Microalbuminuria identifies overall cardiovascular risk in essential hypertension: an artificial neural network-based approach

BACKGROUND : Ultrasound (US) examination of heart and carotid arteries provides an accurate assessment of target organ damage (TOD) and may influence the stratification of the absolute cardiovascular risk profile. Microalbuminuria has recently proved to be a useful cost-effective marker of increased cardiovascular risk but is still too often neglected in clinical practice. OBJECTIVE : To evaluate how well artificial neural networks (ANNs) predict cardiovascular risk stratification by means of routine data and urinary albumin excretion, as compared to prediction by the clinical work-up suggested by the International Society of Hypertension (ISH), with and without ultrasound-determined TOD. METHODS : A group of 346 never previously treated essential hypertensives (212 men, 134 women, mean age 47 +/- 9 years) was studied. Risk was stratified according to the criteria suggested by the 1999 WHO/ISH guidelines; first, by routine procedures alone, and subsequently by reassessment, using data on cardiac and vascular structures obtained by US evaluation. The ANN was trained and tested to predict the overall cardiovascular risk on the basis of routine clinical data and urinary albumin excretion (UAE). The impact of these three approaches on the determination of cardiovascular risk profile was evaluated. RESULTS : According to the first classification, 5.5% (n = 19) of patients were considered at low risk, 47.3% (n = 164) at medium, 26.7% (n = 92) at high and 20.6% (n = 71) at very high risk. A marked change in risk stratification, namely an increase in the prevalence of high- and very-high-risk patients (2.3% low, 29.8% medium, 42.8% high and 25.2% very high risk; chi(2) 15.201, P < 0.0001), was obtained when US examination of TOD was taken into consideration. On the basis of routine clinical data and UAE, the artificial neural network successfully predicted overall cardiovascular risk and allocated patients in different classes as accurately as the US-based evaluation. CONCLUSIONS : The use of US techniques allows a more precise stratification of absolute cardiovascular risk in hypertensive patients as compared to routine clinical data. An ANN can accurately identify the patients' risk status by using low-cost routine data and UAE. These results further emphasize the value of UAE in the stratification of cardiovascular risk.     

Microalbuminuria is an integrated marker of subclinical organ damage in primary hypertension

Increased urine albumin excretion is associated with an unfavourable cardiovascular risk profile and prognosis in primary hypertension, even though its pathogenesis is currently unknown. Microalbuminuria (Mi) has been proposed as an integrated marker to identify patients with subclinical organ damage, but its routine use is still too often neglected in clinical practice. The aim of our study was to evaluate the relationship between urinary albumin excretion and early signs of subclinical target organ damage (TOD), namely left ventricular hypertrophy and carotid atherosclerosis in a large group of non diabetic hypertensive patients. A group of 346 never treated patients with primary hypertension (212 men, 134 women, mean age 47 +/- 9 years) referred to our clinic were included in the study. They underwent the following procedures: (1) family and personal medical history and physical examination; (2) clinical blood pressure measurement; (3) routine blood chemistry and urine analysis including determination of urinary albumin excretion (ACR); (4) electrocardiogram; (5) ultrasound evaluation of left ventricular mass (LVMI) and carotid artery thickness (IMT). The overall prevalence of Mi, left ventricular hypertrophy, and carotid plaque was 13, 51, and 24% respectively. Mi was significantly correlated with LVMI (P < 0.0001), IMT (P < 0.0001) and several metabolic and non-metabolic risk factors (blood pressure, body mass index, serum lipids). Cluster analysis identified three subgroups of patients who differ significantly with regards to TOD and albuminuria (P < or = 0.001 for each of the examined variables). Patients with higher IMT and LVMI values also showed increased ACR levels. Furthermore, patients with microalbuminuria were more likely to have both LVH and IMT values above the median for the study population (OR 21, C.I. 4.6-99.97, P < 0.0001). Mi is an integrated marker of subclinical organ damage in patients with primary hypertension. Evaluation of urinary albumin excretion is a specific, cost-effective way to identify patients at higher risk for whom additional preventive and therapeutic measures are advisable.     

Microalbuminuria in essential hypertension

Microalbuminuria (urinary albumin excretion equal to 30-300 mg/24 h) is a reliable indicator of premature cardiovascular mortality in diabetic patients and in the general population. In insulin-dependent and non-insulin-dependent diabetes mellitus microalbuminuria is a marker of initial diabetic nephropathy and predicts the evolution toward renal insufficiency. In essential hypertension the clinical and prognostic role of microalbuminuria is more controversial. While it is a recognised marker of cardiovascular complications and a reliable predictor of ischaemic heart disease, its prognostic value on the risk of progressive renal alterations is still uncertain because no prospective studies, taking microalbuminuria as a selection criterion and renal insufficiency as an end point, are available. Blood pressure control with antihypertensive drugs is accompanied by a reduction in urinary albumin excretion. The favourable effects of antihypertensive agents on microalbuminuria appear to be proportional to blood pressure reduction, but angiotensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists show an additional beneficial effect on urinary albumin excretion. Whether the reduction of microalbuminuria obtained through pharmacological intervention has favourable prognostic implications remain to be demonstrated. However, screening for microalbuminuria is a relatively easy and inexpensive procedure and reveals a potentially treatable abnormality. Thus, considering that microalbuminuria identifies hypertensive subjects at higher risk than standard, urinary albumin excretion should be routinely measured in hypertensive patients and, in the presence of microalbuminuria, antihypertensive treatment should be intensified in order to obtain an optimal blood pressure control.     

Microalbuminuria: marker of vascular dysfunction,risk factor for cardiovascular disease

Based on the data from large single and multi-center clinical trials, including the Heart Outcomes Prevention Evaluation (HOPE) study, it is clear that the presence of microalbuminuria is a signal from the kidney that cardiovascular risk is increased and that vascular responses are altered. This is exemplified by studies that have demonstrated that the compensatory vasodilation seen following relief from prolonged ischemia or infusion of vasodilators such as nitroglycerin is blunted in people with microalbuminuria. Thus, the presence of between 30 and 299 mg/day of albumin in the urine is associated with abnormal vascular responsiveness, which may be the result of more advanced atherosclerosis and not necessarily related to the presence of hypertension or renal disease. Agents known to reduce the rise in microalbuminuria or actually reduce the level of microalbuminuria, such as ACE inhibitors, angiotensin receptor blockers, HMG-CoA reductase inhibitors, beta blockers, non-dihydropyridine calcium channel blockers and diuretics, have all been shown to reduce cardiovascular mortality and in some cases preserve renal function. This article will present an overview of the data that support the assertion that a reduction in the rise of microalbuminuria is a significant consideration in the selection of agents to treat a given risk factor (cholesterol or blood pressure) to a recommended target goal. Achieving such a goal with agents that also impact microalbuminuria will provide for a more complete cardiovascular risk reduction.     

Microalbuminuria and cardiovascular risk

Microalbuminuria is a marker for generalized vascular dysfunction. Its prevalence in United States and European general population surveys ranges from 6% to 10%. Increased risk for cardiovascular morbidity and mortality begins with albumin excretion rates that are well within normal limits. Although microalbuminuria interacts with the traditional cardiovascular risk factors, it has an independent relationship to renal and cardiovascular outcomes. For example, microalbuminuria doubles the risk for a cardiovascular event in patients with type 2 diabetes mellitus even after adjusting for the usual risk factors. Elevated rates of urinary albumin excretion predict target organ damage, notably renal disease, but are also related to left ventricular dysfunction, stroke, and myocardial infarction. Screening for microalbuminuria, which is recommended by several expert committees and associations, has become a readily accessible procedure. Screening can give clinicians prognostic information concerning cardiovascular risk and assist in guiding therapy. The goal of treatment is to prevent progression of, and even to reverse, microalbuminuria. Abundant evidence demonstrates that antihypertensive therapy is an important key to the control of urinary albumin excretion, and blockade of the renin-angiotensin system (with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) is the treatment of choice. These drugs have successfully halted or delayed the progression to nephropathy and have reversed elevated rates of albumin excretion to normal values, even when blood pressure reduction has been minimal.     

Renal participation in cardiovascular risk in essential hypertension

Renal damage as a consequence of uncontrolled hypertension is well recognized. Antihypertensive therapy has been proved to significantly decrease the vascular damage in the kidneys of hypertensive patients. However, prevalence of mild renal insufficiency remains present in a significant proportion of the hypertensive population. This is accompanied by a marked increase in cardiovascular risk, as a consequence of the clustering of other cardiovascular risk factors and of insufficiently controlled blood pressure. Prevention and protection of renal and cardiovascular damage in these patients will be one of the most relevant healt care tasks in the future.     

Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes

Diabetes is a major risk factor for coronary artery disease and most patients with diabetes die of cardiovascular complications. Reduction of cardiovascular risk is therefore a high priority in the management of patients with diabetes. Microalbuminuria is an important predictor of cardiovascular events and forms one of the components of the insulin resistance/metabolic syndrome, which confers a particularly high risk of cardiovascular death. The currently available glucose-lowering agents vary considerably in their ability to reduce microalbuminuria. The sulfonylureas and metformin appear to have little effect on microalbuminuria expressed as urinary albumin/creatinine ratio, while the thiazolidinediones have unique effects on this risk factor, in parallel with their effects on insulin resistance. In two 1-year European multicenter, randomized, double-blind monotherapy trials (n=2444), pioglitazone produced similar reductions in urinary albumin/creatinine ratio to gliclazide and greater reductions than metformin (P<0.001). Similarly, two further 1-year European multicenter, randomized, double-blind trials assessed the effects of add-on therapy (n=1269) on urinary albumin/creatinine ratio. In the first study, urinary albumin/creatinine ratio was reduced by pioglitazone add-on to sulfonylurea (-15%), but was largely unaffected by metformin add-on to sulfonylurea (2%; P<0.05). In the second, urinary albumin/creatinine ratio was also reduced by pioglitazone add-on to metformin (-10%), but increased by gliclazide add-on to metformin (6%, P<0.05). The results of these studies indicated that compared with metformin or gliclazide, pioglitazone may provide therapeutic benefits, over and above those due to improved glycemic control. These include significant reductions in urinary albumin/creatinine ratio, a known cardiovascular risk marker.     

Microalbuminuria, endothelial dysfunction and cardiovascular risk

Microalbuminuria was originally considered to be an important new risk factor for diabetic nephropathy. More recently, it has been convincingly shown that microalbuminuria is also an independent risk factor for cardiovascular morbidity and mortality in Type 1 and Type 2 diabetic patients. Even in the non-diabetic background population, microalbuminuria is a risk factor for cardiovascular mortality. What is the link between increased loss of albumin in urine and cardiovascular disease and mortality? As microalbuminuria is apparently associated with increased universal vascular sieving of albumin in terms of the transcapillary escape rate of albumin (TER-alb), microalbuminuria may reflect this universal sieving. The pathophysiology of increased TER-alb is unknown, but could be caused by haemodynamics or damage to the functional properties of the vascular wall. A number of studies have provided evidence of endothelial dysfunction in patients with microalbuminuria, which may be the common link accounting for the associations mentioned above. In this context, a number of markers of endothelial cell dysfunction have been found to be increased in patients with microalbuminuria. In addition, a number of functional in vivo tests of endothelial dysfunction have been performed in Type 1 and Type 2 diabetic patients as well as in normal controls. Overall, these studies indicate the existence of a functional vascular dysfunction in Type 1 diabetic patients and normal controls with microalbuminuria, which may be related to dysfunction of endothelial cells.     

Microalbuminuria and oxidative stress in essential hypertension

OBJECTIVE: To assess the relationship between microalbuminuria and oxidative stress in mononuclear peripherals cells in essential hypertension. METHODS: A total of 123 hypertensive patients in absence of antihypertensive treatment were included. A 24-h ambulatory blood pressure (BP) monitoring was performed using a Spacelabs 90207 monitor, and microalbuminuria was measured in 24-h urine collections. Oxidized/reduced glutathione ratio and the content of malondialdehide and damaged base 8-oxo-2'-deoxyguanosine in genomic and mitochondrial DNA were measured in peripheral mononuclear cells. RESULTS: In the 29 (24%) microalbuminuric subjects, the amount of reduced glutathione was significantly lower and the ratio oxidized/reduced glutathione was significantly higher than in the normoalbuminuric subjects. In contrast, the simultaneous measurement of the levels of malondialdehide and 8-oxo-2'-deoxyguanosine from both genomic and mitochondrial DNA oxidation did not achieve statistical significance between the two groups. Subjects with the highest oxidized/reduced glutathione ratio tertile showed the highest urinary albumin excretion (UAE) (P = 0.04 for trend). In a stepwise multiple regression analysis, oxidized/reduced glutathione ratio was the main significant determinant of UAE accounting for the 9% of the variance when 24-h mean BP, age, sex, body mass index, glucose and total cholesterol were included in the model. CONCLUSIONS: Oxidative stress seems to be a determinant of UAE independent of BP levels even in hypertensive subjects.     

Microalbuminuria in type 2 diabetics: an important, overlooked cardiovascular risk factor

The presence of microalbumin in the urine of persons with type 2 diabetes is perhaps the most important early signal heralding the onset of systemic vasculopathy and associated target organ damage to the brain, the heart, and the kidneys. It is easily measured and, unfortunately, frequently overlooked as a screening tool in clinical medicine. If present, it identifies patients at risk for early cardiovascular death and progressive renal disease. Microalbuminuria also identifies patients who need more rigorous cardiovascular risk management, especially more intensive blood pressure control, preferably below 130/80 mm Hg, and strict attention to glycemic control and lipid levels. Therapeutic strategies to facilitate better blood pressure control and reduce microalbuminuria likely will prove to be the most effective way to retard not only the progression of renal disease but also cardiovascular disease. Consequently, the identification and normalization of urine microalbumin excretion should be an important consideration in patients with diabetes.     

Microalbuminuria and early endothelial activation in essential hypertension

We hypothesized that in essential hypertensive patients (EHs), plasma levels of pro-atherogenic adhesion molecules would be increased and related with urine albumin excretion (UAE). Thus, this study was aimed at evaluating biochemical markers of endothelial activation and their relationship with UAE in a group of patients with uncomplicated EH. In basal condition soluble forms of adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, as well as 24-h UAE were assayed. One hundred patients with essential hypertension and no diabetes or ultrasonographic evidence of atherosclerosis were included in the study. Seventy normotensive healthy subjects served as controls. EHs were first studied overall, than were divided into two subgroups: those with UAE > or =20 mcg/min MAUs and those with UAE <20 mcg/min (non-MAUs). ICAM-1 (P<0.001) and VCAM-1 (P<0.0001) plasma concentrations were higher in EHs than in controls. Microalbuminuric EHs had greater levels of adhesion molecules than non-MAUs (ICAM-1 P=0.04; VCAM-1 P=0.02, respectively). In EHs UAE was correlated with ICAM-1 (r=0.29, P=0.003), and VCAM-1 (r=0.30, P=0.002). These associations were confirmed in multiple regression models (P=0.02 for both ICAM-1 and VCAM-1) including, along with adhesion molecules, age, body mass index and blood pressures. Our findings show that in essential hypertension there is a very early activation of endothelial adhesion molecules favouring atherosclerosis.     

Microalbuminuria and transcapillary albumin leakage in essential hypertension.

Microalbuminuria (an increased urinary albumin excretion that is not detectable by the usual dipstick methods for macroproteinuria) predicts cardiovascular events in essential hypertensive patients. A possible reason for this behavior is that albumin leaks through exaggeratedly permeant glomeruli exposed to the damaging impact of subclinical atherogenesis. To evaluate this possibility, the transcapillary escape rate of albumin (TER(alb), the 1-hour decline rate of intravenous (125)I-albumin), a parameter that estimates the integrity of systemic capillary permeability, albuminuria, blood pressure, echocardiographic left ventricular mass, lipids, and body mass index were measured in 73 uncomplicated, glucose-tolerant men with essential hypertension and normal renal function; 53 were normoalbuminuric, and 20 were microalbuminuric. Twenty-one normotensive age-matched male subjects were the controls. TER(alb) was higher in hypertensives, a behavior explained in part by a positive correlation with blood pressure values, although body mass index, lipids, and left ventricular mass showed no association. Transcapillary albumin leakage values did not differ between normoalbuminuric and microalbuminuric patients and were unrelated to albuminuria. Blood pressure, particularly systolic, and cardiac mass were higher in microalbuminuric patients in whom albuminuria correlated with both cardiovascular variables and indicated the influence of the hemodynamic load on urinary albumin levels. Thus, TER(alb), a parameter influenced by the permeability surface area product for macromolecules and the filtration power across the vascular wall, is altered in essential hypertensives. However, this abnormality is dissociated from the amount of albuminuria, which is contrary to the hypothesis that a higher albumin excretion reflects a greater degree of systemic microvascular damage in essential hypertension.     

Pulmonary venous flow and risk of cardiovascular disease in essential hypertension

OBJECTIVE: The prognostic significance of the pulmonary venous flow in essential hypertensive patients was investigated. METHODS AND RESULTS: Doppler transthoracic echocardiograms were analyzed in 705 essential hypertensive subjects with no prior cardiovascular disease. At baseline, most subjects had 'normal diastolic function' or 'mild diastolic dysfunction'. During follow-up (mean, 32 months), 56 participants developed cardiovascular disease. Sex-specific median values were used to separate the higher group from the lower group of the peak velocity ratio of the pulmonary venous systolic to diastolic wave (S/D) (male < 1.51, female < 1.66), and of the transmitral velocity ratio of early diastolic to atrial filling (E/A) (male < 0.84, female < 0.82). Kaplan-Meier curves with log-rank tests showed significantly poorer event-free survival rates in the groups with high S/D (P < 0.01) and low E/A (P < 0.01), respectively. In multivariate Cox regression analysis, the S/D ratio (HR 1.07 for each 0.1 increase, P = 0.03) or E/A ratio (P < 0.01) was an independent predictor of cardiovascular disease events. When divided into four groups based on the respective sex-specific median levels of S/D in the E/A > or = median and E/A < median groups, the group with high S/D and low E/A (S/D; male > or = 1.77, female > or = 1.81) had a significantly poorer event-free survival rate (chi2 = 28.06, P < 0.01), and the adjusted-hazard ratio by multivariate Cox regression analysis was 2.16 (95% CI; 1.40-3.07, P < 0.01). CONCLUSION: Increased S/D or decreased E/A is associated with an increased cardiovascular disease risk, and the combination of high S/D and low E/A may be a powerful predictor of cardiovascular disease in essential hypertension. Pulmonary venous flow evaluation may provide clinically important prognostic information in patients with essential hypertension.     

Microalbuminuria. From diabetes to cardiovascular risk

An increased albuminuria level, known as microalbuminuria is associated with a range of diseases, most frequently with diabetes mellitus and hypertension. Microalbuminuria in type 1 diabetes is an early sign of diabetic nephropathy onset, while it tends to be an indicator of the level of cardiovascular risk in type 2 diabetes and essential hypertension. At present, an increased albumin excretion is considered to be a renal symptom of generalized endothelial dysfunction. A simple investigation, not bothersome to a patient, should be performed early and repeatedly in all patients with diabetes and hypertension, as low microalbuminaemia levels can be managed with appropriate treatment.     

Left ventricular longitudinal systolic dysfunction is an independent marker of cardiovascular risk in patients with hypertension

BackgroundTo explore the prognostic value of left ventricular (LV) longitudinal systolic dysfunction in patients with hypertension.MethodsIn 156 hypertensive subjects, LV longitudinal systolic function was assessed by echocardiographic measurement of M-mode left atrioventricular plane displacement (AVPD) and Tissue Doppler (TD)-derived mitral annulus peak systolic velocity (S(m)). Patients were followed for development of the following cardiovascular events: congestive heart failure requiring hospitalization, new-onset angina, nonfatal myocardial infarction, coronary revascularization procedures, transient ischemic attack, nonfatal stroke, and cardiovascular death.ResultsOver a follow-up of 23.3 +/- 5.4 months, 24 patients had 29 events. Both longitudinal systolic indices were predictive of outcome (hazard ratios: AVPD, 0.24, P < 0.001; S(m), 0.22; P < 0.001). AVPD 相似文献   

Red cell sodium-lithium countertransport and cardiovascular risk factors in essential hypertension

Human red blood cells possess a Na (+)H (+) antiporter in the plasma membrane that can exchange external Na(+) for intracellular H(+) when the intracellular pH falls below 7.0. The antiporter can also exchange Na(+) for Li(+) and that is named Na (+)Li (+) countertransport (SLC). This antiporter activity has been extensively investigated in essential hypertension and diabetes by clinical, epidemiologic, and genetic studies. Elevated values are found in patients with essential hypertension and diabetic nephropathy. In vitro studies in red cells of fasted individuals have demonstrated that physiologic doses of insulin increase the maximal transport rate and the K(m) for Na(+) of both Na (+)Li (+) and Na (+)H (+) exchanges. Ex vivo, SLC also exhibits elevated maximal activity and low affinity for Na(+) in insulin-resistant hypertensives. Patients with elevated antiporter activity manifest metabolic abnormalities (for example, high fasting insulin levels, hyperlipidemia, increased total body exchangeable Na(+), and renal and cardiac hypertrophy) that are part of the syndrome characterized by resistance to insulin-stimulated body glucose disposal. The coexistence of hypertension with insulin resistance and elevated SLC has suggested that a link between the metabolic and ion transport abnormalities may be mediated through chronic elevation of insulin levels. The association between circulating insulin concentrations and prevalence and severity of cardiovascular disease has been documented in many prospective population studies. Insulin modulation of this Na(+) antiporter might be an intermediate risk factor for cardiovascular disease that monitors chronic alterations of Na(+) homeostasis observed in hypertension and diabetes.     

Aortic pulse wave velocity,an independent marker of cardiovascular risk

Aortic pulse wave velocity (PWV), a classical index of aortic stiffness, may be easily measured in humans using non invasive ultrasound methods of high reproducibility. Recent epidemiological studies have shown that, independently of confounding factors as age, blood pressure and cardiac mass, aortic PWV is a predictor of cardiovascular (CV) mortality in populations of hypertensive subjects, whether they have or not end-stage renal disease. Since aortic PWV is dominantly influenced by age, this finding may be of major importance for the evaluation of CV risk in geriatric populations.