP) is an indicator of the stiffness of vascular conduits. Both these parame ters, together with left ventricular hypertrophy (LVH), are linked to cardiovascular morbidity in hypertensive patients. The aim of this study was the analysis of the possible relationships among UAE, PP, and LVH with ultrasonic myocardial textural parameters, which are altered in hypertensives patients. A group of male (n = 70) essential hypertensive patients (mean age: 58 ±7 yr) was analyzed with a group of age-comparable normotensive healthy subjects as controls (n = 32). Ambulatory blood pressure monitoring (ABPM) was performed with an oscil lometric monitor; UAE was measured by nephelometry. A conventional 2D-Doppler echocar diography (to analyze left ventricular mass: LVM) and a quantitative analysis of the echocar diographic digitized imaging with the use of a calibrated digitization system (to calculate the septum and the posterior wall textural parameters) were performed on all subjects. The myocardial mean gray level was calculated to derive the cyclic variation index (CVI). The CVI was significantly lower in hypertensives both for the septum (-16.3 ±22.8 vs 34.7 ±15.3%; p < 0.001 ) and for the posterior wall (-15.2 ±23.6 vs 38.2 ±15.4%; p < 0.001 ). A signifi cant negative correlation was found between logUAE and the CVI of the septum (r = -0.42; p<0.001), between the PP and the CVI of the septum (r = -0.40; p<0.002) and between the CVI and the LVM (r = -0.38; p<0.001). Multiple regression analysis having as dependent variable the CVI at septum level showed as significantly related independent variables: PP (p<0.01), logUAE (p < 0.001), and LVM (p<0.05) (multiple R: 0.76, squared multiple R: 0.57; p<0.001 ). It was found that LVM, logUAE, and PP are all correlated with textural parameters, and the CVI can be considered a sensitive parameter in the identification of an abnormal myocardial texture in hypertension. A high level of arterial stiffness and the presence of vascular dysfunc tion in essential hypertension could participate in the determination of myocardial alterations and permit the identification of patients with the worst prognosis in terms of morbidity or mortality due to cardiovascular events.

Cyclic variation of the myocardial integrated backscatter signal in hypertensive cardiopathy: a preliminary study.

BackgroundUltrasound tissue characterization studies realized through integrated backscatter analysis with end‐diastolic sampling in hypertensive cardiopathy have demonstrated that abnormalities in the left ventricular myocardial ultrasonic texture are present in extreme forms of left ventricular hypertrophy (LVH). Such abnormalities are not evident in the athletes heart. The aim of the present study was to analyze the ultrasonic backscatter myocardial indexes both as peak end‐diastolic signal intensity and as cardiac‐cyclic variation in two models of LVH: hypertensive cardiopathy and athletes heart. MethodsThree groups of 10 subjects each, all men of mean age (31.6 ± 3.5 years), and of comparable weight and height, were analyzed. Group A comprised 10 cyclists of good professional level, while hypertensive patients were grouped in Group H. Both groups presented a comparable left ventricular mass (LVM). Group C included 10 healthy subjects acting as controls. The men with hypertension were selected on the basis of the results of ambulatory monitoring of the blood pressure according to ISH‐World Health Organization guidelines (International Society of Hypertension). A 2D‐color Doppler echocardiography with a digital echograph Sonos 5500 (Agilent Technologies, Andover, Massachusetts, USA), was carried out on all the subjects in the study for conventional analysis of the LVM and function. The ultrasonic myocardial integrated backscatter signal (IBS) was analyzed with an ‘acoustic densitometry’ module implemented on a AT echograph. The signal was also sampled with a region of interest (ROI) placed at interventricular septum and at posterior left ventricular wall level. The systo‐diastolic variation of the backscatter was also considered, as cyclic variation index (CVI ibs). ResultsAccording to the inclusion criteria, the LVM was comparable in groups A and H, but it was significantly higher than group C (left ventricular mass (body surface) (LVM bs ) = 154.5 ± 18.7 (A), 146.8 ± 25.5 (H), 101.4 ± 12.4 (C), p  < 0.001). The end‐diastolic IBS did not show significant statistical differences among the three groups. The CVI IBS both at septum (30.5 ± 5.3 (A), 13.2 ± 13.1 (H), 27.2 ± 7.3(C), p  < 0.002) and posterior wall level (43.7 ± 9.1 (A), 16.5 ± 12.1 (H), 40.7 ± 9.1(C), p  < 0.001) though, was significantly lower in the hypertensive patients than in both the athletes and the control group, where the results were comparable. ConclusionA significant alteration of the myocardial CVI ibs (both for septum and posterior wall) was found in the hypertensive model. This was probably the expression of an alteration in the intramural myocardial function.

Alpha-adducin and angiotensin-converting enzyme polymorphisms in hypertension: evidence for a joint influence on albuminuria.

Background A single-nucleotide polymorphism (Gly460Trp) within the α-adducin gene (ADD1) may influence several renal phenotypes, including salt sensitivity, susceptibility to renal failure, the renal haemodynamics and confer a worse cardiovascular risks profile. However, its relationship with microalbuminuria, a marker of early renal and cardiovascular damage and an independent predictor of morbid events in hypertension, is unknown. For this reason, we related the ADD1 genetic polymorphism to urine albumin levels and other clinical variables in essential hypertensive men. The angiotensin-converting enzyme (ACE) insertion/deletion (ID) polymorphism was also evaluated because of its interactive potential with the ADD1 genotype. Methods Albuminuria (three overnight collections), echocardiographic left ventricular mass index, blood pressure, body mass index, renal function, glucose and lipids were measured in 238 genetically unrelated, never treated, uncomplicated Caucasian essential hypertensive men. Polymerase chain reaction or a 5′ nuclease assay were used to characterize the ACE ID and ADD1 Gly460Trp variants, respectively. Results Microalbuminuria (albuminuria ≥ 15 μg/min) was more frequent in patients with the ACE DD variant, but only in those with a ADD1 Gly460Gly background. In contrast, urine albumin did not differ by ACE ID genotype in the presence of mutated ADD1 Trp alleles. ADD1 polymorphisms per se were not associated with albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed among different genetic backgrounds. Conclusions ACE DD and ADD1 Gly460Gly polymorphisms may jointly influence albuminuria in hypertensive men, 460Gly homozygosis facilitating or, possibly, the 460Trp allele mitigating the noxious renal impact of the ACE DD genotype. The data highlight further the complex pathophysiological implications of microalbuminuria in hypertension.

Coronary microcirculation into different models of left ventricular hypertrophy—hypertensive and athlete's heart: a contrast echocardiographic study

The study was carried out in two different models of left ventricular hypertrophy: athletes heart and essential arterial hypertension. Three groups of strictly age-matched males were studied: one group of 10 young adult untreated essential hypertensive patients (H), a second group of 10 athletes (A), and a group of 10 healthy individuals as controls (C). A Sonos 5500 echograph with S4 harmonic transducer was used with Levovist (ultrasonic tracer) before and after dipyridamole injection; digitised images of quantitative myocardial contrast echocardiography were collected with Power Harmonic Doppler. Angio images were analysed using dedicated PC software by placing a region-of-interest on the septum. Peak intensity, half-time (HT), the area under the curve of appearance and disappearance of microbubbles at 2/3 of PI, both in absolute and indexed values (/LVMi), were sampled. The per cent increase of PI after dipyridamole was significantly higher in C (+73%, P<0.01) than in H (+31%) and in A (+33%) (P<0.05). The area of appearance was significantly lower in H in comparison with C and A, both at rest and after vasodilatation. The disappearance area after dipyridamole was signifi-cantly higher in C and in A (+124%) than in H (+104%) (P<0.05). Some hypothesis could be made: an impairment in the coronary microcirculatory function in hypertensive patients could be because of an in-crease in the arteriolar resistance. Angiogenesis and several different functional adaptations are the mecha-nisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.

Fibrinogen and mortality in chronic critical limb ischaemia

Objective. Plasma fibrinogen predicts cardiovascular events in patients with stable peripheral arterial occlusive disease, but its predictive value in patients with chronic critical limb ischaemia, a condition associated with a high risk of death, is unknown.

Dissociation between albuminuria and insulinaemia in hypertensive and atherosclerotic men.

To better understand the links between circulating insulin and albuminuria in essential hypertension, the plasma insulin response to a 75 gram glucose load and albuminuria were evaluated in 53 glucose-tolerant essential hypertensives and 12 controls. To allow any direct pressure-independent albuminuric effect of insulin to emerge more clearly, those same parameters were also evaluated in 20 glucose-tolerant normotensive patients with stable atherosclerotic peripheral vascular disease, a condition in which hyperinsulinaemia could be anticipated on the basis of previous reports. In response to glucose ingestion, hyperinsulinaemia was evident in both hypertensive and normotensive atherosclerotic patients, while, on average, urine albumin was elevated only in the former. When plasma insulin, systolic and diastolic blood pressure (BP) (by 24-h ambulatory BP monitoring), plasma glucose, triglycerides and body mass index were entered into a multiple regression analysis, only systolic BP appeared to exert an independent effect on urine albumin. Post-glucose load plasma insulin did not differ between hypertensive patients with (n = 14) and without (n = 39) microalbuminuria (albuminuria >20 μg/min). In further analyses, insulin and systolic BP values were divided in quartiles: albuminuria did not differ across insulin quartiles, while it was significantly higher in the top (n = 21) vs the bottom (n = 21) systolic BP quartile. Thus, hyperinsulinaemia and microalbuminuria were unrelated variables in these hypertensive and atherosclerotic patients. Blood pressure, particularly systolic, emerged as a primary predictor of urinary albumin excretion, although the importance of this parameter needs to be proved prospectively.